17150-62-8Relevant articles and documents
Bicyclic Piperidines via [2 + 2] Photocycloaddition
Shcherbakova, Valeriya,Dibchak, Dmitry,Snisarenko, Mariya,Skalenko, Yevhen,Denisenko, Aleksandr V.,Kuznetsova, Anastasiia S.,Mykhailiuk, Pavel K.
, p. 2200 - 2209 (2021)
A synthetic strategy to fused bicyclic piperidines - building blocks for medicinal chemistry - is developed. The key step was an intramolecular [2 + 2]-photocyclization. The photochemical step was performed on a gram scale. Crystallographic analysis of the obtained compounds revealed that they occupy a novel chemical space and can be considered as elongated analogues of 3-substituted piperidines.
Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: Transition state analogs for high affinity binding
Shi, Genbin,Shaw, Gary X.,Zhu, Fengxia,Tarasov, Sergey G.,Ji, Xinhua
, (2020/11/20)
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but absent in mammals; therefore, it is an attractive target for developing novel antimicrobial agents. Previously, based on our studies of the structure and mechanism of HPPK, we created first-generation bisubstrate inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed second-generation inhibitors by replacing the phosphate bridge with a linkage that contains a piperidine moiety. Here, we report third-generation inhibitors designed based on the piperidine-containing inhibitor, mimicking the transition state. We synthesized two such inhibitors, characterized their protein-binding and enzyme inhibition properties, and determined their crystal structures in complex with HPPK, advancing the development of such bisubstrate analog inhibitors.
Carbamoyl Fluoride-Enabled Enantioselective Ni-Catalyzed Carbocarbamoylation of Unactivated Alkenes
Li, Yue,Luan, Yu-Xin,Qi, Shao-Long,Wang, Rong-Hua,Ye, Mengchun,Zhang, Feng-Ping
supporting information, p. 19844 - 19849 (2021/01/01)
A carbamoyl fluoride-enabled enantioselective Ni-catalyzed carbocarbamoylation of unactivated alkenes was developed, providing a broad range of chiral γ-lactams bearing an all-carbon quaternary center in 45-96% yield and 38-97% ee.
Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression
Nirogi, Ramakrishna,Mohammed, Abdul Rasheed,Shinde, Anil K.,Ravella, Srinivasa Rao,Bogaraju, Narsimha,Subramanian, Ramkumar,Mekala, Venkat Reddy,Palacharla, Raghava Choudary,Muddana, Nageswararao,Thentu, Jagadeesh Babu,Bhyrapuneni, Gopinadh,Abraham, Renny,Jasti, Venkat
, p. 2833 - 2853 (2020/03/05)
A series of chemical optimizations guided by in vitro affinity at the α4β2 receptor in combination with selectivity against the α3β4 receptor, pharmacokinetic evaluation, and in vivo efficacy in a forced swim test resulted in identification of 3-(6-chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane hydrochloride (9h, SUVN-911) as a clinical candidate. Compound 9h is a potent α4β2 receptor ligand with a Ki value of 1.5 nM. It showed >10 μM binding affinity toward the ganglionic α3β4 receptor apart from showing selectivity over 70 other targets. It is orally bioavailable and showed good brain penetration in rats. Marked antidepressant activity and dose-dependent receptor occupancy in rats support its potential therapeutic utility in the treatment of depression. It does not affect the locomotor activity at doses several folds higher than its efficacy dose. It is devoid of cardiovascular and gastrointestinal side effects. Successful long-term safety studies in animals and phase-1 evaluation in healthy humans for safety, tolerability, and pharmacokinetics paved the way for its further development.
A practical catalytic reductive amination of carboxylic acids
Andrews, Keith G.,Denton, Ross M.,Hirst, David J.,Stoll, Emma L.,Tongue, Thomas,Valette, Damien
, p. 9494 - 9500 (2020/10/02)
We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.
