Crystalline forms of (s)-1-(pyridazin-3-ylamino formyl)-6-azaspiro [2.5] octane-6-carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-ester as monoacylglycerol lipase inhibitors

Abstract

Described herein are novel crystalline forms of the MAGL inhibitor (S)-1-(pyridazine-3-ylamino formyl)-6-azaspiro [2.5] octane-6-carboxylic acid 1, 1, 1, 3, 3, 3-hexafluoropropan-2-ester. The invention also relates to a preparation method of the MAGL inhibitor (S)-1-(pyridazine-3-ylamino formyl)-6-azaspiro [2.5] octane-6-carboxylic acid.

Description

Technical Field

[0001] The present invention relates to crystalline forms of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester, pharmaceutical compositions comprising such crystalline forms, and methods and uses for treating a variety of conditions that would benefit from inhibition of monoacylglycerol lipase (MAGL). Background Art

[0002] MAGL is a member of the serine hydrolase superfamily. MAGL is expressed throughout the brain in neurons, microglia, astrocytes, and oligodendrocytes. MAGL is the main enzyme that controls the degradation of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) (Blankman et al. Chem Biol [Chemistry and Biology]. 2007; Nomura et al. Science [Science]. 2011).

[0003] 2-AG is the most abundant endocannabinoid ligand in the brain, where it acts as a retrograde messenger to reduce excessive neurotransmission via activation of presynaptic CB1 receptors (Katona et al., Nat Med. 2008 Sep;14(9):923-30), modulate immune responses via activation of microglial CB2 receptors (Turcotte et al. Cell Mol Life Sci. 2016 Dec;73(23):4449-4470), and promote neuroprotection via, for example, its effects on oligodendrocyte generation 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 prostaglandins and leukotrienes, which are known mediators of inflammation.

[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 characterized by 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; et al. Biochem Pharmacol. 2018 Nov;157:18-32).

[0006] Solid form development is highly complex because it is impossible to predict from previous experience whether a compound will exist in various solid forms, let alone how to make them.

[0007] Even after solid forms are synthesized, identification and selection of solid forms for further drug development is complicated because changes in solid form may affect a variety of physical and chemical capabilities that are unpredictable and may 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 compound will form polymorphs, and whether any such polymorphs will be suitable for commercial use in therapeutic compositions, or which polymorphs will exhibit such desirable properties. Thus, there remains a need to produce solid forms having desirable properties (e.g., stability) for further drug development. Summary of the invention

[0009] The object of the present invention is to provide a solid form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester suitable for drug development.

[0010] Thus, in a first aspect of the present invention, there is provided a crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester.

[0011] In another aspect of the present invention, a solid dosage form is provided, comprising a crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester and one or more pharmaceutically acceptable carriers or diluents.

[0012] In a further aspect of the invention there is provided a crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester for use in treating a disease or condition that benefits from inhibition of activation of MAGL. Incorporated by Reference

[0013] All publications and patent applications mentioned in this specification are incorporated herein by reference to the extent applicable and relevant. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shown is an X-ray powder diffraction (XRPD) pattern of Compound (I) Form 1. X-axis: diffraction angle (° 2θ); Y-axis: intensity (counts).

[0015] Figure 2 Shown is a thermogravimetric analysis (TGA) thermogram of Compound (I) Form 1. X-axis: temperature (°C); Y-axis: weight (%).

[0016] Figure 3 Shown is an X-ray powder diffraction (XRPD) pattern of Compound (I) Form 3. X-axis: diffraction angle (° 2θ); Y-axis: intensity (counts).

[0017] Figure 4 Shown is a thermogravimetric analysis (TGA) thermogram of Compound (I) Form 3. X-axis: temperature (°C); Y-axis: weight (%).

[0018] Figure 5 Shown is a Differential Scanning Calorimetry (DSC) thermogram of Compound (I) Form 1. X-axis: temperature (°C); Y-axis: normalized heat flow (W / g).

[0019] Figure 6 Shown is a Differential Scanning Calorimetry (DSC) thermogram of Compound (I) Form 3. X-axis: temperature (°C); Y-axis: normalized heat flow (W / g).

[0020] Figure 7 Shown is a dynamic vapor sorption (DVS) adsorption kinetics plot of Compound (I) Form 1. X-axis: time (min); Y-axis (left): mass change (%); Y-axis (right): relative humidity (%).

[0021] Figure 8 Shown is a dynamic vapor sorption (DVS) adsorption kinetics plot of Compound (I) Form 3. X-axis: time (min); Y-axis (left): mass change (%); Y-axis (right): relative humidity (%). DETAILED DESCRIPTION definition

[0022] Unless defined otherwise, all technical and scientific terms used in this article have the same meanings as those generally understood by those skilled in the art to which the claimed subject matter belongs. It should be understood that the general description above and the detailed description below are exemplary and illustrative only and do not limit any claimed subject matter. In this application, unless otherwise specifically stated, the use of the singular includes the plural. It must be noted that, unless the context clearly indicates otherwise, as used in the specification and the appended claims, the singular forms "a / an" and "the" include plural references. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms such as "include, include, included" is not restrictive.

[0023] As used herein, the term "acceptable" or "pharmaceutically acceptable" (with respect to a formulation, composition or ingredient) means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0024] As used herein, "amelioration" of the symptoms of a particular disease, disorder or condition by the administration of a particular compound or pharmaceutical composition means any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient, attributable to or associated with the administration of the compound or composition.

