Crystalline forms of 1,1,1,3,3,3-hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate as monoacylglycerol lipase inhibitors

Abstract

Described herein are novel 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.

Description

[Technical field]

[0001] The present invention relates to crystalline forms of 1,1,1,3,3,3-hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate, pharmaceutical compositions comprising such crystalline forms, and methods and uses for treating various disorders that would benefit from the inhibition of monoacylglycerol lipase (MAGL). [Background technology]

[0002] MAGL is a member of the serine hydrolase superfamily. MAGL is expressed throughout the brain, including neurons, microglia, astrocytes, and oligodendrocytes. MAGL is the primary enzyme controlling the breakdown of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) (Blankman et al. Chem Biol. 2007; Nomura et al. Science. 2011).

[0003] 2-AG is the most abundant endocannabinoid ligand in the brain, where it functions as a retrograde messenger that reduces excessive neurotransmission via activation of presynaptic CB1 receptors (Katona et al., Nat Med. 2008 Sep;14(9):923-30), modulates immune responses by activation of microglial CB2 receptors (Turcotte et al. Cell Mol Life Sci. 2016 Dec;73(23):4449-4470), and promotes neuroprotection, for example, through its effects on oligodendrocyte production and survival (Front Neurosci. 2018 Oct 26;12:733).

[0004] AA is one of the most abundant fatty acids in the brain and is the major precursor of eicosanoids, such as prostanoids and leukotrienes, which are known inflammatory mediators.

[0005] 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 preventing or treating brain disorders whose pathological characteristics include hyperneurontransmission, 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-Ordonez et al. Biochem Pharmacol. 2018 Nov;157:18-32).

[0006] The development of solid forms is extremely complex because it is impossible to predict from prior experience what different solid forms of a compound will exist, let alone how to prepare them.

[0007] Even after a solid form has been synthesized, the identification and selection of a solid form for further drug development is complex, given that changes in the solid form can affect a variety of unpredictable physical and chemical properties and can provide advantages or disadvantages in areas of drug development such as processing, formulation, stability, bioavailability or storage.

[0008] Against this background, it remains impossible to predict whether a particular compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in therapeutic compositions, or whether the polymorphs will exhibit such desirable properties. Thus, there remains an unmet need to produce solid forms for further drug development that have desirable properties, such as stability. Summary of the Invention

[0009] It is an object of the present invention to provide a solid form of 1,1,1,3,3,3-hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate suitable for pharmaceutical development.

[0010] Thus, in a first aspect of the present invention there is provided 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.

[0011] In another aspect of the present invention, there is provided a solid dosage form comprising 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 and one or more pharma- ceutically acceptable carriers or diluents.

[0012] In a further aspect of the present invention there is provided 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 for use in the treatment of a disease or disorder that benefits from inhibition of activation of MAGL.

[0013] Incorporation by Reference All publications and patent applications mentioned herein are incorporated by reference, to the extent applicable and relevant. [Brief description of the drawings]

[0014] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of Compound (I) Form 1. X-axis: diffraction angle (°2θ); Y-axis: intensity (counts). [Diagram 2] FIG. 1 shows a thermogravimetric analysis (TGA) thermogram of Compound (I) Form 1. X-axis: temperature (° C.); Y-axis: weight (%). [Diagram 3]1 shows the X-ray powder diffraction (XRPD) pattern of Compound (I) Form 3. X-axis: diffraction angle (°2θ); Y-axis: intensity (counts). [Figure 4] FIG. 1 shows a thermogravimetric analysis (TGA) thermogram of Compound (I) Form 3. X-axis: temperature (° C.); Y-axis: weight (%). [Diagram 5] 1 shows a differential scanning calorimetry (DSC) thermogram of Compound (I) Form 1. X-axis: temperature (° C.); Y-axis: normalized heat flow (W / g). [Figure 6] 1 shows a differential scanning calorimetry (DSC) thermogram of Compound (I) Form 3. X-axis: temperature (° C.); Y-axis: normalized heat flow (W / g). [Figure 7] 1 shows a dynamic vapor sorption (DVS) kinetic plot of Compound (I) Form 1. X-axis: time (min); Y-axis (left): mass change (%); Y-axis (right): relative humidity (%). [Figure 8] Figure 1 shows the dynamic vapor sorption (DVS) kinetic plot of Compound (I) Form 3. X-axis: time (min); Y-axis (left): mass change (%); Y-axis (right): relative humidity (%). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Detailed Description of the Invention definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are for purposes of illustration and explanation only, and are not intended to be limiting of the claimed subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0016] As used herein, the term "acceptable" or "pharmaceutical acceptable" with respect to a formulation, composition or ingredient means that it has no lasting deleterious effect on the general health of the subject being treated or that it does not negate the biological activity or properties of the compound, and is relatively non-toxic.

[0017] As used herein, "amelioration" of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to a reduction in severity, delay in onset, slowing in progression, or shortening in duration, whether permanent or temporary, lasting or transient, that can result from or be associated with administration of the compound or composition.

[0018] Terms such as "co-administration," as used herein, are intended to encompass the administration of selected therapeutic agents to a single patient and are intended to include therapeutic regimens in which agents are administered by the same or different routes of administration or at the same time or different times.

[0019] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an administered drug or compound to relieve to some extent one or more symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired modification of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in a disease symptom. An appropriate "effective amount" in any individual case may be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve a desired pharmacological effect or therapeutic improvement. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject, depending on the variability in the metabolism of Compound (I), the age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.

[0020] As used herein, the terms "inhibits," "inhibiting," or "inhibitors" of an enzyme, as used herein, refer to the inhibition of enzyme activity.

