Long-acting muscarinic M3 receptor antagonists

A series of 10 closely related patent applications define Theravance's approach to the development of long-acting M(3) selective antagonists for the treatment of chronic obstructive pulmonary disease. The applications illustrate a modular approach to the design of such agents, comprising a muscarinic pharmacophore attached to a second, less functionalised moiety via a variable length spacer incorporating heteroatoms. Eight of the applications utilise a a 4-piperidinylester of biphenylcarbamic acid as the muscarinic pharmacophore and two utilise 2,2-diphenyl-2-(S)-pyrrolidin-3-ylacetamide. The first group of eight applications encompasses the use of two tail groups and four different sets of linking groups, whereas the second uses two very different tail groups and different spacers.