[0025] As used herein, the terms "co-administered," "co-administered," and the like are intended to encompass administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0026] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound being administered that will alleviate one or more of the symptoms of the disease or condition being treated to some extent. The result can be a reduction and / or alleviation of signs, symptoms, or any other desired change in a disease or biological system. For example, an "effective amount" for therapeutic use is an amount of a composition comprising a compound as disclosed herein that is required to provide a clinically significant reduction in disease symptoms. In any individual case, an appropriate "effective amount" can be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactic effective amount. The "effective amount" of a compound disclosed herein is an effective amount to achieve the desired pharmacological effect or therapeutic improvement. It should be understood that due to changes 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, the "effective amount" or "therapeutically effective amount" may vary between subjects.

[0027] As used herein, the terms "inhibits", "inhibiting" or "inhibitor" of an enzyme refer to inhibiting the activity of an enzyme.

[0028] As used herein, the term "subject" refers to an animal that is the object of treatment, observation or experiment. By way of example only, the subject can be, but is not limited to, a mammal, including, but not limited to, a human. In an embodiment, the subject is a human.

[0029] As used herein, the terms "treat," "treating," or "treatment" include alleviating, reducing, or ameliorating symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing potential metabolic causes of symptoms, inhibiting a disease or condition, such as inhibiting the development of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or terminating symptoms of a disease or condition. The terms "treat," "treating," or "treatment" include, but are not limited to, therapeutic treatment.

[0030] The X-ray diffraction data presented in this paper have an accuracy of ±0.1° 2θ. Compound

[0031] Compound (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester (designated herein as Compound (I)) has the following structure:

[0032] The present invention relates to crystalline forms of compound (I), and the use of the compound for treating various diseases and conditions believed to be associated with the regulation 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" means that compound (I) is in non-salt form.

[0033] Although not intended to be bound by any particular theory, some crystalline forms have different physical and chemical properties suitable for drugs and therapeutic dosage forms, such as stability, solubility and dissolution rate. In addition, although not intended to be bound by any particular theory, some solid forms have different physical and chemical properties (e.g., density, compressibility, hardness, morphology, splitting, adhesion, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability and chemical stability) that affect specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, fluidity, dissolution, formulation and lyophilization), which makes some solid forms suitable for manufacturing solid dosage forms. Such properties can be determined using specific analytical chemistry techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in the art. Embodiments of the present invention

[0034] In the following, embodiments of the present invention are disclosed. The first embodiment is denoted as E1, the second embodiment is denoted as E2, and so on.

[0035] E1. A crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester.

[0036] E2. The crystalline form of Embodiment E1, wherein the crystalline form is (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 1 having at least one of the following properties: a) Using CuK ɑ1 radiation The X-ray powder diffraction (XRPD) obtained showed Figure 1 Substantially the same XRPD pattern as shown in; b) Using CuK ɑ1 radiation An X-ray powder diffraction (XRPD) pattern was obtained, which showed characteristic peaks at the following 2θ-angles: 10.81°, 16.54°, 16.76°, and 19.21°; c) Basically similar to Figure 2 Thermogravimetric analysis (TGA) shown in; d) combinations thereof.

[0037] E3. A crystalline form according to embodiment E2, wherein the crystalline form is (S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 1, which has a crystalline form characterized by: using CuK ɑ1 radiation The obtained XRPD showed peaks at the following 2θ-angles: 10.81°, 16.54°, 16.76° and 19.21°.

[0038] E4. The crystalline form of Embodiment E1, wherein the crystalline form is (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 3 having at least one of the following properties: a) Using CuK ɑ1 radiation The X-ray powder diffraction (XRPD) obtained showed Figure 3 Substantially the same XRPD pattern as shown in; b) Using CuK ɑ1 radiation An X-ray powder diffraction (XRPD) pattern was obtained, which showed characteristic peaks at the following 2θ-angles: 6.61°, 9.16°, 13.09° and 14.32°; c) Basically similar to Figure 4 Thermogravimetric analysis (TGA) shown in; d) combinations thereof.

[0039] E5. A crystalline form according to embodiment E4, wherein the crystalline form is (S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 3, which has a crystalline form characterized by: using CuK ɑ1 radiation The obtained XRPD showed peaks at the following 2θ-angles: 6.61°, 9.16°, 13.09° and 14.32°.

[0040] E6. A solid dosage form comprising the crystalline form according to any one of embodiments E1-E5, and one or more pharmaceutically acceptable carriers or diluents.

[0041] E7. A solid dosage form according to embodiment E6, wherein the solid dosage form is selected from the group consisting of capsules, tablets, dragees, pills, lozenges, powders and granules.

[0042] E8. The solid dosage form of embodiment E7, wherein the solid dosage form is a tablet.

[0043] E9. A solid dosage form according to embodiment E7, wherein the solid dosage form is a capsule.

[0044] E10 The dosage form according to any one of embodiments E7-E9, wherein the dosage form comprises a crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to embodiments E1-E5 in an amount of about 0.1 to 500 mg.

[0045] E11. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 0.1 to 200 mg.

[0046] E12. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 2 to 200 mg.

[0047] E13. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 2 to 100 mg.

[0048] E14. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 2 to 50 mg.

[0049] E15. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 5 to 50 mg.

[0050] E16. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 10 to 50 mg.

[0051] E17. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 10 to 100 mg.

[0052] E18. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 1 to 50 mg.

[0053] E19. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 1 to 40 mg.

[0054] E20. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 1 to 20 mg.

[0055] E21. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 1 to 10 mg.

[0056] E22. The dosage form according to embodiment E10, wherein the dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 10 to 20 mg.