[0021] As used herein, the term "subject," as used herein, refers to an animal that is the object of treatment, observation, or experiment. By way of example only, the subject may be a mammal, including, but not limited to, a human. In certain embodiments, the subject is a human.

[0022] The terms "treat", "treating" or "treatment", as used herein, include alleviating, reducing or ameliorating a disease or condition, such as preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by a disease or condition, or halting the symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying metabolic cause of a symptom, inhibiting a disease or condition. The terms "treat", "treating" or "treatment" include, but are not limited to, therapeutic treatment.

[0023] X-ray diffraction data provided herein is presented with an accuracy of ±0.1 degrees 2θ.

[0024] compound The compound designated herein as Compound (I), 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate, has the following structure: [ka] has.

[0025] The present invention relates to crystalline forms of Compound (I) and the use of the compounds for the treatment of various diseases and disorders believed to be related to the modulation of endocannabinoid system signaling activity. The present invention further provides crystalline forms of Compound (I) described herein as "Compound (I) Form 1" and "Compound (I) Form 3". These are free forms of Compound (I). The term "free form" refers to Compound (I) in a non-salt form.

[0026] Without intending to be bound by any particular theory, certain crystalline forms have different physical and chemical properties, such as stability, solubility and dissolution rate suitable for pharmaceutical and therapeutic dosage forms. Furthermore, without wishing to be bound by any particular theory, certain solid forms have different physical and chemical properties (e.g., density, compressibility, hardness, morphology, shear, stickiness, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability and chemical stability) that affect certain processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation and lyophilization), making certain solid forms suitable for manufacturing solid dosage forms. Such properties can be determined using certain analytical chemistry techniques, such as solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis) described herein and known in the art.

[0027] EMBODIMENTS OF THE PRESENT DISCLOSURE In the following, embodiments of the present invention are disclosed, a first embodiment is denoted as E1, a second embodiment is denoted as E2, and so on.

[0028] E1. 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.

[0029] E2. A crystalline form according to embodiment E1, having the following characteristics: a) CuK, which exhibits an XRPD pattern substantially identical to that shown in FIG. α1 X-ray powder diffraction (XRPD) obtained using a 1000 nm NMR spectroscopy (λ = 1.5406 Å); b) CuK, which exhibits characteristic peaks at the following 2θ angles: 10.81°, 16.54°, 16.76°, and 19.21° α1 X-ray powder diffraction (XRPD) patterns obtained using a 1000 nm NMR spectroscopy (λ = 1.5406 Å); c) Thermogravimetric analysis (TGA) substantially similar to the thermogravimetric analysis described in FIG. 2; d) combinations thereof; The crystalline form is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate Form 1, having at least one of:

[0030] E3. A crystalline form according to embodiment E2, exhibiting peaks at the following 2θ angles: 10.81°, 16.54°, 16.76°, and 19.21°. α1 A crystalline form which is 1,1,1,3,3,3-hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate Form 1, having a crystalline form characterized by XRPD obtained using line (λ=1.5406 Å).

[0031] E4. A crystalline form according to embodiment E1, having the following characteristics: a) CuK, which exhibits an XRPD pattern substantially identical to that shown in FIG. α1 X-ray powder diffraction (XRPD) obtained using a 1000 nm NMR spectroscopy (λ = 1.5406 Å); b) CuK, which exhibits characteristic peaks at the following 2θ angles: 6.61°, 9.16°, 13.09°, and 14.32°. α1 X-ray powder diffraction (XRPD) patterns obtained using a 1000 nm NMR spectroscopy (λ = 1.5406 Å); c) Thermogravimetric analysis (TGA) substantially similar to the thermogravimetric analysis depicted in FIG. 4; d) combinations thereof; The crystalline form is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate Form 3, having at least one of:

[0032] E5. A crystalline form according to embodiment E4, exhibiting peaks at the following 2θ angles: 6.61°, 9.16°, 13.09°, and 14.32°. α1A crystalline form which is 1,1,1,3,3,3-hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate Form 3, having a crystalline form characterized by XRPD obtained using line (λ=1.5406 Å).

[0033] E6. A solid dosage form comprising the crystalline form of any one of embodiments E1-E5 and one or more pharma- ceutically acceptable carriers or diluents.

[0034] E7. A solid dosage form according to embodiment E6 selected from capsules, tablets, dragees, pills, lozenges, powders and granules.

[0035] E8. The solid dosage form according to embodiment E7, which is a tablet.

[0036] E9. The solid dosage form according to embodiment E7, which is a capsule.

[0037] E10. A dosage form according to any one of embodiments E7-E9, comprising 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 according to embodiments E1-E5 in an amount of about 0.1 to 500 mg.

[0038] E11. The dosage form according to embodiment E10, comprising 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 in an amount of about 0.1 to 200 mg.

[0039] E12. The dosage form according to embodiment E10, comprising 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 in an amount of about 2 to 200 mg.

[0040] E13. The dosage form according to embodiment E10, comprising 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 in an amount of about 2 to 100 mg.

[0041] E14. The dosage form according to embodiment E10, comprising 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 in an amount of about 2 to 50 mg.

[0042] E15. The dosage form according to embodiment E10, comprising 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 in an amount of about 5 to 50 mg.

[0043] E16. The dosage form according to embodiment E10, comprising 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 in an amount of about 10 to 50 mg.

[0044] E17. The dosage form according to embodiment E10, comprising 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 in an amount of about 10 to 100 mg.

[0045] E18. The dosage form according to embodiment E10, comprising 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 in an amount of about 1 to 50 mg.

[0046] E19. The dosage form according to embodiment E10, comprising 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 in an amount of about 1 to 40 mg.

