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Cycloelimination-assisted combinatorial synthesis of diverse heterocyclic scaffolds of chemotherapeutic values

Recent advances in high-throughput, automated techniques combined with the identification of new therapeutic targets in genome sequencing and molecular biology have generated a need for a large collection of diverse heterocyclic scaffolds. This inspires toward the development of novel reaction sequences and linking strategies to generate libraries of diverse simple to complex heterocyclic systems. In this regard, combinatorial chemistry has emerged as an excellent technology platform for the rapid assembly of building blocks to synthesize complex molecular structures with great ease in a few synthetic steps. By means of the implementation of high-throughput screening for the biological evaluation of hits and leads, combinatorial libraries have become important assets in drug discovery and development. In the last two decades, the cyclorelease strategy that minimizes the chemical and tethering implications by releasing the intact desired target molecule in the final step of reaction has attracted much attention. Recently, a particular interest is developing in linking strategies, where loading and cleavage steps contribute to the complexity of the target structure rather than only extraneous manipulations. This review summarises the practical and high-yielding approaches of solid phase combinatorial synthesis for diverse high-purity heterocyclic skeletons of pharmacological importance involving the cycloelimination strategy.

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

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1-PHENYL-SUBSTITUTED HETEROCYCLYL DERIVATIVES AND THEIR USE AS PROSTAGLANDIN D2 RECEPTOR MODULATORS

The present invention relates to 1-phenyl-substituted heterocyclyl derivatives of the formula (I), O Y R5 R6 N R2 R3 R4 X Z R1 R7 R7 R10 n (I) 5 wherein X, Y,Z,n,R1, R2, R3, R4, R5, R6, R7 and R10 are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D 2 receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.10

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

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Preparation of 2-hydroxybenzamidines from 3-aminobenzisoxazoles

2-Hydroxybenzamidines have been prepared from 3-aminobenzisoxazoles by reductive cleavage of the nitrogen-oxygen bond using catalytic hydrogenation, Zn/AcOH or NiCl2/NaBH4. This ring-opening reaction can be accomplished chemoselectively in the presence of a variety of hydrogenation-sensitive functional groups including an aryl bromide, benzyl carbamate, and olefin.

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Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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HEPATITIS C VIRUS INHIBITORS

The present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which inhibit the function of the NS3 protease (also referred to herein as “serine protease”) encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS3 protease. ”

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

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Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility.

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

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PIPERIDINE/CYCLOHEXANE CARBOXAMIDE DERIVATIVES FOR USE AS VANILLOID RECEPTOR MODULATORS

Certain compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, P, P”, X, m and n are as defined in the specification, a process for preparing such compounds, a pharmaceutical composition comprising such compounds and the use of such compounds in medicine, as vanilloid receptor modulators.

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

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1,2-Benzisoxazol-3-yl Diphenyl Phosphate: A New, Reactive Activating Agent for the Synthesis of Amides, Esters, and Peptides via Condensation

A new activating agent for condensations, 1,2-benzisoxazol-3-yl diphenyl phosphate (1), was readily prepared in high yield by the reaction of 1,2-benzisoxazol-3-ol (2) with diphenyl phosphorochloridate (3) in the presence of triethylamine in benzene.The reaction of the carboxylic acids with the amines in the presence of 1 was investigated by two procedures, a two-step method and a one-step procedure.Both methods gave the corresponding amides and esters in high yields under mild conditions, but the one-step procedure was found to be superior to the two-step procedure because of its simplicity and speed.Furthermore, the activating agent 1 was shown to be a useful peptide forming reagent.

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

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(S)-3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2-(piperazin-1-yl)propanoic acid compounds: Synthesis and biological evaluation of dual PPARalpha/gamma agonists

A series of novel, potent PPARalpha/gamma dual agonists were synthesized and appraised. The most potent analogue, compound 2b demonstrated EC50 value of 0.012 ¡À 0.002 and 0.032 ¡À 0.01 muM, respectively, for hPPARalpha and hPPARgamma in transactivation assay. Additionally, compound 2b demonstrated good glucose and lipid lowering effect in genetic diabetic (db/db) mice.

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Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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Synthesis and Biological Evaluation of 1-(1,2-Benzisothiazol-3-yl)- and (1,2-Benzisoxazol-3-yl)piperazine Derivatives as Potential Antipsychotic Agents

Members of the series of title compounds were tested for potential antipsychotic activity in relevant receptor binding assays and behavioral screens.Structure-activity relationships within the series are discussed.Compound 24 (BMY 13859-1), a (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further study because of its potent and selective profile in primary CNS tests.It was active in the Sidman avoidance paradigm and blocked amphetamine-induced stereotyped behavior in dogs for up to 7 h.The compound’s lack of typical neuroleptic-like effects in therat catalepsy test and its failure to produce dopamine receptor supersensitivity following chronic administration indicate that it should not cause the movement disorders commonly associated with antipsychotic therapy.Although 24 has potent affinity for dopaminergic binding sites, its even greater affinity for serotonin receptors suggests that a serotonergic component may be relevant to its atypical profile.Compound 24 is currently undergoing clinical evaluation in schizophrenic patients.

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Benzisoxazole – Wikipedia,
Benzisoxazole – an overview | ScienceDirect Topics

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TRICYCLIC DELTA-3-PIPERIDINES AS ALPHA2- ANTAGONISTS

The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Alk is C 1-6alkanediyl; n is 1 or 2; X 1is–O–,–S–,–S(=O)–or–S(=O) 2–; each R 1is independently hydrogen, halogen, C 1-6alkyl, nitro, hydroxy or C 1-4alkyloxy; D is an optionally substituted mono, bi-or tricyclic nitrogen containing heterocycle, a 2H-benzopyranone, a benzamide, a benzophenone or a phenoxyphenyl having central alpha 2-adrenoceptor antagonist activity. It further relates to their preparation, pharmaceutical use and compositions.

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