EP-4739680-A1 - SOLID FORMS OF TRPV4 ANTAGONISTS

Abstract

The disclosure provides a solid form of 5-fluoro-1-(((5S,7S,8R)-8- fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1- oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6- carbonitrile: The compound is useful as TRPV4 antagonists.

Inventors

• KATANA, ASHLEY
• LINK, JOHN OTTO

Assignees

• Actio Biosciences, Inc.

Dates

Publication Date

20260513

Application Date

20240705

Claims (1)

1. WHAT IS CLAIMED IS: 1. A solid form of 5-fluoro-1-(((5S,7S,8R)-8-fluoro-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6- carbonitrile: . 2. The solid form of claim 1, wherein the form exhibits an X-ray powder diffraction pattern having one or more signal expressed in degrees 2-theta selected from the group consisting of about 7.02, about 7.04, about 7.07, about 7.09, about 10.31, about 10.33, about 10.35, about 10.37, about 15.56, about 15.58, about 15.60, about 18.85, about 18.87, about 18.89, about 18.91, about 19.20, about 19.22, about 19.24, about 19.42, about 19.45, about 19.47, about 19.49, about 22.39, about 22.41, about 22.43, about 24.00, about 24.02, about 24.04, about 24.06, about 25.15, about 25.21, about 7.11, about 25.23, about 26.51, about 26.53, about 26.55, and about 26.59. 3. The solid form of claim 1, wherein the form exhibits an X-ray powder diffraction pattern having at least three signals expressed in degrees 2-theta selected from the group consisting of about 7.02, about 7.04, about 7.07, about 7.09, about 10.31, about 10.33, about 10.35, about 10.37, about 15.56, about 15.58, about 15.60, about 18.85, about 18.87, about 18.89, about 18.91, about 19.20, about 19.22, about 19.24, about 19.42, about 19.45, about 19.47, about 19.49, about 22.39, about 22.41, about 22.43, about 24.00, about 24.02, about 24.04, about 24.06, about 25.15, about 25.21, about 7.11, about 25.23, about 26.51, about 26.53, about 26.55, and about 26.59. 4. The solid form of claim 1 that exhibits an X-ray powder diffraction pattern having at least six signals expressed in degrees 2-theta selected from the group consisting of about 7.02, about 7.04, about 7.07, about 7.09, about 10.31, about 10.33, about 10.35, about 10.37, about 15.56, about 15.58, about 15.60, about 18.85, about 18.87, about 18.89, about 18.91, about 19.20, about 19.22, about 19.24, about 19.42, about 19.45, about 19.47, about 19.49, about 22.39, about 22.41, about 22.43, about 24.00, about 24.02, about 24.04, about 24.06, about 25.15, about 25.21, about 7.11, about 25.23, about 26.51, about 26.53, about 26.55, and about 26.59. 5. The solid form of claim 1 that exhibits an X-ray powder diffraction pattern having at least nine signals expressed in degrees 2-theta selected from the group consisting of about 7.02, about 7.04, about 7.07, about 7.09, about 10.31, about 10.33, about 10.35, about 10.37, about 15.56, about 15.58, about 15.60, about 18.85, about 18.87, about 18.89, about 18.91, about 19.20, about 19.22, about 19.24, about 19.42, about 19.45, about 19.47, about 19.49, about 22.39, about 22.41, about 22.43, about 24.00, about 24.02, about 24.04, about 24.06, about 25.15, about 25.21, about 7.11, about 25.23, about 26.51, about 26.53, about 26.55, and about 26.59. 6. The solid form of claim 1 that exhibits an X-ray powder diffraction pattern having at least 12 signals expressed in degrees 2-theta selected from the group consisting of about 7.02, about 7.04, about 7.07, about 7.09, about 10.31, about 10.33, about 10.35, about 10.37, about 15.56, about 15.58, about 15.60, about 18.85, about 18.87, about 18.89, about 18.91, about 19.20, about 19.22, about 19.24, about 19.42, about 19.45, about 19.47, about 19.49, about 22.39, about 22.41, about 22.43, about 24.00, about 24.02, about 24.04, about 24.06, about 25.15, about 25.21, about 7.11, about 25.23, about 26.51, about 26.53, about 26.55, and about 26.59. 7. The solid form of claim 1 that exhibits an X-ray powder diffraction pattern having signals expressed in degrees 2-theta at about 7.04, about 7.07, about 7.09, about 10.33, about 10.35, about 18.87, and about 24.02. 8. A pharmaceutical composition comprising a solid form of any one of claims 1-7 and a pharmaceutically acceptable excipient, diluent, adjuvant, or carrier. 9. A method for treating a condition associated with TRPV4, comprising administering to a subject a solid form of any one of claims 1-7 or a pharmaceutical composition of claim 8. 10. A solid form of any one of claims 1-7 for the prophylactic or therapeutic treatment of a condition associated with TRPV4. 11. Use of a solid form of any one of claims 1-7 for the manufacture of a medicament for treating a condition associated with TRPV4. 12. Use of a solid form of any one of claims 1-7, or the pharmaceutical composition of claim 8, for the treatment of a condition associated with TRPV4.