[0047] E20. The dosage form according to embodiment E10, comprising 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 in an amount of about 1 to 20 mg.

[0048] E21. The dosage form according to embodiment E10, comprising 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 in an amount of about 1 to 10 mg.

[0049] E22. The dosage form according to embodiment E10, comprising 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 in an amount of about 10 to 20 mg.

[0050] E23. The dosage form according to any one of embodiments E6-E22, wherein the crystalline form is selected from 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate Form 1 or 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate Form 3.

[0051] E24. The dosage form according to any one of embodiments E6-E22, wherein the crystalline form is 1,1,1,3,3,3-hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate Form 1.

[0052] E25. A tablet comprising about 0.1 to 200 mg of a crystalline form according to any one of embodiments E1 to E5, and one or more pharma- ceutically acceptable carriers or diluents.

[0053] E26. A tablet according to embodiment E25, comprising about 2 to 100 mg of 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 according to any one of embodiments E1 to E5.

[0054] E27. A tablet according to embodiment E25, comprising about 10 to 100 mg of 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 according to any one of embodiments E1 to E5.

[0055] E28. A tablet according to embodiment E25, comprising about 1 to 20 mg of 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 according to any one of embodiments E1 to E5.

[0056] E29. A tablet according to embodiment E25, comprising about 1 to 40 mg of 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 according to any one of embodiments E1 to E5.

[0057] E30. A tablet according to embodiment E25, comprising about 5 to 30 mg 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 of any one of embodiments E1 to E5.

[0058] E31. A tablet according to embodiment E25, comprising about 10 to 20 mg 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 of any one of embodiments E1 to E5.

[0059] E32. 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, childbirth, 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 disorders, peripheral nerves 4. 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 according to any one of embodiments E1 to E5, or a dosage form according to any one of embodiments E6 to E31, for use in the treatment of a disease or disorder selected from: chronic kidney disease, migraine, visceral hypersensitivity, osteoarthritis, pancreatitis, pharyngitis, post-mastectomy pain syndrome, trigeminal neuralgia, postoperative pain, post traumatic stress disorder, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, spasticity, spasticity in patients with multiple sclerosis, sunburn, systemic lupus erythematosus, toothache, epilepsy, treatment resistant focal epilepsy, vasoocclusive painful crises in sickle cell disease and visceral pain.

[0060] E33. 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, as used according to embodiment E32, wherein the disease or disorder is spasticity.

[0061] E34. 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, as used according to embodiment E32, wherein the disease or disorder is multiple sclerosis.

[0062] E35. 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, as used according to embodiment E32, wherein the disease or disorder is spasticity in patients with multiple sclerosis.

[0063] E36. 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, as used according to embodiment E32, wherein the disease or disorder is epilepsy.

[0064] E37. 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, as used according to embodiment E32, wherein the disease or disorder is treatment-resistant focal epilepsy.

[0065] E38. 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, childbirth, 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 disorders, peripheral neuropathy, migraine, visceral hypersensitivity, osteoarthritis, pancreatitis, pharyngitis, post-mastectomy pain syndrome, trigeminal neuralgia, postoperative pain, post-traumatic stress disorder, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin A method of treating a disease or disorder selected from skin diseases, sunburn, systemic lupus erythematosus, toothache, epilepsy, treatment-resistant focal epilepsy, vaso-occlusive pain crisis in sickle cell disease and visceral pain comprising administering to a patient in need thereof a therapeutically effective amount of 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 according to any of embodiments E1-E5, or a dosage form according to any one of embodiments E6-E31.

[0066] E39. 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, childbirth, 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 disorders, peripheral neuropathy, migraine, visceral hypersensitivity, osteoarthritis, pancreatitis, pharyngitis, post-mastectomy pain syndrome, trigeminal neuralgia, postoperative pain, post-traumatic stress disorder, renal ischemia, joint pain Use of 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 according to any of embodiments E1 to E5, or a dosage form according to any one of embodiments E6 to E31, in the manufacture of a medicament for treating a disease or disorder selected from horses, skeletal muscle contusion, skin disorders, sunburn, systemic lupus erythematosus, toothache, epilepsy, treatment-resistant focal epilepsy, vaso-occlusive pain crisis in sickle cell disease and visceral pain.

[0067] E40. 1,1,1,3,3,3-Hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate, or a pharma- ceutically acceptable salt thereof, for use in the treatment of treatment-resistant focal epilepsy.

[0068] E41. 1,1,1,3,3,3-Hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate, or a pharma- ceutically acceptable salt thereof, for use in the treatment of post-traumatic stress disorder.

[0069] E42. 1,1,1,3,3,3-Hexafluoropropan-2-yl (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate, or a pharma- ceutically acceptable salt thereof, for use in the treatment of spasticity.

[0070] Pharmaceutical Compositions The crystalline form of Compound (I) may be present in the composition as the sole active ingredient or in combination with other active ingredients. In addition, one or more pharma- ceutically acceptable carriers or diluents may be present in the composition.

[0071] The pharmaceutical compositions may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes, with the oral route being preferred. It will be understood that the preferred route will depend on the general condition and age of the subject being treated, the nature of the condition being treated, and the active ingredient selected.

[0072] The pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules.If appropriate, they can be prepared with coatings.Oral dosage forms, especially tablets, are often preferred by patients and physicians due to their ease of administration and resulting good compliance.

[0073] Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups, and elixirs.

[0074] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted with sterile injectable solutions or dispersions prior to use.

[0075] Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, and the like.

