Synthesis of 3-Oxo-2,3-Dihydroisoquinolines from Ethyl 2-Acylphenylacetates and Formamides

Venkov, Atanas P.; Ivanov, Iliyan

doi:10.1080/00397919408011710

Cited by 14 publications

(9 citation statements)

References 6 publications

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“…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. Since it was reported that P 2 O 5 can effect Friedel-Crafts reaction of acids with aromatic compounds, 17 ester 8 was refluxed with 4-nitrobenzoic acid in ClCH 2 CH 2 Cl in the presence of P 2 O 5 to provide 9e in 50% yield. 2,3-Benzodiazepin-4-one 10e was obtained by refluxing 9e with hydrazine in ethanol.…”

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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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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“…The capability of 3c, 4b, and 5c to antagonize KA-evoked current was tested and compared with that of parent compounds 1 and 2. Chemistry 2,3-Benzodiazepines 3d,e, used as starting material, were prepared via Friedel-Crafts acylation of methyl 3,4-methylenedioxyphenylacetate with 3-or 4-nitrobenzoic acid, following a methodology previously reported, 13 and subsequently reacted with an excess of hydrazine. These intermediates were then treated with an excess of the appropriate alkyl isocyanate in the presence of triethylamine to yield the corresponding N-3-alkylcarbamoyl derivatives, which were then transformed into final derivatives 4a-h (Scheme 1) by a catalytic reduction of their nitro group.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticonvulsant Activity of Novel and Potent 2,3-Benzodiazepine AMPA/Kainate Receptor Antagonists

Grasso¹,

G²,

A³

et al. 1999

J. Med. Chem.

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We have previously shown that 1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (3) possess marked anticonvulsant properties and antagonize seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) in analogy to the structurally related 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA/kainate receptor antagonist. We now report the synthesis of 3-(N-alkylcarbamoyl)-1-aryl-3,5-dihydro-7, 8-methylenedioxy-4H-2,3-benzodiazepin-4-ones (4a-h) and 1-aryl-3, 5-dihydro-7,8-methylenedioxy-4H-2,3-benzodiazepine-4-thiones (5a-c). The activity of all compounds, intraperitoneally (ip) injected, was evaluated against audiogenic seizures in DBA/2 mice and against seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in Swiss mice. Some of the new compounds 4 and 5 showed remarkable anticonvulsant activity, and their toxicity, as evidenced by the rotarod test, is lower than that of 1. The time course of anticonvulsant activity of derivatives 4b and 5b,c was studied and compared to that of 1 and 3b,c. Compounds 4a,b and 5a-c antagonize seizures induced by AMPA and kainate (KA) and their anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 3c, 4b, and 5c to antagonize KA-evoked currents in primary cultures of granule neurons was tested and compared with that of the parent compounds 1 and 1-(4-aminophenyl)-3, 4-dihydro-4-methyl-3-methylcarbamoyl-7,8-methylenedioxy-5H-2, 3-benzodiazepine (2, GYKI 53655).

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“…2-[(3,4,-Dimethoxyphenyl)acetyl]-4,5-dimethoxyphenylacetic acid 4, synthesized from self-condensation of 3,4-dimethoxyphenylacetic acid 3 in polyphosphoric acid (PPA), was subjected to a cyclization with ammonium acetate in refluxing acetic acid to give 1-(3,4dimethoxybenzyl)-3-hydroxy-6,7-dimethoxyisoquinoline 5 according to a reported protocol. 12 Oxidation of compound 5 with selenium dioxide in dioxane or acetic acid gave the corresponding ketone 6, but in low yield (16%). We also tried a direct oxidation of papaverine with vanadium pentoxide as reported 13 Isoquinoline analogues 14a-d were also synthesized from D,L-(3,4-dihydroxyphenyl)alanine and 3,4-methylenedioxyphenyl-, 2,4-dichlorophenyl-, 1-naphthyl-, or 2-naphthylacetic acid, respectively, according to a procedure similar to that described in Scheme 3.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a Series of Nonpeptide Small Molecules That Inhibit the Binding of Insulin-like Growth Factor (IGF) to IGF-Binding Proteins

et al. 2001

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Insulin-like growth factors (IGF-I and II) play an important role in metabolic and mitogenic activities through stimulation of the IGF-I receptor on the cell surface. Although the concentration of IGF in blood and cerebrospinal fluid is quite high (>100 nM), this large pool of IGF is biologically inactive because of its association with six distinct binding proteins, which form high-affinity complexes with IGF. Thus, inhibitors of IGF-binding proteins (IGFBPs), especially IGFBP-3, could potentially alter the distribution between the "free" and "bound" forms of IGF and thereby elevate biologically active IGF-I to exert a beneficial effect on those patients with diseases that respond to the application of exogenous IGF-I. Whereas IGF-I peptide variants, which bind to IGFBPs but not the IGF-I receptor, have been shown to be potent IGF/IGFBP inhibitors, small molecule nonpeptide IGF/IGFBP inhibitors have the potential advantages of oral bioavailability and flexible dosing regimen. Here we report the discovery of several isoquinoline analogues, exemplified by 1 and 2, which bind IGFBP-3 as well as other IGFBPs at low nanomolar concentrations. More importantly, both compounds were shown to be able to release biologically active IGF-I from the IGF-I/IGFBP-3 complex. These results point to the feasibility of developing orally active therapeutics to treat IGF-responsive diseases by optimization of the lead molecules 1 and 2.

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Synthesis of 3-Oxo-2,3-Dihydroisoquinolines from Ethyl 2-Acylphenylacetates and Formamides

Cited by 14 publications

References 6 publications

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

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

Synthesis and Anticonvulsant Activity of Novel and Potent 2,3-Benzodiazepine AMPA/Kainate Receptor Antagonists

Discovery of a Series of Nonpeptide Small Molecules That Inhibit the Binding of Insulin-like Growth Factor (IGF) to IGF-Binding Proteins

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