[0057] E23. A dosage form according to any one of embodiments E6-E22, wherein the crystalline form is selected from (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 1 or (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 3.

[0058] E24. The dosage form of any one of embodiments E6-E22, wherein the crystalline form is (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 1.

[0059] E25. A tablet containing about 0.1-200 mg of the crystalline form according to any one of embodiments E1-E5 and one or more pharmaceutically acceptable carriers or diluents.

[0060] E26. The tablet according to embodiment E25, wherein the tablet comprises about 2-100 mg of the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of embodiments E1-E5.

[0061] E27. The tablet according to embodiment E25, wherein the tablet comprises about 10-100 mg of the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of embodiments E1-E5.

[0062] E28. The tablet of embodiment E25, wherein the tablet comprises about 1-20 mg of the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester of any one of embodiments E1-E5.

[0063] E29. The tablet of embodiment E25, wherein the tablet comprises about 1-40 mg of the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester of any one of embodiments E1-E5.

[0064] E30. The tablet according to embodiment E25, wherein the tablet comprises about 5-30 mg of the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of embodiments E1-E5.

[0065] E31. A tablet according to embodiment E25, wherein the tablet comprises about 10-20 mg of the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of embodiments E1-E5.

[0066] E32. A crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of Examples E1 to E5 or a dosage form according to any one of Examples E6 to E31 for treating a disease or condition selected from the following: 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, 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 disorders, spasticity, spasticity in patients with multiple sclerosis, sunburn, systemic lupus erythematosus, toothache, epilepsy, treatment-resistant focal epilepsy, vaso-occlusive painful crises in sickle cell disease, and visceral pain.

[0067] E33. A crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester for use according to embodiment E32, wherein the disease or condition is spasticity.

[0068] E34. A crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester for use according to embodiment E32, wherein the disease or disorder is multiple sclerosis.

[0069] E35. A crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester for use according to embodiment E32, wherein the disease or condition is spasticity in a patient with multiple sclerosis.

[0070] E36. A crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester for use according to embodiment E32, wherein the disease or disorder is epilepsy.

[0071] E37. A crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester for use according to embodiment E32, wherein the disease or disorder is treatment-resistant focal epilepsy.

[0072] E38. A method for treating a disease or condition selected from the group consisting of 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 symptoms, trigeminal neuralgia, postoperative pain, post-traumatic stress disorder, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin diseases, sunburn, systemic lupus erythematosus, toothache, epilepsy, treatment-resistant focal epilepsy, vaso-occlusive painful crises in sickle cell disease, and visceral pain; the method comprising administering to a patient in need thereof a therapeutically effective amount of a crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of Examples E1 to E5 or a dosage form according to any one of Examples E6-E31.

[0073] E39. Use of a crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of Examples E1 to E5 or a dosage form according to any one of Examples E6 to E31 in the manufacture of a medicament for treating a disease or condition selected from the following: 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 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 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 disorders, sunburn, systemic lupus erythematosus, dental pain, epilepsy, treatment-resistant focal epilepsy, vaso-occlusive painful crisis in sickle cell disease, and visceral pain.

[0074] E40. (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester, or a pharmaceutically acceptable salt thereof, for use in the treatment of resistant focal epilepsy.

[0075] E41. (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester, or a pharmaceutically acceptable salt thereof, for use in treating post-traumatic stress disorder.

[0076] E42. (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ate, or a pharmaceutically acceptable salt thereof, for use in treating spasms. Pharmaceutical composition

[0077] The crystalline form of Compound (I) may be used as the sole active ingredient in a composition or in combination with other active ingredients. Additionally, one or more pharmaceutically acceptable carriers or diluents may be present in the composition.

[0078] The pharmaceutical composition can 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 to be treated, the nature of the condition to be treated and the active ingredient selected.

[0079] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings. Oral dosage forms, especially tablets, are generally favored by patients and doctors due to their ease of administration and the resulting better compliance.

[0080] Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

[0081] Pharmaceutical compositions for parenteral administration include sterile injectable aqueous and non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.

[0082] Other suitable administration forms include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, and the like.

[0083] Conveniently, the crystalline form of compound (I) is administered in a unit dosage form containing about 0.1 to 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 of the compound. In another embodiment, the unit dosage form contains about 2 mg to 100 mg, such as 5 mg to 100 mg, 10 mg to 100 mg, 15 mg to 100 mg, 20 mg to 100 mg, 25 mg to 100 mg, 30 mg to 100 mg, 35 mg to 100 mg, 40 mg to 100 mg, 45 mg to 100 mg or 50 mg to 100 mg of the compound. In further embodiments, the unit dosage form contains the compound in an amount of about 2 mg to 50 mg, such as 5 mg to 50 mg, 10 mg to 50 mg, 15 mg to 50 mg, 20 mg to 50 mg, 25 mg to 50 mg, 30 mg to 50 mg, 35 mg to 50 mg, 40 mg to 50 mg, or 45 mg to 50 mg.

[0084] For parenteral administration, a solution of the crystalline form of Compound (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E, or sesame or peanut oil may be used. Such aqueous solutions should be appropriately buffered if necessary and the liquid diluent should first be rendered isotonic with sufficient saline or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. The sterile aqueous media employed can be readily obtained by standard techniques known to those of ordinary skill in the art.

[0085] Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyethylene oxide and water. The pharmaceutical composition formed by combining the crystalline form of compound (I) with a pharmaceutically acceptable carrier is then easily administered in a variety of dosage forms suitable for the disclosed route of administration.