[0076] Conveniently, the crystalline form of Compound (I) is administered in a unit dosage form containing the compound in an amount of about 0.1-500 mg, such as 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg 100 mg, 150 mg, 200 mg or 250 mg. In another embodiment, the unit dosage form contains the compound in an amount of about 2-100 mg, such as 5-100 mg, 10-100 mg, 15-100 mg, 20-100 mg, 25-100 mg, 30-100 mg, 35-100 mg, 40-100 mg, 45-100 mg or 50-100 mg. In further embodiments, the unit dosage form contains the compound in an amount of about 2-50 mg, such as 5-50 mg, 10-50 mg, 15-50 mg, 20-50 mg, 25-50 mg, 30-50 mg, 35-50 mg, 40-50 mg, or 45-50 mg.

[0077] For parenteral administration, sterile aqueous solutions, aqueous propylene glycol solutions, aqueous vitamin E solutions or solutions of the crystalline forms of Compound (I) in sesame or peanut oil may be used. Such aqueous solutions should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All sterile aqueous media employed are readily available by standard techniques known to those skilled in the art.

[0078] Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. Lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phosphorescent lipids, fatty acids, fatty acid amines, polyoxyethylene, and water. The pharmaceutical composition formed by combining the crystalline form of Compound (I) with a pharma-ceutically acceptable carrier is then easily administered in various dosage forms suitable for the disclosed administration route.

[0079] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, which may include a suitable excipient. Further, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.

[0080] If a solid carrier is used for oral administration, the preparation may be in the form of a tablet, capsule, or pellet, or in the form of a troche or lozenge. The amount of solid carrier varies but will usually be from about 25 mg to about 1 g.

[0081] If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

[0082] Tablets may be prepared by mixing the active ingredient with conventional adjuvants and / or diluents, followed by compressing the mixture in a conventional tablet machine. Examples of adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, etc. Any other auxiliary or additives normally used for such purposes as colorants, flavors, preservatives, etc. may also be used, provided that they are compatible with the active ingredients.

[0083] In one embodiment, crystalline 1,1,1,3,3,3-hexafluoropropan-2-yl (S)-1-(14yridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate is provided in an oral solution comprising a buffer, benzoic acid, hydroxypropyl betadex, acesulfame potassium, denatonium benzoate, and water.

[0084] Conditions for treatment Also disclosed herein are methods for treating a disease or disorder that may benefit from inhibition of MAGL. The disclosed methods include administering a crystalline form of Compound (I) in a pharma- ceutical effective amount.

[0085] Atopic dermatitis Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin disease associated with a malfunction of the body's immune system. AD ​​affects up to 20% of children, but can extend into adulthood, affecting up to 3% of adults. In AD, the skin becomes very itchy. Excessive scratching results in redness, swelling, cracking, "wet" clear fluid, and crusting of the skin. A functional endocannabinoid signaling system is present in the skin and mediates multiple aspects of skin biology. Independent studies have shown that CB1 and CB2 receptors are upregulated in atopic dermatitis, and that the endocannabinoid system exerts a protective effect in models of skin allergy. Additionally, it has been demonstrated that MAGL inhibitors can reduce MAGL activity and increase levels of 2-AG in rodent skin.

[0086] In some embodiments, the MAGL inhibitors described herein have efficacy in treating atopic dermatitis. In some embodiments, disclosed herein is a method of treating atopic dermatitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3. In some embodiments, disclosed herein is a method of treating atopic dermatitis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3.

[0087] fibromyalgia Fibromyalgia (FM) is a common, chronic, idiopathic condition characterized by widespread pain in the body and tactile allodynia. Several independent studies of exocannabinoids in FM have demonstrated activity. For example, pain measures (e.g., NRS-11, Pain VAS) and the Fibromyalgia Questionnaire (FIQ), which measures limitations in several activities of daily living affected by FM, have demonstrated activity of the drug in FM clinical trials. In an 8-week, 40-patient study, exocannabinoids improved pain as measured by a 10 cm VAS, FIQ domains of anxiety, and FIQ total scores compared to placebo.

[0088] In some embodiments, the MAGL inhibitors described herein have efficacy in treating FM. In some embodiments, disclosed herein is a method of treating fibromyalgia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3.

[0089] Epilepsy and seizure treatment A study by Sugaya et al., Cell Rep. 2016 suggests that 2-AG is important in suppressing seizures. Thus, in another embodiment, disclosed herein is a crystalline form of Compound (I) for use in treating epilepsy / seizure disorders. In a further embodiment, disclosed herein is a crystalline form of Compound (I) for use in treatment-resistant focal epilepsy.

[0090] Furthermore, it is suggested by Yeh et al., Perspectives on the Role of Endocannabinoids in Autism Spectrum Disorders, OBM Neurobiol. 2017 that targeting endocannabinoid signaling is a promising future method for treating symptoms within autism spectrum disorders.

[0091] In further embodiments, disclosed herein are crystalline forms of Compound (I) for use in the treatment of acute recurrent seizures, temporal lobe epilepsy, Dravet syndrome, Lennox-Gastaut syndrome, or Angelman syndrome.

[0092] Migraine Migraine is a common recurrent disorder of headache and facial pain. Migraine attacks can be acutely treated with NSAIDs, acetaminophen, various triptans (e.g., sumatriptan), and antiemetics, but some migraine patients have pain that is unresponsive to existing treatment options. Third-party data suggests that the endocannabinoid pathway may be relevant in migraine. In patients with chronic migraine and headaches suspected to be overusing analgesics, CSF samples showed higher levels of the endocannabinoid palmitoylethanolamide and lower levels of anandamide compared to healthy controls. Furthermore, patients with a primary diagnosis of migraine showed a decrease in migraine frequency after initiating cannabis therapy.

[0093] In some embodiments, the MAGL inhibitors described herein have efficacy in treating migraine. In some embodiments, disclosed herein is a method of treating migraine in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3.

