ChemInform Abstract: A MODIFIED METHOD FOR THE SYNTHESIS OF 1,2‐BENZISOXAZOLES

Thakar, K. A.; Goswami, D. D.; Bhawal, B. M.

doi:10.1002/chin.197816193

Cited by 2 publications

(6 citation statements)

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“…Starting 3-methyl-l,2-benzisoxazoles 2a-m were prepared according to the method of Thakar et al 16 or as described in Scheme 1. Known 4-acetamido-2-hydroxy-acetophenone17 was converted via the oxime, oxime acetate, and pyridine-mediated cyclization16 to the required IV-acetyl benzisoxazole 2g.…”

Section: Chemistrymentioning

confidence: 99%

“…Hydrolysis of In with powdered KOH in £er£-butyl alcohol20 gave the primary carboxamide lo. °Reagents: (a) 48% aqueous HBr, 110 °C, 16 h; (b) 1 N HC1, reflux, 30 min; (c) aqueous HC1, NaN02, CuCN, 0 -50 °C, 2.5 h; (d) KOH, t-BuOH, 85 °C, 20 min.…”

Section: Chemistrymentioning

confidence: 99%

“…Furthermore, a strategy was envisioned in which the novel prototypes would be devoid of chiral centers that could undergo facile racemization. E-2020 has been tested as a mixture of enantiomers, presumably due to the ease of racemization of the chiral a-keto 0022-2623/94/1837-2721$04.50/0 © 1994 American Chemical Society a Reagents: (a) NH20H*HC1, Na0Ac-3H20, EtOH, H20, reflux, 2 h; (b) Ac20, reflux, 2 min; (c) pyr, reflux, 12 h; (d) 1 N HC1, reflux, 45 min; (e) PhCOCl, EtsN, DMAP, CH2C12, room temperature, 16 h; (f) PhS02Cl, pyr, CH2C12, 0 °C, 1.3 h; (g) [Br(CH2)2]20, Et(i-Pr)2N, PhMe, reflux, 15 h. center at physiological pH. Our attention turned to a series of heterocyclic substitutions which resulted in the identification of the benzisoxazole ring (la, Figure 1) as a suitable benzoyl bioisostere.…”

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confidence: 99%

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Novel Benzisoxazole Derivatives as Potent and Selective Inhibitors of Acetylcholinesterase

Villalobos¹,

Blake²,

Biggers³

et al. 1994

J. Med. Chem.

109

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A series of N-benzylpiperidine benzisoxazoles has been developed as potent and selective inhibitors of the enzyme acetylcholinesterase (AChE). The benzisoxazole heterocycle was found to be an appropriate bioisosteric replacement for the benzoyl functionality present in the N-benzylpiperidine class of inhibitors. The title compounds were synthesized by alkylating 3-methyl-1,2-benzisoxazoles with an iodo piperidine derivatives as the key step. Benzisoxazoles 1b-j,o displayed potent inhibition of AChE in vitro with IC50's = 0.8-14 nM. Particularly interesting were N-acetyl and morpholino derivatives 1g (IC50 = 3 nM) and 1j (IC50 = 0.8 nM), respectively, which displayed outstanding selectivity for acetyl-over butyrylcholinesterase, in excess of 3 orders of magnitude. N-Acetyl 1g also displayed a favorable profile in vivo. This analog showed a dose-dependent elevation of total acetylcholine in mouse forebrain after oral administration with an ED50 = 2.4 mg/kg. In addition, 1g was able to reverse amnesia in a mouse passive avoidance model at doses of 3.2 and 5.6 mg/kg with an average reversal of 89.7%. Molecular dynamics simulations were used to study the possible binding modes of N-benzylpiperidine benzisoxazoles to AChE from Torpedo californica. Key structural insights were obtained regarding the potency of this class of inhibitors. Specifically, Asp-72, Trp-84, Trp-279, Phe-288, and Phe-330 are implicated in the binding of these inhibitors. The N-benzylpiperidine benzisoxazoles may be suitable compounds for the palliative treatment of Alzheimer's Disease.

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Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

mentioning

confidence: 99%

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Novel Benzisoxazole Derivatives as Potent and Selective Inhibitors of Acetylcholinesterase

Villalobos¹,

Blake²,

Biggers³

et al. 1994

J. Med. Chem.

109

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“…Melting points were recorded on a Buchi B 540 melting point apparatus and mass spectra were recorded on a GCMS-QP 5050A Shimadzu GC MS instrument. 3-Methyl-1,2-benzisoxazole was prepared by a reported procedure 3 from o-hydroxy aceto phenone. * Correspondent.…”

Section: Methodsmentioning

confidence: 99%

“…In continuation of our work in the synthesis of new entities for anti-inflammatory agents we needed to develop a convenient method for the preparation of 1,2-benzisoxazole-3-carboxaldehyde derivatives from 3-methyl-1,2-benzisoxazole which is easily made by reported procedures. 3,4 Here we report a simple and convenient method for the preparation of 1,2-benzisoxazole-3-carboxaldehyde (1) from 3-methyl-1,2-benzisoxazole (2) via 3-ethoxymethyl-1, 2-benz isoxazole (4) (Scheme 1).…”

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confidence: 99%