- Ahmed F. Abdel-Magid*
Important Compound Classes
Title
Hexahydro-5,8-epoxycyclohepta[c]pyrazole derivatives useful as modulators of the CB1 and/or CB2 receptors
Patent Publication Number
WO 2021/069671 A1
Publication Date
Fifteen April 2021
Priority Application
US 62/912,842
Priority Date
09 October 2019
Inventors
Meegalla, S. K.; Player, M. R.
Assignee Company
Janssen Pharmaceutica NV [BE/BE]; Turnhoutseweg 30, 2340 Beerse (BE).
Disease Area
Pain, neurodegenerative disorders, eating disorders, fibrotic diseases, obesity, and more
Biological Target
Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2).
Summary
The invention in this patent application relates to hexahydro-5,8-epoxycyclohepta[c]pyrazole derivatives represented generally by either formula 1 or formula 2. These compounds are CB1, CB2, or dual CB1/CB2 agonists and may be useful for the treatment of a wide variety of diseases and disorders including but not limited to appetite, diabetes, obesity, glaucoma associated intraocular pressure, mood disorders, seizures, cognition disorders, memory disorders, respiratory disorders, gastrointestinal disorders, and cardiovascular disease.Cannabinoids are chemical substances that can be found in both plants and animals. Cannabinoids have been extensively used for a long time throughout the world for their medicinal and/or recreational effects. Until recently, scientists had identified cannabinoids only in Cannabis sativa, which is a plant commonly known as marijuana or hemp. The plant produces about 100 phytocannabinoids such as the psychoactive delta-9-tetrahydrocannabinol (Δ9-THC) as well as the nonpsychoactive cannabidiol (CBD) and cannabinol (CBN). Most of the remaining phytocannabinoids are minor components. The plant has a long history of medicinal and recreational use. Recently, scientists have identified the presence of cannabinoids in other plants, such as clove, black pepper, echinacea, broccoli, ginseng, and carrots.
The research to understand the mechanism of action of cannabinoids on the human body has led in the late 1980s and early 1990s to the remarkable discoveries of the cannabinoid receptors, the endogenous cannabinoids (endocannabinoids), which are produced by the human and mammalian bodies, and the endocannabinoid system (ECS).
The human ECS is a complex highly regulated biological system that is composed of the cannabinoid receptors, endocannabinoids, and related enzymes. The ECS regulates many functions such as sleep, mood, memory, appetite, reproduction, and pain sensation. The receptors of the ECS are known as cannabinoid (CB) receptors, which are G-protein coupled receptors (GPCRs). Scientists have identified two CB receptors in mammalian tissues, named CB receptor 1 (CB1) and CB receptor 2 (CB2).
CB1 is mainly expressed in CNS neurons but is also present in other peripheral tissues at lower concentrations. It is believed that CB1 is responsible for the psychotropic effects resulting from its activation by the cannabinoid Δ9-THC. In addition, the interaction of CB1 with other ligands plays a key role in regulating pain, stress responses, energy regulation, lipogenesis, and immune function.
CB2 is expressed predominantly in the immune system. It is mainly associated with the immune functions including microglial cells within the CNS, but its presence in the CNS is much less than that of CB1.
There are two known endocannabinoids, and both are arachidonic acid metabolites: anandamide (AEA) and 2-arachidonoylglyerol (2-AG) (structures below). The levels of these endocannabinoids in the body are regulated by specific biosynthetic pathways and the actions of degradative enzymes.
Cannabinoids function as extracellular signaling molecules through binding to and activating the CB receptors of the body and brain to trigger specific effects. For example, endocannabinoids may bind to the CB1 receptor in a spinal nerve to relieve pain while their binding to CB2 receptor in the immune system may occur as a response to an autoimmune disorder.
The ECS uses two key degradative enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). FAAH main function is to break down anandamide, while MAGL functions to break down 2-AG. These two enzymes can only degrade the endocannabinoids but are not capable of breaking down phytocannabinoids.
Since its discovery, the ECS has been shown to play vital roles in a wide variety of biological functions. Thus, any alteration or dysfunction in the ECS can potentially lead to multiple disorders and diseases. Recently, ECS has been targeted for the treatment of several diseases including neurodegenerative diseases (such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and MS) as well as cancer, obesity, inflammatory bowel disease and neuropathic pain. Studies have shown that compounds capable of activating the CB receptors can potentially provide treatments for many CB receptor-mediated diseases.
In addition, studies have demonstrated a potential clinical efficacy by several known CB1 and CB1/CB2 dual agonists in treating pain, glaucoma, depression, and GI disorders. However, a major drawback associated with some agonists was the occurrence of undesirable CB1-mediated CNS side effects such as dizziness, dry mouth, fatigue, muscle pain, and palpitations. Researchers were able to largely minimize these CNS side effects by the introduction of polar functional groups such as the carboxy group into the agonist molecules to restrict their blood-brain barrier permeability.
Consequently, there remains a need for the development of highly selective and potent CB1, CB2, and dual CB1/CB2 agonists for the treatment of the diseases and disorders modulated by the CB receptors. The compounds of formula 1 and/or formula 2 described in this patent application possess activities as agonists of either the CB1 receptor, CB2 receptor, or dual CB1/CB2 receptors. These compounds may potentially provide a therapy for the treatment of many diseases or disorders including but not limited to appetite, metabolism, diabetes, obesity, glaucoma associated intraocular pressure, mood disorders, seizures, cognition disorders, memory disorders, muscle spasm, respiratory disorders, locomotor activity disorders, immune disorders, inflammation, allergies and allergic reactions, pain, anxiety, gastrointestinal disorders, nausea, vomiting, cardiovascular disease, and dermatological disorders.
Key Structures
The inventors described the structures and synthesis of 50 examples of formula 1 and formula 2 including the following representative examples.
Biological Assay
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Assaying agonism of CB1 or CB2 by detection of cAMP using homogeneous time-resolved fluorescence (HTRF)
The inventors used Chinese Hamster Ovary K1 (CHO-K1) cells stably expressing the CB1 or the CB2 receptor in this assay to measure the CB1 and CB2 agonist activities of the invention compounds. CHO-K1 is an adherent cell line characterized by possessing fewer chromosomes than a typical mammalian cell and does not express the epidermal growth factor receptor (EGFR).
Biological Data
The results obtained from testing the above representing examples of formula 1 and formula 2 are listed in the following table.
“LA” denotes compounds with EC50 > 5 μM and/or %Emax < 50
“LA” denotes compounds with EC50 > 5 μM and/or %Emax < 50Recent Review Articles
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