[0094] Acute pain, inflammatory pain, cancer pain, and pain caused by peripheral neuropathy MAGL inhibitors have shown efficacy in several rodent models of acute pain, inflammatory pain, cancer pain, and pain caused by chemotherapy-induced peripheral neuropathy.

[0095] In some embodiments, the MAGL inhibitors described herein have efficacy in treating acute pain, inflammatory pain, cancer pain, and pain caused by chemotherapy-induced peripheral neuropathy. In some embodiments, disclosed herein is a method of treating acute pain, inflammatory pain, cancer pain, and pain caused by peripheral neuropathy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3.

[0096] Functional dyspepsia Functional dyspepsia (FD) is one of the most common gastrointestinal disorders encountered in clinical practice. Several pathophysiological mechanisms have been proposed to underlie the development of symptoms in FD, including visceral hypersensitivity due to central or peripheral sensitization, low-grade inflammatory states, altered gastrointestinal hormone secretion, genetic predisposition, and abnormal gastric emptying or stasis. Third-party data support the hypothesis that the function of the endocannabinoid system is altered in FD patients.

[0097] In some embodiments, the MAGL inhibitors described herein have efficacy in treating functional dyspepsia. Disclosed herein, in some embodiments, is a method of treating functional dyspepsia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3.

[0098] Skeletal muscle contusion Skeletal muscle contusion represents a direct blunt compressive force to a muscle. Contusions are one of the most common sports-related injuries. Contusions range in severity from simple skin contusions to muscle contusions, and from bone contusions to visceral contusions. Independent data demonstrated anti-inflammatory effects from MAGL inhibition in a rat skeletal muscle contusion model.

[0099] In some embodiments, the MAGL inhibitors described herein have efficacy in treating a skeletal muscle contusion. Disclosed herein, in some embodiments, is a method of treating a skeletal muscle contusion in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3.

[0100] Symptomatic treatment of multiple sclerosis Nearly all MS patients of all subtypes have one or more symptoms of spasticity, pain, sleep disturbance, bladder dysfunction, and fatigue. Disease-modifying therapies do not improve symptoms. More than 80% of MS patients are affected by spasticity; 34% have moderate, severe, or total spasticity. Severe spasticity is associated with costs and nursing levels, and is independently associated with quality of life in MS. Two recent reviews support the use of exocannabinoids to treat spasticity and pain in MS (Whiting et al., JAMA. 2015); Hill et al., JAMA. 2015).

[0101] Exocannabinoid preparations are approved treatments for spasticity associated with MS. Sativex, an oromucosal spray mixture of the CB1 agonist THC and another cannabis plant-derived alcohol, has been shown to reduce self-reported spasticity-related symptoms. In a pivotal trial of Sativex using a randomized treatment withdrawal design, continuation of Sativex improved seizure frequency, sleep disturbance due to spasticity, subject global impression of change, carer global impression of change, and physician global impression of change. Other clinical trials have shown activity of various exocannabinoids in spasticity due to MS (Zajicek et al., Lancet. 2003; Collin et al., Eur J Neurol. 2007; Collin et al., Neurol Res. 2010). These parallel group studies illustrate the clinical trial design and endpoints that can be used to show the benefit of MAGL on spasticity in MS.

[0102] In one embodiment, disclosed herein is a crystalline form of Compound (I) for use in the treatment of multiple sclerosis.

[0103] Disclosed herein, in one embodiment, is a crystalline form of Compound (I) for use in one or more treatments in multiple sclerosis selected from fatigue, spasticity, depression, behavioral disorders, irritability-agitation, and pain.

[0104] In a further embodiment, disclosed herein is a crystalline form of Compound (I) for use in the treatment of spasticity.

[0105] MAGL is also believed to be beneficial in the treatment of indications related to autoimmune encephalomyelitis. Thus, in further embodiments, crystalline forms of Compound (I) are disclosed herein for use in the treatment of Rasmussen's encephalitis, systemic lupus erythematosus, Behcet's disease, Hashimoto's encephalopathy, and Sydenham's chorea.

[0106] Combination therapy Combination therapy is also contemplated herein, for example, co-administration of a crystalline form of Compound (I) with an additional active agent as part of a particular treatment regimen intended to provide beneficial effects from the interaction of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic interactions resulting from the combination of therapeutic agents. The administration of these therapeutic agents in combination typically occurs over a defined period of time (usually weeks, months, or years, depending on the combination selected). Combination therapy is intended to encompass administration of multiple therapeutic agents sequentially, i.e., administration of each therapeutic agent at different times, as well as administration of the therapeutic agent or at least two of the therapeutic agents substantially simultaneously.

[0107] Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single formulation or composition having a fixed ratio of each therapeutic agent (e.g., a tablet or capsule), or by administering multiple single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination can be administered by intravenous injection and the other therapeutic agent of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection.

[0108] Combination therapy also includes administering the above-mentioned therapeutic agent in further combination with other bioactive ingredients and non-drug therapy.When combination therapy further includes non-drug therapy, the non-drug therapy is administered at any appropriate time, as long as the beneficial effect of the interaction of the combination of the therapeutic agent and the non-drug therapy is achieved.For example, in appropriate cases, the beneficial effect is still achieved even if the radiation therapy is separated in time from the administration of the therapeutic agent, perhaps by days or weeks.

[0109] The components of the combination are administered to a patient simultaneously or sequentially. It will be understood that the components may be present in the same pharma- ceutically acceptable carrier and thus be administered simultaneously. Alternatively, the active ingredients may be present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered simultaneously or sequentially.