Description

SOLID FORMS OF GSK2798745, A TRPV4 ANTAGONIST RELATED APPLICATIONS This application claims priority to United States Provisional Application Number 63/512,404, filed July 7, 2023, the entire contents of which is incorporated by reference. FIELD This disclosure relates to pharmaceutical compositions that act as antagonists of both wildtype TRPV4 channels and of TRPV4 channels that carry disease-causing activating mutations. BACKGROUND The transient receptor potential vanilloid type 4, TRPV4, is a member of the Transient Receptor Potential (TRP) super family (Venkatachai am and Craig Montell 2007 Annual Reviews Biochemistry). The TRPV4 gene encodes a non-selective cation channel highly permeable to calcium. TRPV4 is activated by a variety of different stimuli including heat, mechanical stress, and chemicals including arachidonic acid metabolites. TRPV4 is expressed in a number of different tissues including the brain, bladder, skin, heart, lung and musculoskeletal tissues, among others. The TRPV4 channel is widely expressed in diverse human cell types. In particular, TRPV4 is expressed in epithelial and endothelial cells, fibroblasts, chondrocytes, neurons, and various inflammatory cells (Koivisto et al 2021 NRDD). TRPV4 has been directly implicated in epithelial and endothelial barrier function with relevance to lung injury and has been further associated with respiratory diseases through TRPV4-induced ATP release (Koivisto). Genetic and pharmacologic studies have implicated TRPV4 as therapeutic target for chronic cough, pulmonary edema, chronic obstructive pulmonary disease, and pulmonary fibrosis (Grace et al 2017, Pharmacology and Therapeutics). Genetic knockout of TRPV4 results in decreased osteoclast function and calcium regulation and is critical for bone homeostasis, suggesting a role for TRPV4 in osteoporosis and other joint diseases. Inflammatory hyperalgesia and mechanical pain are reduced in TRPV4 knockout mice (J Neurosci. 2004, 18, 4444-4452, Qu, et al., 2016 BioMed Research International) and a variety of functional studies have demonstrated TRPV4 signaling in neuropathic pain. TRPV4 is also expressed in urothelium and detrusor muscles of the bladder and activation causes muscle contraction (Birder et al 2007 J. Pharmacol. Exp. Ther.). Consistent with a role for TRPV4 in bladder related conditions, it has been shown that inhibition of TRPV4 improves bladder function in mice and rat models of cyclophosphamide- induced cystitis ( Prog. Biophys. Mol. Biol.2010, 1, 2-17). This provides evidence for TRPV4 as a therapeutic target in multiple diseases, including respiratory disease, joint diseases, pain, and bladder dysfunction. Additionally, activating pathogenic mutations in TRPV4 have been shown to cause multiple severe Mendelian diseases including a set of skeletal dysplasias (Nishimura et al 2012 AJMG) and a peripheral neuropathy (Landoure et al. Nature Genetics 2009). All disease- causing mutations appear to contribute to risk of disease by increasing calcium influx into cells (Toft-Beterlsen and MacAulay 2021 Cells) suggesting therapeutic benefit of TRPV4 inhibitors. These observations suggest a benefit of inhibition of TRPV4 in genetic diseases due to activating mutations, in addition to a number of different common diseases resulting from activation of the wildtype receptor. GSK2798745 advanced to Phase II clinical trials. Further exploration uncovered a circulating active metabolite (ACS Med. Chem. Lett.2021, 12, 9, 1498-1502) and a lower safety margin established by a three month dog toxicity study resulted in a 4.8-fold decrease in the maximum clinically administered dose (Am. J. Cardiovasc. Drugs 2019, 19, 335-342). GSK2798745 failed to show efficacy across several human disease indications. Currently there is a need for agents that are useful for antagonizing TRPV4. In particular, there is a need for agents with lower toxicity, improved potency, improved metabolic stability (e.g., against CYP3A4), lower levels of active circulating metabolites, and/or a higher safety margin. SUMMARY OF THE DISCLOSURE In one aspect, the disclosure provides compounds that are useful for antagonizing TRPV4. In some aspects, the disclosure provides a compound of formula I: or a salt thereof, wherein: L1 is CRaRb; L2 is CRcRd; Ra is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, or (C3- C5)cycloalkyl, wherein any (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, and (C3- C5)cycloalkyl is optionally substituted with one or more fluoro; Rb is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, or (C3-C5)cycloalkyl, wherein any (C1- C5)alkyl, (C1-C5)alkoxy, and (C3-C5)cycloalkyl is optionally substituted with one or more fluoro; or Ra and Rb taken together are oxo (=O) methylene (=CH2), or Ra and Rb taken together with the atom to which they are attached form a spiro(C3- C5)cycloalkyl; Rc is H, halo, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, (C3-C5)cycloalkyloxy, or (C3- C5)cycloalkyl, wherein any