Pyrans and their Benzo Derivatives - Synthesis

Previous structure-activity relationship studies in the search for a potent, noncompetitive alpha-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist led to 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638). However, the first synthesis had some drawbacks regarding reagents, processes, and overall yield, which furthermore decreased when the synthesis was scaled up. Therefore, we now report a new synthetic route for this compound which requires fewer steps and is suited for large-scale production. This compound significantly relieved the symptoms of neuromuscular deficit in mnd mice, a model of neuronal ceroid lipofuscinosis with motor neuron dysfunction. After oral administration, the concentrations of the compound in the brain and spinal cord were about threefold higher than those in the plasma. In summary, this novel AMPA antagonist is accessible through an optimized synthetic route, has good neurobehavioral activity, oral bioavailability, and favorable brain penetration. This opens new possibilities for the treatment of devastating neurological diseases that are mediated by the AMPA receptor.

Optimized synthesis of AMPA receptor antagonist ZK 187638 and neurobehavioral activity in a mouse model of neuronal ceroid lipofuscinosis.

A group of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones was synthesized and assayed for antagonism of rat brain α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus oocytes. The benzodiazepinones inhibited AMPA-activated membrane current responses in a manner consistent with noncompetitive, allosteric inhibition of the receptor−channel complex. The most potent compound in the series was 1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5-dihydro-4H-2,3-benzodiazepin-4-one (6), which had an IC50 of 2.7 μM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 μM. Compound 6 also had potent anticonvulsant activity in a mouse maximum electroshock-induced seizure (MES) assay:  the ED50 was 2.8 mg/kg iv, whereas the ED50 for GYKI 52466 was 4.6 mg/kg iv. In contrast to a previous report, the 7,8-dimethoxy analogue of 6 was a low-potency AMPA antagonist (IC50 >100 μM) and weak anticonvulsant (ED50 >10 mg/kg iv). The benzodiazepinones descri...

Synthesis of 7,8-(Methylenedioxy)-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin- 4-ones as Novel and Potent Noncompetitive AMPA Receptor Antagonists

Total synthesis of the proposed structure of yuremamine has been achieved for the first time based on the intermolecular [3+2]-cycloaddition reaction of the platinum-containing azomethine ylide. All the possible diastereomers of yuremamine were also synthesized via the common intermediate. Through these syntheses, it was confirmed that the proposed structure of yuremamine and the diastereomers differ from the natural product.

Total Synthesis of Proposed Structure of Yuremamine and All Diastereomers Using [3+2]-Cycloaddition of Platinum-Containing Azomethine Ylide.

Pyrans and their Benzo Derivatives - Structure

5,6-Dimethoxy-1,3-diphenylinde-2-one 4 and 5,6-dimethoxy-1,3-di-o-tolylinden-2-one 5 have been generated by dehydrobromination of 1-bromo-5,6-dimethoxy-1,3-diarylindan-2-ones. They appear more stable than the corresponding inden-2-ones lacking methoxyl substituents. In particular, 5 fails to dimerise at 20 °C whereas other known inden-2-ones dimerise even at low temperature. 6,7-Dimethoxy-1,4-diphenyl-2,3-naphthoquinone 8 generated by lead tetraacetate oxidation of the corresponding dihydroxynaphthalene appears less persistent than the corresponding quinone lacking methoxyl substituents, perhaps because of easier reaction with the lead tetraacetate.

Stability of alkoxy-substituted inden-2-ones and 6,7-dimethoxy-1,4-diphenyl-2,3-naphthoquinone

In contrast to the corresponding compounds lacking alkoxy substituents, the 2-benzopyran-3-ones 5, 6, 7 and 9 are stable and easily isolated. In contrast to the 6-methoxy derivative 7, the 7-methoxy isomer 8 cannot be isolated; the stabilising effect of the 6,7-methylenedioxy group in 5 and 9 is therefore due to the alkoxy group at C-6. This is consistent with a donor-acceptor interaction involving the C-6 alkoxy group and the pyrone carbonyl which decreases reactivity towards nucleophilic attack by water.

David P. Bradshaw

Papers

Stability of alkoxy-substituted inden-2-ones and 6,7-dimethoxy-1,4-diphenyl-2,3-naphthoquinone

2-Benzopyran-3-ones stabilised by alkoxy substituents

2‐Benzopyran‐3‐ones Stabilised by Alkoxy Substituents.

Stability of Alkoxy-Substituted Inden-2-ones and 6,7-Dimethoxy-1,4- diphenyl-2,3-naphthoquinone.