[0110] For example, for the contemplated treatment of pain, the crystalline form of Compound (I) is co-administered with another therapeutic agent for pain, such as an opioid, a cannabinoid receptor (CB1 or CB2) modulator, a COX-2 inhibitor, acetaminophen, and / or a nonsteroidal anti-inflammatory agent. For example, additional therapeutic agents co-administered for the treatment of pain include morphine, pregabalin, gabapentin, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol, and levorphanol.

[0111] Other contemplated therapeutic agents for co-administration include aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, celecoxib, parecoxib, rimonabant, and / or etoricoxib.

[0112] Experimental Section List of abbreviations As used above, and throughout the present specification, the following abbreviations, unless otherwise specified, shall be understood to have the following meanings: t-Bu: t-Butyl DCM: dichloromethane (CH2Cl2) DMF: Dimethylformamide DMSO: Dimethyl sulfoxide equiv: equivalent amount EtOH: Ethanol EtOAc: ethyl acetate HPLC: High-performance liquid chromatography i-PrOAc: isopropyl acetate MS: Mass spectrometry NMR: nuclear magnetic resonance MeCN: Acetonitrile 2-MeTHF: 2-methyltetrahydrofuran MIBK: Methyl isobutyl ketone MTBE: Methyl t-butyl ether TFA: Trifluoroacetic acid TGA: Thermogravimetric analysis RT: room temperature XRPD: X-ray powder diffraction DSC: Differential scanning calorimetry DVS: Dynamic Vapor Sorption LC-MS: Liquid chromatography-mass spectrometry

[0113] chemical synthesis Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and not optimized.

[0114] Analysis method LC-MS method The LC-MS analytical system was equipped with a Shimadzu LCMS-2020, a PDA detector (operating at 254 nm), an ELSD detector, and an ESI source operated in positive ion mode. LC conditions:

[0115] Method C: The column is an Express C18 50 x 3.0 mm, operated at 40 °C with a binary gradient of 1.5 mL / min consisting of water + 0.05% TFA (A) and I + 0.05% TFA (B). R ) is expressed in minutes, based on the UV trace at 254 nm. gradient: 0.01 min B20% 3.50 minutes B50% 4.30 minutes B95% 4.00 minutes B95% 5.10 minutes B5%

[0116] Method O: The column is a HALO C18 30×3.0 mm, 2 μm, operated at 40° C. with a binary gradient of 1.5 mL / min consisting of water + 0.05% TFA (A) ailaCN + 0.05% TFA (B). R ) is expressed in minutes based on the UV trace at 200 nm. gradient: 2.20 minutes B100% 2.70 minutes B100% 2.72 minutes B5% Total: 3.0 minutes execution time

[0117] 1 H NMR method 1 H NMR spectra were recorded on a Bruker Avance HD at 300 or 400 MHz. Chemical shift values ​​are expressed in ppm relative to tetramethylsilane. The following abbreviations or combinations thereof are used for the multiplicity of NMR signals: br = broad, d = doublet, dd = doublet of doublets, dt = doublet of triplets, hept = sevent, m = multiplet, q = quartet, quint = quintet, s = singlet, t = triplet, td = triplet of doublets. EXAMPLES

[0118] Example 1: Synthesis of Compound (I) Form 1 Step 1: Synthesis of 1-benzyl 6-(t-butyl) 6-azaspiro[2.5]octane-1,6-dicarboxylate [ka] Into a flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 6-(t-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (240 g) in acetone (5 L). Benzyl bromide (170.6 g) and K2CO3 (259.8 g) were added. The resulting solution was refluxed for 2-3 hours. The reaction was then cooled to room temperature and filtered. The filter cake was washed with ethyl acetate. The combined filtrate was concentrated under vacuum to give 297 g of crude 1-benzyl 6-(t-butyl) 6-azaspiro[2.5]octane-1,6-dicarboxylate.

[0119] Step 2: Synthesis of benzyl 6-azaspiro[2.5]octane-1-carboxylate hydrochloride [ka] Into a flask purged and maintained with an inert atmosphere of nitrogen was added a solution of crude 1-benzyl 6-(t-butyl) 6-azaspiro[2.5]octane-1,6-dicarboxylate (297 g) in DCM (1.5 L). HCl (g) in 1,4-dioxane (4 M, 1.5 L) was added dropwise. The resulting solution was stirred at room temperature for 1 h and concentrated under vacuum. The crude product was slurried with Et2O (10 V) to provide 198.3 g of benzyl 6-azaspiro[2.5]octane-1-carboxylate.

[0120] Step 3: Synthesis of 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate [ka] In a flask purged and maintained with an inert atmosphere of nitrogen, a solution of 1,1,1,3,3,3-hexafluoropropan-2-ol (393 g) in DCM (2 L) was added. The mixture was cooled to 0° C. and triphosgene (106.9 g) was added in a batch. DIPEA (550 g) was then added dropwise at 0-10° C. The mixture was stirred at this temperature for 1.5 h. A solution of benzyl 6-azaspiro[2.5]octane-1-carboxylate hydrochloride (198 g) in DCM (2 L) was then added dropwise at 0° C. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched by pouring into water (6 L) and then extracted with DCM (2×2 L). The combined organic layers were washed with brine (1×3 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was chromatographed on a silica gel column with EtOAc / petroleum ether (1 / 30) to give 265 g of 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate.

