Important Compound Classes
Title
Thienopyrimidones as TRPA1 Inhibitors
Patent Publication Number
WO 2021/074196 A1
Publication Date
April 22, 2021
Priority Application
EP 19203171.4
Priority Date
October 15, 2019
Inventors
Fleck, M. T.; Binder, F. P. C.; Dahmann, G.; Hehn, J. P.; Heimann, A.C.; Willwacher, J.
Assignee Company
Boehringer Ingelheim International Gmbh [DE/DE]; Binger Strasse 173, 55216 Ingelheim Am Rhein (DE)
Disease Area
Fibrotic diseases, inflammatory and autoimmune diseases, and CNS-related diseases
Biological Target
Transient receptor potential cation channel, subfamily A, member 1 (TRPA1), also known as transient receptor potential ankyrin 1
Summary
The invention in this patent application relates to thienopyrimidinone derivatives represented generally by formula 1. These compounds are inhibitors of TRPAl and may be useful for the treatment and/or prevention of pain such as neuropathic pain, dysesthesia, allodynia and migraine, cough, pulmonary fibrotic diseases, and inflammatory and autoimmune diseases.
Transient receptor potential channels (TRP channels) are a family of integral membrane proteins that are located mostly on the plasma membrane of numerous mammalian cell types and function as voltage-gated ion channels. Researchers have identified approximately 30 family members of structurally related TRP channels. They are sorted into subfamilies including the ankyrin TRP (TRPA), the canonical TRP (TRPC), the melastatin-related TRP (TRPM), the mucolipin TRP (TRPML), the no mechanoreceptor TRP (TRPN), the polycystic TRP (TRPP), and the vanilloid TRP (TRPV).
The members of the TRP superfamilies are a class of cationic channels that act as signal transducer by altering membrane potential or intracellular calcium ion (Ca2+) concentration. They play a key role in interpreting environmental stimuli and several studies have shown them to be involved in various physiological and pathophysiological processes such as pain, inflammation, metabolism, swallowing function, gut motility, thermoregulation, and adipogenesis
The ankyrin TRP subfamily (TRPA) contains a sole member known as TRP ankyrin 1 (TRPAl). The TRPA channel is characterized by multiple ankyrin repeats at the N-terminal (∼14 in the N-terminus of human TRPAl).
TRPAl is a nonselective cation channel, which is highly expressed in the plasma membrane of nociceptive sensory neurons in the dorsal root and nodose ganglia that serve both skin and lung. It is also expressed in small intestine, colon, pancreas, skeletal muscle, heart, brain, bladder, and lymphocytes as well as in lung fibroblasts. TRPA1 is a sensory nerve receptor for environmental irritants including a wide range of chemical irritants that cause somatosensory modalities such as pain, cold and itch. For example, it is activated by electrophilic chemical substances such as allyl isothiocyanate (pungent active ingredient in mustard oil, horseradish, and wasabi), cinnamaldehyde (in cinnamon) and allicin (in garlic). It can also be activated by nonelectrophilic substances such as icilin. TRPA1 has been linked to airway irritation resulting from exposure to environmental irritants such as cigarette smoke and cleaning supplies. TRPA1 has been implicated in cough associated with asthma, chronic pulmonary obstructive disease (COPD), idiopathic pulmonary fibrosis (IPF), or postviral cough or for chronic idiopathic cough as well as cough in sensitive patients.
Aberrant sensory functions of TRPA1 were implicated in a wide variety of diseases such as acute neuropathic and inflammatory pains. For example, N855S is a gain-of-function mutation in TRPA1 that was associated with the rare familial episodic pain syndrome. Other mutations have been linked to altered chemosensation.
Studies have identified TRPA1 as a therapeutic target for the treatment of multiple diseases and disorders. The following is a summary of some of the findings of these studies:
Numerous chemically diverse pronociceptive agonists can activate the TRPA1 pathway, which induces pain and inflammation. Thus, the use of TRPA1 antagonists promises a potentially superior pain treatment compared to drugs targeting single nociceptive signaling pathways.
Studies using experimental models of pathophysiological pain showed that blocking TRPA1 attenuates mechanical and cold pain hypersensitivity with little or no side effects.
TRPA1 is mainly located in nociceptive neurons of the peripheral nervous system (PNS); it is also found at different sites of the central nervous system (CNS). TRPA1 antagonists acting on the peripheral nervous system may be optimal for attenuating primary hyperalgesia (such as inflammation-induced sensitization of peripheral nerve terminals). On the other hand, TRPA1 antagonists acting on the central nervous system may better attenuate pain conditions in which central amplification of transmission plays a role (such as secondary hyperalgesia and tactile allodynia caused by various types of peripheral injuries).
TRPA1 inhibitors are useful in the treatment of idiopathic pulmonary fibrosis (IPF) in which cough is highly prevalent because of the link between cough and lung injury.
TRPA1 is a major contributor to the migraine pathway and has emerged as a novel target for the treatment of pain and migraine. A TRPA1 antagonist was effective in a behavioral model of migraine-related allodynia.
Several anesthetics such as the general anesthetic isoflurane are known to be TRPA1 agonists, which may give a rationale for the use of TRPA1 inhibitors to relief postsurgical pain.
Prolonged blocking of TRPA1 in an experimental model of peripheral diabetic neuropathy has resulted in delaying the loss of nociceptive nerve endings and their function. Thus, TRPA1 inhibitors may be beneficial in the treatment of diabetic neuropathy.
Reduction in myelin damage was associated with either TRPA1 knockout or the use of TRPA1 antagonists in a mouse brain ischemia model.
Reductions in urate crystals and joint inflammation were observed in TRPA1 knockout mice in a monosodium urate mouse model of gout.
A study using a rat model of acute gout flares showed that deletion of TRPA1 in rats ameliorated joint inflammation and hyperalgesia.
The activation of TRPAl caused an inflammatory response in osteoarthritic chondrocytes. On the other hand, the inhibition and genetic deletion of TRPA1 reduced inflammatory mediators in osteoarthritic mouse chondrocytes and murine cartilage.
TRPAl receptor modulation attenuates bladder overactivity in a rat model of spinal cord injury and intrathecal administration of TRPA1 antagonists attenuate cyclophosphamide-induced cystitis in rats with hyperreflexia micturition.
These findings have validated TRPA1 as a therapeutic target to satisfy a highly unmet medical need for the treatment of disorders related to activation of this channel. It is therefore desirable to discover and develop potent TRPAl inhibitors. The compounds of formula 1 described in this patent application are inhibitors of TRPAl and may be useful for treatment and/or prevention of pain such as neuropathic pain, dysesthesia, allodynia and migraine, cough, pulmonary fibrotic diseases, and inflammatory and autoimmune diseases.
Key Structures
The inventors described the structures
and methods of synthesis of 16 examples of formula 1 including the
examples shown below:
Biological Assay
Assay A: TRPA1 assay
Assay B: Microsomal clearance
Assay C: Hepatocyte clearance
Biological Data
The biological data obtained from testing
the above representative examples are presented in the following table.
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The author declares no competing financial interest.