[0086] The preparations of the present invention suitable for oral administration can be presented in discrete unit form, such as capsules or tablets each containing a predetermined amount of active ingredient and which may include a suitable excipient. In addition, the orally available preparations can be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions.

[0087] If a solid carrier is used for oral administration, the preparation may be in the form of tablets, capsules or granules 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.

[0088] If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

[0089] Tablets can be prepared by mixing the active ingredient with common adjuvants and / or diluents and subsequently compressing the mixture in a conventional tablet press. Examples of adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, etc. Any other adjuvants or additives commonly used for such purposes, such as coloring agents, flavoring agents, preservatives, etc., may be used provided that they are compatible with the active ingredient.

[0090] In an embodiment, crystalline (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester is provided in an oral solution comprising a buffer, benzoic acid, hydroxypropyl beta-cyclodextrin, acesulfame potassium, denatonium benzoate, and water. Conditions treated

[0091] Also disclosed herein are methods of treating diseases or conditions that may benefit from MAGL inhibition. The disclosed methods comprise administering a pharmaceutically effective amount of a crystalline form of Compound (I). Atopic dermatitis

[0092] Atopic dermatitis (AD), also known as eczema, is a common chronic inflammatory skin condition associated with dysfunction 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 can cause the skin to become red, swollen, cracked, "oozing" clear fluid, and crusted. A functional endocannabinoid signaling system is present in the skin and mediates multiple aspects of skin biology. Third-party studies have shown that CB1 and CB2 receptors are upregulated in atopic dermatitis and that the endocannabinoid system plays a protective role in skin allergy models. In addition, MAGL inhibitors have been shown to reduce MAGL activity and increase 2-AG levels in rodent skin.

[0093] 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, the method 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, the method comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3. Fibromyalgia

[0094] Fibromyalgia (FM) is a common, chronic, idiopathic condition characterized by diffuse body pain and the presence of pressure-evoked allodynia. Several third-party studies of exogenous cannabinoids in FM have demonstrated activity. For example, pain (e.g., NRS-11, pain VAS) measures and the Fibromyalgia Impact Questionnaire (FIQ), which measures limitations in several activities of daily living affected by FM, have demonstrated activity of drugs in FM clinical trials. In an 8-week, 40-patient study, exogenous cannabinoids improved pain measured on a 10 cm VAS and improved the FIQ domain of anxiety and the FIQ total score compared to placebo.

[0095] 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, the method comprising administering a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3 to the patient. Epilepsy and Seizure Treatment

[0096] In a study by Sugaya et al., Cell Rep. 2016, 2-AG was shown to be essential for inhibiting epileptic seizures. Therefore, in another embodiment, a crystalline form of compound (I) is disclosed herein for use in treating epilepsy / epileptic seizure disorders. In a further embodiment, a crystalline form of compound (I) is disclosed herein for use in treating resistant focal epilepsy.

[0097] Additionally, Yeh et al., Perspectives on the Role of Endocannabinoids in Autism Spectrum Disorders, OBM Neurobiol. 2017, have suggested that targeting endocannabinoid signaling is a potential approach for treating symptoms within autism spectrum disorders.

[0098] In further embodiments, disclosed herein is a crystalline form of Compound (I) for use in treating acute recurrent epileptic seizures, temporal lobe epilepsy, Dravet syndrome, Ringer-Gordian syndrome, or Angelman syndrome. Migraine

[0099] Migraine is a common episodic disorder of head and facial pain. Migraine attacks can be treated acutely 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 suggest that the endocannabinoid pathway may be involved in migraine. In patients with chronic migraine and possible analgesic overuse headaches, CSF specimens showed higher levels of the endocannabinoid palmitoylethanolamide and lower levels of anandamide compared to healthy controls. In addition, patients initially diagnosed with migraine found that the frequency of migraines decreased after starting cannabis treatment.

[0100] 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, the method comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3. Acute pain, inflammatory pain, cancer pain, and pain caused by peripheral neuropathy

[0101] MAGL inhibitors have shown efficacy in several rodent pain models, including acute pain, inflammatory pain, cancer pain, and pain caused by chemotherapy-induced peripheral neuropathy.

[0102] In some embodiments, the MAGL inhibitors described herein are effective in treating acute pain, inflammatory pain, cancer pain, and pain caused by peripheral neuropathy. In some embodiments, disclosed herein is a method for treating acute pain, inflammatory pain, cancer pain, and pain caused by peripheral neuropathy in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3. Functional dyspepsia

[0103] Functional dyspepsia (FD) is one of the most common gastrointestinal disorders encountered in clinical practice. Several pathophysiological mechanisms have been proposed to underlie the symptoms of FD, including visceral hypersensitivity due to central or peripheral sensitization, a low-grade inflammatory state, altered gastrointestinal hormone secretion, genetic susceptibility, and abnormalities in gastric emptying or regulation. Third-party data support the hypothesis that the endocannabinoid system is altered in FD.

[0104] In some embodiments, the MAGL inhibitors described herein have efficacy in treating functional dyspepsia. In some embodiments, disclosed herein is a method of treating functional dyspepsia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3. Skeletal muscle contusion

[0105] Skeletal muscle contusion represents a direct, blunt, compressive force to the muscle. Contusion is one of the most common sports-related injuries. The severity of contusions ranges from simple skin contusions to muscle and bone contusions to visceral contusions. In third-party data, MAGL inhibition showed anti-inflammatory effects in a rat skeletal muscle contusion model.