[0121] Step 4: Isolation of (S)-1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate (Intermediate 2A and (R)-1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate (Intermediate 3A) [ka] The racemic mixture of 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate (265 g) prepared in step 3 was separated by preparative SFC-HPLC (column: CHIRAL PAK IG-3 3.0×50 mm, 3 μm; mobile phase: Phase A: CO2, Phase B: MeOH (0.1% DEA); flow rate: 2 mL / min; gradient: 2% B; 220 nm) to give intermediates 2A and 2B. The absolute configuration was confirmed by vibrational circular dichroism spectroscopy (Appl. Spectrosc. 65(7), 699(2011); PCT / EP2021 / 081522) studies. Spectra were obtained using ChiralR with a DualPEM VCD-spectrometer and compared with calculated values ​​(Density Functional Theory (DFT) calculations using CPCM (chloroform) = B3LYP / 6311Gdp methodology and basis set).

[0122] Intermediate 2A; (S)-1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate 110 g. 1 H NMR(300MHz,chloroform-d)δ 7.46-7.28(m,5H),5.75(p,J=6.3Hz,1H),5.13(s,2H),3.57(m,3H),3.28(m,1H),1. 86-1.61(m,3H),1.56-1.36(m,2H),1.27-1.19(m,1H),0.99(dd,J=8.2,4.7Hz,1H).t R =1.572 min.LCMS(Method O)(ESI,m / z):440[M+H] + and

[0123] Intermediate 3A; 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropl2-yl) (R)-6-azaspiro[2.5]octane-1,6-dicarboxylate 100 g. 1H NMR(300MHz,chloroform-d)δ 7.36(d,J=2.6Hz,5H),5.75(p,J=6.3Hz,1H),5.13(d,J=1.4Hz,2H),3.71-3.40(m,3H),3.39-3.13(m,1H), 1.71(ddd,J=29.4,9.4,5.2Hz,3H),1.57-1.36(m,2H),1.23(d,J=5.2Hz,1H),0.99(dd,J=8.1,4.7Hz,1H).t R =1.572 min.LCMS(Method O)(ESI,m / z):440[M+H] + .

[0124] Step 5: Synthesis of (S)-6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 2B) [ka] A solution of 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl)(S)-6-azaspiro[2.5]octane-1,6-dicarboxylate (110 g) in THF (2 L) was added to the flask. Wet Pd / C (22 g, 10 wt%, HO 50%) was added to the mixture. The resulting mixture was purged and replaced with hydrogen three times, then stirred under H at room temperature for 3 h. The mixture was filtered and the filter cake was washed with THF (2×500 mL). The combined filtrate was concentrated under vacuum and the crude product was coevaporated with toluene (2×1 L) to give 90 g of crude (S)-6-(((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (Intermediate 2B). 0.2 g of the crude product was purified by silica column chromatography to give pure characterization data. 1H NMR(300MHz,クロロホルム-d)δ 5.78(h,J=6.3Hz,1H),3.79-3.40(m,4H),1.85(q,J=6.1Hz,2H),1.65(dd,J=8.0,5.4Hz,1 H),1.54(dq,J=10.9,5.8,5.0Hz,2H),1.28(t,J=5.1Hz,1H),1.09(dd,J=8.1,4.8Hz,1H).t R =1.441 min. LCMS (method O) (ESI, m / z): 350 [M+H] + .

[0125] Project 6: Synthesis of Compound (I) Form 1

change

[0126] Example 2: Preparation of Compound (I) Form 3 [ka] Compound (I) Form 1 (500 mg) was slurried in a 1:1 mixture of MeCN / water in a vial for 24 hours at room temperature. A small sample of the wet precipitate was analyzed by XRPD and the diffractogram is shown in FIG.

[0127] Example 3: XRPD measurements CuK on a PANalytical X'Pert PRO X-ray Diffractometer α1 X-ray powder diffractograms were measured using a 400 nm X-ray diffraction (λ=1.5406 Å) line. Samples were measured in reflection mode over the 2θ range 3-40° using a PIXcel detector. X-ray diffraction data provided herein are accurate to ±0.1° 2θ.

[0128] [Table 1]

[0129] XRPD analysis of the obtained compounds XRPD analysis of Compound (I) Form 1 (Figure 1) showed that the form was crystalline.

[0130] XRPD analysis of Compound (I) Form 3 (Figure 3) showed that the form was crystalline.

[0131] Example 4: Thermogravimetric Analysis (TGA) TGA was performed using a TA-instruments Discovery TGA, with 1-15 mg samples heated at 10° C. / min in an open pan under nitrogen flow.

[0132] TGA analysis of Compound (I) Form 1 (FIG. 2) showed that the form was non-solvated / non-hydrated.

[0133] TGA analysis of Compound (I) Form 3 (FIG. 4) showed that the form was non-solvated / non-hydrated.

[0134] Example 5: Differential Scanning Calorimetry (DSC) DSC was measured using a TA-Instruments Discovery-DSC calibrated at 5° C. / min to take the melting point as the onset value. Approximately 2 mg of sample is heated at 5° C. / min under nitrogen flow in a closed pan with a pinhole in the lid.

[0135] The curve in Figure 5 shows an exotherm between the two endotherms. XRPD of a sample of Compound (I) Form 1 after heating to 150°C showed Compound (I) Form 3. Thus, heating Compound (I) Form 1 resulted in the formation of Compound (I) Form 3. This formation of Compound (I) Form 3 at elevated temperatures, combined with the transformation of Compound (I) Form 1 to Compound (I) Form 3 when slurried, indicates that Compound (I) Form 3 is more thermodynamically stable than Compound (I) Form 1.

[0136] Example 6: Procedure used for Dynamic Vapor Sorption (DVS) measurements DVS was measured using a Surface Measurements Science Adventure instrument (for measurements in Configuration 1) or a DVS advantage 01 instrument (for measurements in Configuration 3). Relative humidity was ramped from 0% RH to 95% RH in 10% RH increments (5% increments between 90% and 95% RH). Starting at 30% RH, two cycles were performed using 1-10 mg.

