2-Benzopyran-3-ones stabilised by alkoxy substituents

Bradshaw, David P.; Jones, David W.; Tideswell, John

doi:10.1039/p19910000169

Cited by 10 publications

(5 citation statements)

References 8 publications

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“…The introduction of the benzoyl side chain on ester 4 can be envisioned by using Friedel-Crafts alkylation conditions. This has been reported repeatedly, [9][10][11][12] but in most cases, the cited yield of 5 is only moderate (31-48 %), [9][10][11] and we obtained similar results by using standard reaction conditions. One report by De Sarro et al [12] describes this Friedel-Crafts reaction to give 81 % yield.…”

Section: Chemistrysupporting

confidence: 91%

Optimized Synthesis of AMPA Receptor Antagonist ZK 187638 and Neurobehavioral Activity in a Mouse Model of Neuronal Ceroid Lipofuscinosis

Elger¹,

Schneider²,

Winter

et al. 2006

ChemMedChem

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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.

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Section: Chemistrysupporting

confidence: 91%

Optimized Synthesis of AMPA Receptor Antagonist ZK 187638 and Neurobehavioral Activity in a Mouse Model of Neuronal Ceroid Lipofuscinosis

Elger¹,

Schneider²,

Winter

et al. 2006

ChemMedChem

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“…As outlined in Scheme , reaction of 3,4-(methylenedioxy)phenylacetic acid ( 7 ) with methanol in the presence of sulfuric acid provided the corresponding methyl ester 8 in 86% yield. Friedel−Crafts acylation of 8 with various acyl chlorides 4-R-PhCOCl (R = a , H; b , CH 3 ; c , OCH 3 ; d , F) with SnCl 4 as the catalyst in CH 2 Cl 2 furnished 9a − d in 18−63% yields . Compounds 9a − d were refluxed with hydrazine hydrate in ethanol or propanol to afford the 2,3-benzodiazepin-4-ones 10a − d in 24−52% yields …”

Section: Chemistrymentioning

confidence: 99%

“…Friedel-Crafts acylation of 8 with various acyl chlorides 4-R-PhCOCl (R ) a, H; b, CH 3 ; c, OCH 3 ; d, F) with SnCl 4 as the catalyst in CH 2 Cl 2 furnished 9a-d in 18-63% yields. 15 Compounds 9a-d were refluxed with hydrazine hydrate in ethanol or propanol to afford the 2,3-benzodiazepin-4-ones 10a-d in 24-52% yields. 16 Reaction of ester 8 with 4-nitrobenzoyl chloride under the same conditions, however, did not give the desired compound 9e, and the starting material 8 was recovered.…”

Section: Chemistrymentioning

confidence: 99%

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

Wang¹,

Konkoy²,

Ilyin³

et al. 1998

J. Med. Chem.

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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 alpha-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 microM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 microM. 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 microM) and weak anticonvulsant (ED50 >10 mg/kg iv). The benzodiazepinones described herein are potent noncompetitive AMPA receptor antagonists that could have therapeutic potential as anticonvulsants and neuroprotectants.

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“…Stirring was continued for 5 min, and the chromium salts were removed by suction filtration and washed with acetone. The filtrate was evaporated to dryness, treated with 100 mL of water, and filtered off to obtain 4,5-methylenedioxy-2-benzoylphenylacetic acid ( 8a , 16.98 g, 81%) as ochre crystals (mp 181.2 °C; lit . 182−184 °C).…”

Section: Methodsmentioning

confidence: 99%

“…The organic layer was washed, dried, filtered, and concentrated to dryness. The residue was triturated with a mixture of ethyl acetate and hexane to obtain 5-phenyl-8-methyl-11H-1,3-dioxolo [4,5- (17,258 mg, 77% in 2 batches (mp 214.3 °C). 1 H NMR (DMSO), δ: 2.3 (s, 3H), 3.9 (s, 2H), 6.1 (s, 2H), 6.6 (s, 1H), 6.65 (s, 1H), 7.2 (s, 1H), 7.5 (m, 3H), 7.7 (m, 2H).…”

Section: -Phenyl-8-methyl-11h-13-dioxolo[45-h]imidazo[12c][23]benzodi...mentioning

confidence: 99%

Novel α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA) Receptor Antagonists of 2,3-Benzodiazepine Type: Chemical Synthesis, in Vitro Characterization, and in Vivo Prevention of Acute Neurodegeneration

et al. 2005

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Under pathophysiological conditions, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor activation is considered to play a key role in several disorders of the central nervous system. In the search for AMPA receptor antagonists, the synthesis and pharmacological characterization of a series of novel compounds that are structurally related to GYKI 52466 (1), a well-known selective noncompetitive AMPA receptor antagonist, was performed. In vitro, 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638, 14a) antagonized the kainate-induced currents in cultured hippocampal neurons with an IC(50) of 3.4 microM in a noncompetitive fashion. When tested in a clinically predictive rat model of acute ischemic stroke, this noncompetitive AMPA receptor antagonist significantly reduced brain infarction, indicating that it is neuroprotective after permanent focal cerebral ischemia.

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2-Benzopyran-3-ones stabilised by alkoxy substituents

Cited by 10 publications

References 8 publications

Optimized Synthesis of AMPA Receptor Antagonist ZK 187638 and Neurobehavioral Activity in a Mouse Model of Neuronal Ceroid Lipofuscinosis

Optimized Synthesis of AMPA Receptor Antagonist ZK 187638 and Neurobehavioral Activity in a Mouse Model of Neuronal Ceroid Lipofuscinosis

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

Novel α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA) Receptor Antagonists of 2,3-Benzodiazepine Type: Chemical Synthesis, in Vitro Characterization, and in Vivo Prevention of Acute Neurodegeneration

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