[0106] In some embodiments, the MAGL inhibitors described herein have efficacy in treating skeletal muscle contusions. In some embodiments, disclosed herein is a method of treating skeletal muscle contusions in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of Compound (I) Form 1 or Compound (I) Form 3. Symptomatic treatment of multiple sclerosis

[0107] Almost all MS patients of all subtypes have one or more symptoms of spasticity, pain, sleep disturbances, bladder dysfunction, and fatigue. Disease-modifying treatments do not improve symptoms. Spasticity affects more than 80% of people with MS; 34% have moderate, severe, or complete spasticity. Severe spasticity is associated with cost and level of care and is independently associated with quality of life in MS. Two recent reviews support the use of exocannabinoids for the treatment of MS spasticity and pain (Whiting et al., JAMA [Journal of the American Medical Association]. 2015; Hill et al., JAMA [Journal of the American Medical Association]. 2015).

[0108] Exogenous cannabinoid 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 (cannabidiol)) was shown to reduce self-reported spasticity-related symptoms. In the Sativex pivotal trial using a randomized discontinuation design, continued Sativex improved spasticity frequency, sleep disruption caused by spasticity, subject overall impression of change, caregiver overall impression of change, and physician overall impression of change. Other clinical trials have shown the activity of multiple exogenous cannabinoids in spasticity due to MS (Zajicek et al., Lancet. [Lancet] 2003; Collin et al., Eur J Neurol. [European Journal of Neurology] 2007; Collin et al., Neurol Res. [Journal of Neurological Research] 2010). These parallel group studies exemplify clinical trial designs and endpoints that can be used to show that MAGL is beneficial for spasticity in MS.

[0109] In the Examples, disclosed herein are crystalline forms of Compound (I) for use in the treatment of multiple sclerosis.

[0110] In an embodiment, disclosed herein is a crystalline form of Compound (I) for use in treating one or more symptoms of multiple sclerosis selected from fatigue, spasticity, depression, behavioral disorders, irritability, and pain.

[0111] In further embodiments, disclosed herein are crystalline forms of Compound (I) for use in treating spasticity.

[0112] It is believed that MAGL will also be beneficial in treating indications associated with autoimmune encephalomyelitis. Accordingly, in further embodiments, disclosed herein are crystalline forms of Compound (I) for use in treating Rasmussen encephalitis, systemic lupus erythematosus, Behcet's disease, Hashimoto's encephalopathy, and Sydenham's chorea. Combination therapy

[0113] Combination therapy is also contemplated herein, e.g., co-administering a crystalline form of compound (I) and other active agents as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-actions produced by the combination of therapeutic agents. These therapeutic agents are typically administered in combination over a limited time period (usually a few weeks, months, or years, depending on the selected combination). Combination therapy is intended to encompass the administration of multiple therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at different times, and the administration of these therapeutic agents or at least two of these therapeutic agents in a substantially simultaneous manner.

[0114] Substantially simultaneous administration is achieved, for example, by administering to a subject a single formulation or composition (e.g., a tablet or capsule of each therapeutic agent in a fixed ratio), or a plurality of single formulations of each therapeutic agent (e.g., a plurality of capsules). The sequential or substantially simultaneous administration of each therapeutic agent is achieved by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. The therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0115] Combination therapy also encompasses the further combined administration of therapeutic agents as described above with other biologically active ingredients and non-drug therapies. When the combination therapy further includes non-drug therapy, the non-drug therapy is performed at any appropriate time, as long as the beneficial effects of the combined effects of the therapeutic agent and the non-drug therapy are obtained. For example, in appropriate cases, when the non-drug therapy is temporarily removed from the administration of the therapeutic agent, it may be several days or even weeks, and still obtain a beneficial effect.

[0116] The components of the combination are administered to the patient simultaneously or sequentially. It will be understood that these components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms that are administered simultaneously or sequentially.

[0117] For example, for the intended treatment of pain, the crystalline form of Compound (I) is co-administered with another pain therapeutic agent such as an opioid, a cannabinoid receptor (CB1 or CB2) modulator, a COX-2 inhibitor, acetaminophen and / or a non-steroidal anti-inflammatory drug. For example, co-administered additional therapeutic agents for the treatment of pain include morphine, pregabalin, gabapentin, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol and levorphanol.

[0118] Other therapeutic agents contemplated 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. Experimental Section List of abbreviations

[0119] As used above and throughout the description of the present invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings: t-Bu: tert-butyl DCM: Dichloromethane (CH2Cl2) DMF: Dimethylformamide DMSO: dimethyl sulfoxide equiv: equivalent 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 tert-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 Chemical synthesis

[0120] Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations that were sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times were approximate and not optimized. Analytical methods LC-MS method

[0121] The LC-MS analysis system was equipped with a Shimadzu LCMS-2020, a PDA detector (operated at 254 nm), an ELSD detector, and an ESI source operated in positive ion mode. LC-conditions:

[0122] Method C: The column was Express C18 50*3.0 mm, which was operated at 40°C with a binary gradient of 1.5 mL / min consisting of water + 0.05% TFA (A) and ACN + 0.05% TFA (B). Retention times (t R ). Gradient: 0.01 min 20% B 3.50min 50% B 4.30min 95% B 4.00min 95% B 5.10min 5% B

[0123] Method O: The column was HALO C18 30*3.0 mm, 2 μm, which was operated at 40°C with a binary gradient consisting of water + 0.05% TFA (A) and ACN + 0.05% TFA (B) at 1.5 mL / min. Retention times (t R ). Gradient: 2.20 min 100% B 2.70min 100% B 2.72min 5% B Total running time: 3.0min 1 H NMR methods

