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Synthesis of a bicyclic piperazine from l-aspartic acid and application of a fluoride-promoted SNAr coupling

The process development is reported of a pivotal C-N bond formation involving ((7R,9aS)-octahydro-1H-pyrido[1,2-a]pyrazin-7-yl)methanol (2) undergoing nucleophilic aromatic substitution with 3-chlorobenzo[d]isoxazole (3) to furnish ((7R,9aS)-2-(benzo[d]isoxazol-3-yl)octahydro-1H-pyrido[1,2-a] pyrazin-7-yl)methanol (4) as a key intermediate for a family of compounds (1). Essential to the success of the coupling is the use of fluoride in combination with a phase transfer catalyst. The development of an alternative route to bicyclic piperazine 2 that uses l-aspartic acid (20) as a starting material to avoid the need for a classical salt resolution is described.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Benzo[d]isoxazol-3-ol DAAO inhibitors

Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer”s disease, ataxia, or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutic amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof: wherein

  • Z1 is N or CR3;
  • Z2 is N or CR4;
  • Z3is O or S;
  • A is hydrogen, alkyl or M+; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof;
  • R1, R2, R3 and R4 are independently selected from hydrogen, alkyl, hydroxy alkoxy, aryl, acyl, halo, cyano, haloalkyl, NHCOOR5 and SO2NH2;
  • R5 is aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • at least one of R1, R2, R3 and R4 is other than hydrogen; and
  • at least one of Z1 and Z2 is other than N.

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    Reference£º
    Benzisoxazole – Wikipedia,
    Benzisoxazole – an overview | ScienceDirect Topics

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Discovery and structure-activity relationships of a novel series of benzopyran-based KATP openers for urge urinary incontinence

A novel series of benzopyran derivatives were synthesized and evaluated as KATP channel openers. Structure-activity relationships were investigated around 4-position of the benzopyran nucleus. Optimization of 4-substituent with some heterocyclic rings led to compound 13b bearing a benzo[d]isoxazol-3-one moiety as a potent and selective KATP channel opener in vitro. In two anesthetized rat models of myogenic bladder overactivity, compound 13b was found to inhibit spontaneous bladder contractions.

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Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

Extracurricular laboratory:new discovery of Benzo[d]isoxazol-3-ol

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Catalysts function by providing an alternate reaction mechanism that has a lower activation energy than would be found in the absence of the catalyst. In a patent, 21725-69-9, molecular formula is C7H5NO2, introducing its new discovery. Formula: C7H5NO2

SELECTIVE ANDROGEN RECEPTOR MODULATORS AND METHODS FOR THEIR IDENTIFICATION, DESIGN AND USE

Selective androgen receptor modulators (SARMs) having antagonist activity in hormone-dependent tumors while exhibiting no activity or agonist activity against other nontumor tissues containing the androgen receptor as well as methods for identifying, designing and using SARMs are provided.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Synthesis of an Optically Active Octahydro-2H-pyrido<1,2-a>pyrazine Based CNS Agent

A synthesis of an optically active octahydro-2H-pyrido<1,2-a>pyrazine is presented.The key sequence involved the equilibration of an optically active cis-aldehyde to give the thermodynamic transaldehyde that was trapped by nitromethane anion.

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Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Processes and intermediate compounds for the preparation of 2-(N,N-disubstituted) amino-4-(perfluoroalkyl)-1, 3- oxazin-6-one and 6-(perfluoroalkyl) uracil compounds

An improved process and intermediate compounds for the preparation of 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds having the structural formula I and an improved process for the preparation of 6-(perfluoroalkyl)uracil compounds having the structural formula V

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Selective [5 + 1] and [5 + 2] Cycloaddition of Ynamides or Propargyl Esters with Benzo[ d]isoxazoles via Gold Catalysis

Benzo[d]isoxazoles are found to act as novel nucleophiles to undergo gold-catalyzed [5 + 1] or [5 + 2] cycloaddition reactions with ynamides. The reaction provides a concise and chemoselective access to polysubstituted 2H-benzo[e][1,3]oxazines or benzo[f][1,4]oxazepines. In addition, benzo[d]isoxazoles can also react with gold-carbene intermediates derived from propargyl esters to afford [5 + 1] annulation products.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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METHOD FOR THE PREPARATION OF FUSED HETEROCYCLIC SUCCINIMIDE COMPOUNDS AND ANALOGS THEREOF

Fused cyclic compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Chromatography-free, Mitsunobu-triggered heterocyclizations of salicylhydroxamic acids to 3-hydroxybenzisoxazoles

The Mitsunobu reaction has become one of the most powerful tools to alkylate acidic pronucleophiles. A significant caveat of Mitsunobu chemistry, however, is that the reaction mixture is often plagued with purification problems owing to the phosphine oxide and hydrazine dicarboxylate by-products. In addition to the development of more readily separable Mitsunobu reagents, the product’s physicochemical properties may be exploited to facilitate purification. In this regard, we present a swift and efficient preparation of 3-hydroxybenzisoxazoles by the Mitsunobu-triggered heterocyclizations of salicylhydroxamic acids, which can be isolated by an acid?base work-up. As expected, a range of functional groups was compatible with the chemistry.

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Validation of tautomeric and protomeric binding modes by free energy calculations. A case study for the structure based optimization of d-amino acid oxidase inhibitors

Abstract: Optimization of fragment size d-amino acid oxidase (DAAO) inhibitors was investigated using a combination of computational and experimental methods. Retrospective free energy perturbation (FEP) calculations were performed for benzo[d]isoxazole derivatives, a series of known inhibitors with two potential binding modes derived from X-ray structures of other DAAO inhibitors. The good agreement between experimental and computed binding free energies in only one of the hypothesized binding modes strongly support this bioactive conformation. Then, a series of 1-H-indazol-3-ol derivatives formerly not described as DAAO inhibitors was investigated. Binding geometries could be reliably identified by structural similarity to benzo[d]isoxazole and other well characterized series and FEP calculations were performed for several tautomers of the deprotonated and protonated compounds since all these forms are potentially present owing to the experimental pKa values of representative compounds in the series. Deprotonated compounds are proposed to be the most important bound species owing to the significantly better agreement between their calculated and measured affinities compared to the protonated forms. FEP calculations were also used for the prediction of the affinities of compounds not previously tested as DAAO inhibitors and for a comparative structure?activity relationship study of the benzo[d]isoxazole and indazole series. Selected indazole derivatives were synthesized and their measured binding affinity towards DAAO was in good agreement with FEP predictions. Graphical Abstract: [Figure not available: see fulltext.].

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Reference£º
Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics