Cholinergic muscarinic receptors are members of the G-protein coupled receptor super-family and are further divided into 5 subtypes, M1 to M5. Muscarinic receptor sub-types are widely and differentially expressed in the body. Genes have been cloned for all 5 sub-types and of these, M1, M2 and M3 receptors have been extensively pharmacologically characterized in animal and human tissue. M1 receptors are expressed in the brain (cortex and hippocampus), glands and in the ganglia of sympathetic and parasympathetic nerves. M2 receptors are expressed in the heart, hindbrain, smooth muscle and in the synapses of the autonomic nervous system. M3 receptors are expressed in the brain, glands and smooth muscle. In the airways, stimulation of M3 receptors evokes contraction of airway smooth muscle leading to bronchoconstriction, while in the salivary gland M3 receptor stimulation increases fluid and mucus secretion leading to increased salivation. M2 receptors expressed on smooth muscle are understood to be pro-contractile while pre-synaptic M2 receptors modulate acetylcholine release from parasympathetic nerves. Stimulation of M2 receptors expressed in the heart produces bradycardia.
Short and long-acting muscarinic antagonists are used in the management of asthma and COPD; these include the short acting agents Atrovent® (ipratropium bromide) and Oxivent® (oxitropium bromide) and the long acting agent Spiriva® (tiotropium bromide). These compounds produce bronchodilation following inhaled administration. In addition to improvements in spirometric values, anti-muscarinic use in chronic obstructive pulmonary disease (COPD) is associated with improvements in health status and quality of life scores.
As a consequence of the wide distribution of muscarinic receptors in the body, significant systemic exposure to muscarinic antagonists is associated with effects such as dry mouth, constipation, mydriasis, urinary retention (all predominantly mediated via blockade of M3 receptors) and tachycardia (mediated by blockade of M2 receptors). A commonly reported side-effect following inhaled administration of therapeutic dose of the current, clinically used non-selective muscarinic antagonists is dry-mouth and while this is reported as only mild in intensity it does limit the dose of inhaled agent given.
Accordingly, there is still a need for improved M3 receptor antagonists that would have an appropriate pharmacological profile, for example in term of potency, pharmacokinetics or duration of action. In this context, the present invention relates to novel M3 receptor antagonists. In particular, there is a need for M3 receptor antagonists that would have a pharmacological profile suitable for an administration by the inhalation route.
The scientific literature discloses many compounds having a muscarinic receptor antagonist activity. As a matter of example, EP0948964A1 discloses compounds of formula
in which R denotes a hydrogen atom, a halogen atom or a lower alkoxy group.