[0124] Recorded on Bruker Avance HD at 300 or 400 MHz 1 H NMR spectra. Chemical shift values ​​are expressed in ppm relative to tetramethylsilane. The following abbreviations or combinations thereof are used for the multiplicities of NMR signals: br = broad, d = doublet, dd = doublet of doublet, dt = doublet of triplet, hept = septet, m = multiplet, q = quartet, quint = quintet, s = singlet, t = triplet, td = triplet of doublet. Example 1: Synthesis of Compound (I) Form 1 Step 1: Synthesis of 1-benzyl 6-(tert-butyl) 6-azaspiro[2.5]octane-1,6-dicarboxylate

[0125] A solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (240g) in acetone (5L) is added to a flask purged and maintained with a nitrogen inert atmosphere. Benzyl bromide (170.6g) and K2CO3 (259.8g) are added. The resulting solution is refluxed for 2-3h. The reaction is then cooled to room temperature and filtered. The filter cake is washed with ethyl acetate. The combined filtrate is concentrated in vacuo to obtain 297g of crude 6-azaspiro[2.5]octane-1,6-dicarboxylic acid 1-benzyl 6-(tert-butyl) ester. Step 2: Synthesis of 6-azaspiro[2.5]octane-1-carboxylic acid benzyl ester hydrochloride

[0126] A solution of crude 6-azaspiro [2.5] octane-1,6-dicarboxylic acid 1-benzyl 6-(tert-butyl) ester (297 g) in DCM (1.5 L) was added to a flask purged and maintained with a nitrogen inert atmosphere. 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 in vacuo. The crude product was slurried with EtO (10 V) to provide 198.3 g of 6-azaspiro [2.5] octane-1-carboxylic acid benzyl ester. Step 3: Synthesis of 1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate

[0127] A solution of 1,1,1,3,3,3-hexafluoropropane-2-ol (393g) in DCM (2L) is added to a flask purged and maintained with a nitrogen inert atmosphere. The mixture is cooled to 0 ° C and triphosgene (106.9g) is added in batches. Then DIPEA (550g) is added dropwise at 0 ° C-10 ° C. The mixture is stirred for 1.5h at this temperature. Then a solution of 6-azaspiro [2.5] octane-1-carboxylic acid benzyl ester hydrochloride (198g) in DCM (2L) is added dropwise at 0 ° C. The resulting solution is stirred at room temperature for 2h. The reaction mixture is quenched by pouring into water (6L) and then extracted with DCM (2×2L). The combined organic layer is washed with brine (1×3L), dried over anhydrous sodium sulfate and concentrated in vacuo. 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. Step 4: Separation 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)

[0128] The racemic mixture (265 g) of 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate prepared in step 3 was separated by preparative SFC-HPLC (column: CHIRALPAK 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 obtain intermediates 2A and 2B. The absolute configuration was confirmed by vibrational circular dichroism (Appl. Spectrosc. [Applied Spectroscopy] 65 (7), 699 (2011); PCT / EP 2021 / 081522) studies. The spectra were obtained using a ChirallR with a DualPEM VCD spectrometer and compared with calculated values ​​(DFT calculations using CPCM (chloroform) = B3LYP / 6311Gdp method and basis set).

[0129] Intermediate 2A; 110 g of (S)-1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl)6-azaspiro[2.5]octane-1,6-dicarboxylate. 1 H NMR (300 MHz, chloroform-d) δ 7.46-7.28 (m, 5H), 5.75 (p, J = 6.3 Hz, 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, 4.7 Hz, 1H). R =1.572 min. LCMS (Method O) (ESI, m / z): 440 [M+H] + as well as

[0130] Intermediate 3A; 100 g of (R)-1-benzyl 6-(1,1,1,3,3,3-hexafluoropropan-2-yl) 6-azaspiro[2.5]octane-1,6-dicarboxylate. 1 H NMR (300 MHz, chloroform-d) δ7.36 (d, J = 2.6 Hz, 5H), 5.75 (p, J = 6.3 Hz, 1H), 5.13 (d, J = 1.4 Hz, 2H), 3.71-3.40 (m, 3H), 3.39-3.13 (m, 1H), 1.71 (ddd, J = 29.4, 9.4, 5.2 Hz, 3H), 1.57-1.36 (m, 2H), 1.23 (d, J = 5.2 Hz, 1H), 0.99 (dd, J = 8.1, 4.7 Hz, 1H). R=1.572 min. LCMS (Method O) (ESI, m / z): 440 [M+H] + . 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)

[0131] A solution of (S)-6-azaspiro [2.5] octane-1,6-dicarboxylic acid 1-benzyl 6-(1,1,1,3,3,3-hexafluoroprop-2-yl) ester (110 g) in THF (2 L) was added to a flask. Wet Pd / C (22 g, 10% wt, 50% H2O) was added to the mixture. The resulting mixture was purged and replaced 3 times with H2, and then stirred at room temperature for 3 h under H2. The mixture was filtered and the filter cake was washed with THF (2×500 mL). The combined filtrate was concentrated in vacuo, and the crude product was co-evaporated with toluene (2×1 L) to give 90 g of crude (S)-6-(((1,1,1,3,3,3-hexafluoroprop-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 gel column chromatography to provide pure characterization data. 1 H NMR (300 MHz, chloroform-d) δ 5.78 (h, J = 6.3 Hz, 1H), 3.79-3.40 (m, 4H), 1.85 (q, J = 6.1 Hz, 2H), 1.65 (dd, J = 8.0, 5.4 Hz, 1H), 1.54 (dq, J = 10.9, 5.8, 5.0 Hz, 2H), 1.28 (t, J = 5.1 Hz, 1H), 1.09 (dd, J = 8.1, 4.8 Hz, 1H). R =1.441 min. LCMS (Method O) (ESI, m / z): 350 [M+H] + . Step 6: Synthesis of Compound (I) Form 1

