147804-30-6

Usage

Uses

1. Used in Pharmaceutical Industry:
1-OXA-6-AZASPIRO[2.5]OCTANE-6-CARBOXYLIC ACID, 1,1-DIMETHYLETHYL ESTER is used as an intermediate compound for the synthesis of various pharmaceuticals, specifically for the development of T-type Ca2+ channel antagonists. These antagonists are crucial in the treatment of various neurological disorders and conditions related to calcium channel dysfunction.
2. Used in Synthesis of 4-Aminomethyl-4-fluoropiperidine:
1-OXA-6-AZASPIRO[2.5]OCTANE-6-CARBOXYLIC ACID, 1,1-DIMETHYLETHYL ESTER is used as a key component in the synthesis of 4-Aminomethyl-4-fluoropiperidine, a T-type Ca2+ channel antagonist. 1-OXA-6-AZASPIRO[2.5]OCTANE-6-CARBOXYLIC ACID, 1,1-DIMETHYLETHYL ESTER has potential therapeutic applications in the treatment of neurological disorders, such as epilepsy and chronic pain, by modulating the activity of T-type calcium channels in the nervous system.

InChI:InChI=1/C11H19NO3/c1-10(2,3)8-11(15-8)4-6-12(7-5-11)9(13)14/h8H,4-7H2,1-3H3,(H,13,14)/p-1

Upstream product

• 1774-47-6 trimethylsulfoxonium iodide 
• 79099-07-3 N-tert-butyloxycarbonylpiperidin-4-one 
• 6814-64-8 methylenedimethyl sulfurane 
• 1030268-24-6 trimethylsulphoxonium iodide 
• 70775-39-2 dimethylsulfoxonium methylide 
• 7613-15-2 4-vinyl-piperidine 
• 159635-49-1 tert-butyl 4-methylidenepiperidine-1-carboxylate 
• 148133-82-8 4-methylene piperidine 
• 937-14-4 3-chloro-benzenecarboperoxoic acid 
• 2181-42-2 trimethylsulphonium iodide 

Downstream Products

• 211108-41-7 1-tert-butyloxycarbonyl-4-(2-(3-fluorophenyl)ethyl)-4-hydroxypiperidine 
• 191327-99-8 tert-butyl 4-hydroxy-4-[[2-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate 
• 1003567-08-5 4-(5-chloro-2-methoxy-benzyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 
• 676517-49-0 1,1-dimethylethyl 4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-4-hydroxy-1-piperidinecarboxylate 
• 666853-66-3 C₁₅H₃₀N₂O₃ 
• 614730-97-1 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester 
• 392331-66-7 4-aminomethyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester 
• 844502-01-8 4-(4-acetyl-phenoxymethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 
• 1055710-50-3 C₁₇H₂₃ClFNO₃ 
• 700834-36-2 methyl 4-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-ylmethylthio]benzoate 
• 644968-01-4 4-[(5-fluoro-2-methoxyphenyl)methyl]-4-hydroxy-1-piperidinecarboxylic acid 1,1-dimethylethyl ester 
• 871112-57-1 tert-butyl 4-[(4-fluorophenoxy)methyl]-4-hydroxypiperidine-1-carboxylate 
• 239073-94-0 tert-butyl 4-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate 
• 239073-93-9 4-formyl-4-methoxypiperidine-1-carboxylic acid 1,1-dimethylethyl ester 

Relevant academic research and scientific papers

Synthesis and SAR of Imidazo[1,5-a[pyridine derivatives as 5-HT4 receptor partial agonists for the treatment of cognitive disorders associated with Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition.

Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7

Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5–10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high-resolution DUB?small-molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small-molecule?ubiquitin-specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are non-covalent active-site inhibitors. Lamberto et al. report the structure-guided development of inhibitors of the deubiquitinating enzyme (DUB) USP7. The studies provide optimized and well-characterized probes for studying USP7 in normal and disease biology and, furthermore, lend validation to the notion that potent and selective active-site inhibitors of DUBs can be achieved.

