Muscarinic agonists and methods of use thereof

Abstract

A method of forming analogs of CDD- 0304, i.e., tetra(ethyleneglycol) (4-methoxy- 1,2,5-thiadiazol-3 -yl)[3 -(1 -methyl- 1.2,4,5-tetrahydropyrid-3 -yl)- 1,2,5-thiadiazol-4-yl]ether hydrochloride includes one or more of the following steps: a) replacing the tetrahydropyridine moiety with one of the following heterocyclic rings, including quinuclidine, [2.2.1]-exo- azabicycloheptane, [2.2.1]-endo-azabicycloheptane and terahydropyrimidine; b) varying the length of the linking group by replacing the tetra (ethylene) glycol moiety with one of: ethylene glycol, di(ethylene) glycol, penta(ethylene) glycol, or diether diol; and / or, c) replacing the 1,2,5-thiadiazole moiety with an ester isostere. Also, a method for an asymmetric analog CCD-0304 includes replacing at least one moiety with an ester isostere and at least a second moiety with an ammonium isostere. Also, such analogs compounds and their uses are disclosed.

Description

Background technique [0001] Schizophrenia is a mental disorder that afflicts approximately two million Americans. The annual societal cost for patient care is estimated to be about $23 billion per year in the United States alone. Approximately $2.3 billion was spent on antipsychotics in 1999, and the antipsychotic market is expected to grow to more than $6 billion in 2006. [0011] The underlying causes of schizophrenia are unknown, although unbalanced activity at dopamine synapses is thought to play a role in positive symptoms such as hallucinations, delusions, and abnormal thought patterns 1，2 . For many years, dopamine antagonists such as haloperidol and chlorpromazine have been widely used in the treatment of schizophrenia. Unfortunately, many classic antipsychotic compounds produce undesired side effects such as Parkinson's syndrome, acute dystonia and akathisia. Side effects are primarily due to blockade of dopamine (D2) receptors, although many antipsychotic compoun...

AI Technical Summary

Problems solved by technology

Unfortunately, xanomeline produces undesired and M 3 Side effects associated with receptor activation, including hypersalivation, diarrhea, and profuse sweating, which limit patient compliance 10

Side effects appear to be related to rapid metabolism of alkoxy side chains after oral administration, leading to non-selectivity and thus limited utility of active compounds

Xanomeline's disadvantages outweigh its advantages despite second phase II trial with patch composition

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