[0132] (S)-6-(((1,1,1,3,3,3-hexafluoroprop-2-yl)oxy)carbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (intermediate 2B) (38.5 g), DCM (800 mL) and DMF (0.40 g) were added to a flask purged and maintained with a nitrogen inert atmosphere. The mixture was cooled to 0 ° C and (COCl) 2 (11.5 g) was added dropwise. The resulting mixture was stirred at room temperature for 3 h. The mixture was then concentrated in vacuo to obtain a crude acid chloride for later use. Pyridazine-3-amine (12.6 g), pyridine (17.4 g) and THF (800 mL) were added to another flask purged and maintained with a nitrogen inert atmosphere. A solution of the previous acid chloride in THF (500 mL) was added dropwise at room temperature. The resulting solution was stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with 3L ice water and extracted with EtOAc (2×1 L). The combined organic phases were washed with H2O (1 × 1L) and brine (1 × 1L), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1 / 10) to provide 34.3g of product. The product was slurried with n-hexane (20V) and filtered to obtain 26.7g of (S)-1-(pyridazine-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester. The product was separated by slurrying with n-heptane (10V) to provide 24.13g of compound (I) form 1. 1 H NMR (300MHz, chloroform-d) δ10.82(s,1H),8.87(d,J=4.7Hz,1H),8.61(d,J=9.1Hz,1H),7.55(s,1H),5.90-5.62(m,1H),3. 73-3.27(m,4H),2.26(dd,J=8.0,5.4Hz,1H),1.95-1.72(m,4H),1.41(t,J=5.0Hz,1H),1.11(dd,J=7.9,4.6Hz,1H). t R =1.443 min. LCMS (Method O) (ESI, m / z): 427 [M+H] + CHIRALPAK AD, 3.0*100mm, 3mm; Mobile phase: Phase A: CO2, Phase B: MeOH (0.1% DEA); Flow rate: 2mL / min; Gradient: 10% to 50% in 2.0min, hold at 50% for 1.0min; Detection: 220nm: t R =1.032min. Example 2: Preparation of Compound (I) Form 3

[0133] In a vial, Compound (I) Form 1 (500 mg) was slurried in a 1:1 mixture of MeCN / water at room temperature for 24 hours. A small sample of the wet precipitate was analyzed by XRPD, showing Figure 3 The diffraction pattern of . Example 3: XRPD measurement

[0134] X-ray powder diffraction patterns were obtained on a PANalytical X'Pert PRO X-ray diffractometer using CuK ɑ1 radiation The samples were measured in reflection mode in the 2θ range 3°-40° using a PIXcel detector. The X-ray diffraction data presented herein have an accuracy of ±0.1° 2θ.

[0135] Table 1 - Characteristic XRPD peaks of the crystalline form of Compound (I) Crystalline form Peak expressed as diffraction angle [°2θ] Compound (I) Form 1 10.81, 16.54, 16.76, and 19.21 Compound (I) Form 3 6.61, 9.16, 13.09, and 14.32 XRPD analysis of the obtained compounds

[0136] XRPD analysis of Compound (I) Form 1 ( Figure 1 ) shows that the form is crystalline.

[0137] XRPD Analysis of Compound (I) Form 3 ( Figure 3 ) shows that the form is crystalline. Example 4: Thermogravimetric analysis (TGA)

[0138] TGA was measured using a TA-instruments Discovery TGA. 1-15 mg of sample was heated at 10°C / min in an open pan under nitrogen flow.

[0139] TGA analysis of Compound (I) Form 1 ( Figure 2 ) shows that this form is unsolvated / unhydrated.

[0140] TGA analysis of Compound (I) Form 3 ( Figure 4 ) shows that this form is unsolvated / unhydrated. Example 5: Differential Scanning Calorimetry (DSC)

[0141] DSC was measured using a TA Instruments Discovery-DSC calibrated at 5°C / min to give the melting point as a starting value. Approximately 2 mg of sample was heated at 5°C / min in a closed pan with a pinhole in the lid under a nitrogen flow.

[0142] Figure 5The curve of shows an exothermic peak between two endothermic peaks. After heating a sample of Compound (I) Form 1 to 150°C, XRPD shows Compound (I) Form 3. Therefore, Compound (I) Form 3 is formed when Compound (I) Form 1 is heated. This formation of Compound (I) Form 3 at high temperature combined with the change from Compound (I) Form 1 to Compound (I) Form 3 upon slurrying indicates that Compound (I) Form 3 is thermodynamically more stable than Compound (I) Form 1. Example 6: Procedure for Dynamic Vapor Sorption (DVS) Measurements

[0143] DVS was measured using a Surface Measurements Science Adventure instrument (for Form 1 measurements) or a DVSadvantage 01 instrument (for Form 3 measurements). Relative humidity was varied from 0% RH to 95% RH in steps of 10% RH (5% between 90% and 95% RH). 1-10 mg was used, and 2 cycles were performed starting at 30% RH.