The synthesis of a 2-azabicyclo[3.1.0]hexane by rearrangement of a spirocyclic epoxide

An unusual rearrangement of a 1-oxa-6-azaspiro[2.5]octane derivative giving access to novel 5-substituted 2-azabicyclo[3.1.0]hexanes is described. The synthetic application of the reaction is demonstrated by the synthesis of N-Boc-2,3-methano-β-proline. The amino acid was prepared through a three-step synthesis from easily available reagents in an overall yield of 15%.

Synthesis of 5-Acyl-4-methylene-1,2,3,4-Tetrahydropyridines

Several approaches to monocyclic N-protected 4-methylene-1,2,3,4-Tetrahydropyridines are reported. N-Boc-4-methylenepiperidin-3-one was found to be unstable and its enol triflate was not easily accessible. However, N-protected 2,3-dihydropyridin-4-ones ar

Design, synthesis, biological evaluation and structure-activity relationship study of quinazolin-4(3H)-one derivatives as novel USP7 inhibitors

Recent research has indicated that the abnormal expression of the deubiquitinase USP7 induces tumorigenesis via multiple cell pathways, and in particular, the p53-MDM2-USP7 pathway is well understood. USP7 is emerging as a promising target for cancer therapy. However, there are limited reports on USP7 inhibitors. Here we report design, synthesis and biological evaluation of novel quinazolin-4(3H)-one derivatives as potent USP7 inhibitors. Our results indicated that the compounds C9 and C19 exhibited the greatest potency against the USP7 catalytic domain, with IC50 values of 4.86 μM and 1.537 μM, respectively. Ub-AMC assays further confirmed IC50 values of 5.048 μM for C9 and 0.595 μM for C19. MTT assays indicated that gastric cancer MGC-803 cells were more sensitive to these compounds than BGC-823 cells. Flow cytometry analysis revealed that C9 restricted cancer cell growth at the G0/G1 and S phases and inhibited the proliferation and clone formation of MGC-803 cells. Further biochemical experiments indicated that C9 decreased the MDM2 protein level and increased the levels of the tumour suppressors p53 and p21 in a dose-dependent manner. Docking studies predicted that solvent exposure of the side chains of C9 and C19 would uniquely form hydrogen bonds with Met407 of USP7. Additionally, C9 exhibited a remarkable anticancer effect in a zebrafish gastric cancer MGC-803 cell model. Our results demonstrated that quinazolin-4(3H)-one derivatives were suitable as leads for the development of novel USP7 inhibitors and especially for anti-gastric cancer drugs.

Synthesis of Non-symmetrical Dispiro-1,2,4,5-Tetraoxanes and Dispiro-1,2,4-Trioxanes Catalyzed by Silica Sulfuric Acid

A novel protocol for the preparation of non-symmetrical 1,2,4,5-tetraoxanes and 1,2,4-trioxanes, promoted by the heterogeneous silica sulfuric acid (SSA) catalyst, is reported. Different ketones react under mild conditions with gem-dihydroperoxides or peroxysilyl alcohols/β-hydroperoxy alcohols to generate the corresponding endoperoxides in good yields. Our mechanistic proposal, assisted by molecular orbital calculations, at the ωB97XD/def2-TZVPP/PCM(DCM)//B3LYP/6-31G(d) level of theory, enhances the role of SSA in the cyclocondensation step. This novel procedure differs from previously reported methods by using readily available and inexpensive reagents, with recyclable properties, thereby establishing a valid alternative approach for the synthesis of new biologically active endoperoxides.

IMINO SULFANONE INHIBITORS OF ENPP1

The present disclosure relates generally to inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to sulfoximine- based inhibitors of ENPP1 of Formula (I) and methods of their use for treating disease mediated by ENPP1.

Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate

The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.

Discovery of EST73502, a Dual μ-Opioid Receptor Agonist and σ1Receptor Antagonist Clinical Candidate for the Treatment of Pain

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the μ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.

N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure–activity relationships and X-ray crystallographic studies

USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the rep