[0137] DVS analysis of Compound (I) Form 1 showed that this form is non-hygroscopic with a water absorption of 0.2 wt% up to 90% RH. DVS analysis of Compound (I) Form 3 showed that this form is non-hygroscopic with a water absorption of about 0.1 wt% up to 90% RH.

[0138] Example 7 - Biological evaluation Compound (I) was tested to assess its MAGL activity in the following in vitro and in vivo assays:

[0139] In vitro competitive activity-based protein profiling PC3 human cell membrane proteome (50 μL, total protein concentration 2.0 mg / mL) was preincubated with various concentrations of compound (I) at 37 °C. After 30 min, ABPP probe JW912-Bodipy (1.0 μL, 50 μM in DMSO) was added and the mixture was incubated at room temperature for 30 min. The reaction was quenched with SDS loading buffer (15 μL-4x) and run on SDS-PAGE. Following gel imaging, serine hydrolase activity was determined by measuring the fluorescence intensity of the gel band corresponding to MAGL using ImageJ 1.43u software. Intensity was converted to percent enzyme activity by normalizing to DMSO control. IC was calculated by fitting the percent enzyme activity to a nonlinear regression, four-parameter, sigmoidal dose-response function in Prism GraphPad. 50 value was determined.

[0140] In vitro competitive substrate hydrolase activity assay HEK293 cell lysates expressing recombinant human MAGL enzyme and 4-nitrophenyl acetate (pNPA) substrate were diluted separately in 50 mM HEPES (pH 7.0) containing 200 mM KCl and 1 mM EDTA. Lysates (50 μL, approximately 1.2 μg total protein) were preincubated with various concentrations of Compound (I) at 25° C. After 30 min, 2× pNPA substrate (50 μL, 2.5 mM) was added and substrate turnover was monitored by measuring the increase in absorbance at a wavelength of 405 nm for 20 min at 25° C. using a Biotek Neo2 plate reader. Mean viscosities were converted to percent enzyme activity following background subtraction and normalization to DMSO controls. IC was calculated by fitting percent enzyme activity to a nonlinear regression, four-parameter, sigmoidal dose-response function in Prism GraphPad. 50 value was determined.

[0141] In vivo Compound (I) in polyethylene glycol vehicle was administered by oral gavage to wild-type C57Bl / 6J mice. Four hours after administration, each animal was sacrificed and brain proteomes were prepared and analyzed according to previously established methods (see Niphakis, MJ, et al. (2011) ACS Chem. Neurosci. and Long, JZ, et al. Nat. Chem. Biol. 5:37-44).

[0142] The compounds demonstrated activity in the assays described herein, as shown in Table 2.

[0143] [Table 2]

Claims

1. The crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.

2. The crystalline morphology exhibits peaks at the following 2θ angles: 10.81°, 16.54°, 16.76°, and 19.21°, in CuK α１ The crystalline form according to claim 1, characterized by having an XRPD obtained using a wire (λ = 1.5406 Å), which is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 1.

3. The crystalline morphology exhibits peaks at the following 2θ angles: 6.61°, 9.16°, 13.09°, and 14.32°, in CuK α１ The crystalline form according to claim 1, characterized by having an XRPD obtained using a line (λ = 1.5406 Å), which is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 3.

4. A solid dosage form comprising a crystalline form according to any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers or diluents.

5. The solid dosage form according to claim 4, selected from capsules, tablets, sugar-coated pills, pills, lozenges, powders, and granules.

6. The solid dosage form according to claim 4, which is a tablet.

7. The solid dosage form according to claim 4, comprising about 0.1 to 200 mg of the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.

8. The solid dosage form according to claim 4, comprising about 1 to 40 mg of the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.

9. The solid dosage form according to claim 4, comprising about 1 to 30 mg of the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.

10. The solid dosage form according to claim 4, comprising about 1 to 20 mg of the crystalline form of 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate.

11. The solid dosage form according to claim 4, wherein the crystalline form is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 1.

12. The solid dosage form according to claim 4, wherein the crystalline form is 1,1,1,3,3,3-hexafluoropropan-2-yl(S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylate form 3.

13. 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, childbirth, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, arthralgia, menstrual pain, metabolic disorders, musculoskeletal disorders, peripheral neuropathy, migraine, visceral hypersensitivity A solid dosage form according to claim 4, for use in the treatment of a disease or disorder selected from hypersensitivity, osteoarthritis, pancreatitis, pharyngitis, post-mastectomy pain syndrome, trigeminal neuralgia, postoperative pain, post-traumatic stress disorder, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, occlusive pain attacks and visceral pain in sickle cell disease.

14. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 3 for treating 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, childbirth, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, arthralgia, menstrual pain, metabolic disorders, musculoskeletal disorders, peripheral neuropathy, migraine, visceral hypersensitivity, osteoarthritis, pancreatitis, pharyngitis, post-mastectomy pain syndrome, trigeminal neuralgia, postoperative pain, post-traumatic stress disorder, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vaso-occlusive pain attacks and visceral pain in sickle cell disease.

15. Use of the crystalline form according to any one of claims 1 to 3 in the manufacture of a pharmaceutical product for 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, childbirth, abdominal pain, abdominal pain associated with irritable bowel syndrome, acute pain, back pain, cancer pain, chest pain, functional chest pain, arthralgia, menstrual pain, metabolic disorders, musculoskeletal disorders, peripheral neuropathy, migraine, visceral hypersensitivity, osteoarthritis, pancreatitis, pharyngitis, post-mastectomy pain syndrome, trigeminal neuralgia, postoperative pain, post-traumatic stress disorder, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, vaso-occlusive pain attacks and visceral pain in sickle cell disease.

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