[0144] DVS analysis of Compound (I) Form 1 showed that this form was not hygroscopic, with a water absorption of 0.2 wt% up to 90% RH. DVS analysis of Compound (I) Form 3 showed that this form was not hygroscopic, with a water absorption of approximately 0.1 wt% up to 90% RH. Example 7 - Biological Evaluation

[0145] Compound (I) was tested using the following in vitro and in vivo assays to assess its MAGL activity. Protein profiling based on in vitro competitive activity

[0146] PC3 human cell membrane proteome (50 μL, total protein concentration of 2.0 mg / mL) was pre-incubated with different concentrations of compound (I) at 37°C. After 30 min, the 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. After gel imaging, the serine hydrolase activity was determined by measuring the fluorescence intensity of the gel band corresponding to MAGL using ImageJ1.43u software. The intensity was converted into percentage of enzyme activity by normalization to the DMSO control. The IC was determined by fitting the percentage of enzyme activity to a 4-parameter sigmoid dose response function of nonlinear regression in Prism GraphPad. 50 value. In vitro competitive substrate hydrolase activity assay

[0147] HEK293 cell lysates expressing recombinant human MAGL enzyme and 4-nitrophenyl acetate (pNPA) substrate were diluted in 50mM HEPES (pH 7.0) containing 200mM KCl and 1mM EDTA, respectively. The lysates (50μL, total protein is about 1.2μg) were pre-incubated with different concentrations of compound (I) at 25°C. After 30min, 2X pNPA substrate (50μL, 2.5mM) was added and the rate of substrate conversion was monitored by measuring the increase in absorbance at a wavelength of 405nm for 20 minutes at 25°C using a Biotek Neo2 microplate reader. After background subtraction and normalization to DMSO control, the average speed was converted to percentage of enzyme activity. The IC50 value was determined by fitting the percentage of enzyme activity to a 4-parameter sigmoid dose response function using nonlinear regression in Prism GraphPad. in vivo

[0148] Compound (I) was administered to wild-type C57Bl / 6J in a polyethylene glycol vehicle by oral gavage. Each animal was sacrificed 4 h after administration, and the brain proteome was prepared and analyzed according to previously established methods (see Niphakis, MJ et al. (2011) ACS Chem. Neurosci. [American Chemical Society, Chemical Neuroscience] and Long, JZ et al. Nat. Chem. Biol. [Nature Chemical Biology] 5: 37-44).

[0149] As shown in Table 2, the compounds exhibited activity in the assays described herein. Table 2: In vivo and in vitro MAGL activity of compound (I)

Claims

1. A crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester.

2. The crystalline form according to claim 1, wherein The crystalline form is (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 1, characterized in that it has the properties of using CuK ɑ1 radiation The obtained XRPD exhibited peaks at the following 2θ-angles: 10.81°, 16.54°, 16.76° and 19.21°.

3. The crystalline form of claim 1, wherein The crystalline form is (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 3, characterized in that it has a CuKα1 irradiation The obtained XRPD exhibited peaks at the following 2θ-angles: 6.61°, 9.16°, 13.09° and 14.32°.

4. A solid dosage form comprising the crystalline form of 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, wherein The solid dosage form is selected from the group consisting of capsules, tablets, dragees, pills, lozenges, powders and granules.

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

7. The solid dosage form according to any one of claims 4 to 6, wherein The dosage form comprises the crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 0.1 to 200 mg.

8. The solid dosage form according to any one of claims 4 to 6, wherein The dosage form comprises the crystalline form of (S)-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 1 to 40 mg.

9. The solid dosage form according to any one of claims 4 to 6, wherein The dosage form comprises the crystalline form of (S)-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 1 to 30 mg.

10. The solid dosage form according to any one of claims 4 to 6, wherein The dosage form comprises the crystalline form of (S)-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester in an amount of about 1 to 20 mg.

11. The solid dosage form according to any one of claims 4 to 10, wherein The crystalline form is (S)-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 1.

12. The solid dosage form according to any one of claims 4 to 10, wherein The crystalline form is (S)-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester Form 3.

13. A crystalline form of (S)-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of claims 1 to 3 or a solid dosage form according to any one of claims 4 to 12 for use in treating a disease or condition selected from the group consisting of 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 disease 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 disorders, peripheral neuropathy, migraine, visceral hypersensitivity, osteoarthritis, pancreatitis, pharyngitis, post-mastectomy pain syndrome, trigeminal neuralgia, post-surgical pain, post-traumatic stress disorder, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin disorders, sunburn, systemic lupus erythematosus, dental pain, vaso-occlusive painful crisis in sickle cell disease, and visceral pain.

14. A method for treating a disease or condition selected from the group consisting of 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, mastectomy Postoperative 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 painful crisis in sickle cell disease, and visceral pain; the method comprises administering to a patient in need thereof a therapeutically effective amount of a crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of claims 1-3 or a solid dosage form according to any one of claims 4-12.

15. Use of a crystalline form of (S)-1-(pyridazin-3-ylcarbamoyl)-6-azaspiro[2.5]octane-6-carboxylic acid 1,1,1,3,3,3-hexafluoropropane-2-ester according to any one of claims 1 to 3 or a solid dosage form according to any one of claims 4 to 12 in the manufacture of a medicament for treating a disease or condition selected from the group consisting of atopic dermatitis, bladder dysfunction associated with multiple sclerosis, cardiovascular disease, contact dermatitis, cystic fibrosis, dermatomyositis, eczema, endometriosis, enteritis, fibromyalgia, inflammatory bowel disease, interstitial bladder inflammation, 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 disorders, peripheral neuropathy, migraine, visceral hypersensitivity, osteoarthritis, pancreatitis, pharyngitis, post-mastectomy pain syndrome, trigeminal neuralgia, post-surgical pain, post-traumatic stress disorder, renal ischemia, rheumatoid arthritis, skeletal muscle contusion, skin disorders, sunburn, systemic lupus erythematosus, toothache, vaso-occlusive pain crisis in sickle cell disease, and visceral pain.

Images