A 5 + 1 Protic Acid Assisted Aza-Pummerer Approach for Synthesis of 4-Chloropiperidines from Homoallylic Amines
Ebule, Rene,Mudshinge, Sagar,Nantz, Michael H.,Mashuta, Mark S.,Hammond, Gerald B.,Xu, Bo
, p. 3249 - 3259 (2019/03/20)
We report that HCl·DMPU induces the formation of (thiomethyl)methyl carbenium ion from DMSO under mild conditions. Homoallylic amines react with this electrophile to generate 4-chloropiperidines in good yields. The method applies to both aromatic and aliphatic amines. The use of HCl·DMPU as both non-nucleophilic base and chloride source constitutes an environmentally benign alternative for piperidine formation. The reaction has a broad substrate scope, and the conditions offer good chemical yields with high functional group tolerance and scalability.
Catalytic, Enantioselective Synthesis of Cyclic Carbamates from Dialkyl Amines by CO2-Capture: Discovery, Development, and Mechanism
Yousefi, Roozbeh,Struble, Thomas J.,Payne, Jenna L.,Vishe, Mahesh,Schley, Nathan D.,Johnston, Jeffrey N.
supporting information, p. 618 - 625 (2019/01/11)
Cyclic carbamates are a common feature of small-molecule therapeutics, offering a constrained hydrogen bond acceptor that is both polar and sterically small. Methods for their preparation most often focus first on amino alcohol synthesis and then reaction with phosgene or its equivalent. This report describes an enantioselective synthesis of cyclic carbamates in which carbon dioxide engages an unsaturated basic amine, facilitated by a bifunctional organocatalyst designed to stabilize a carbamic acid intermediate while activating it toward subsequent enantioselective carbon-oxygen bond formation. Six-membered cyclic carbamates are prepared in good yield with high levels of enantioselection, as constrained 1,3-amino alcohols featuring a chiral tertiary alcohol carbon. Spectroscopic analysis (NMR, DOSY) of various substrate-reagent combinations provides insight into the dominant species under the reaction conditions. Two peculiar requirements were identified to achieve highest consistency: a "Goldilocks" amount of water and the use of a noncrystalline form of the ligand. These atypical features of the final protocol notwithstanding, a diverse range of products could be prepared. Their functionalizations illustrate the versatility of the carbamates as precursors to enantioenriched small molecules.
Reductive C-O, C-N, and C-S Cleavage by a Zirconium Catalyzed Hydrometalation/β-Elimination Approach
Matt, Christof,K?lblin, Frederic,Streuff, Jan
, p. 6983 - 6988 (2019/09/09)
A zirconium catalyzed reductive cleavage of Csp3 and Csp2 carbon-heteroatom bonds is reported that makes use of a tethered alkene functionality as a traceless directing group. The reaction is successfully demonstrated on C-O, C-N, and C-S bonds and proposed to proceed via a hydrozirconation/β-heteroatom elimination sequence of an in situ formed zirconium hydride catalyst. The positional isomerization of the catalyst further enables the cleavage of homoallylic ethers and the removal of terminal allyl and propargyl groups.
HPPK INHIBITORS USEFUL AS ANTIBACTERIAL AGENTS
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Paragraph 0118; 0119, (2018/04/27)
The disclosure provides linked purine pterin compounds of Formula I that are novel inhibitors of HPPK, a kinase responsible for an essential step in the biosynthesis of folic acid. (Formula I) The variables, e.g., A1-A3, R1-R4, B1-B2, and L1 are defined in the disclosure. These linked purine pterin inhibitors bind to HPPK with high affinity and specificity. Pharmaceutical compositions containing the HPPK inhibitors and methods of treating a bacterial infection in a patient with one or more of the HPPK inhibitors of the disclosure are also provided.
A Simple, Broad-Scope Nickel(0) Precatalyst System for the Direct Amination of Allyl Alcohols
Sweeney, Joseph B.,Ball, Anthony K.,Lawrence, Philippa A.,Sinclair, Mackenzie C.,Smith, Luke J.
supporting information, p. 10202 - 10206 (2018/08/06)
The preparation of allylic amines is traditionally accomplished by reactions of amines with reactive electrophiles, such as allylic halides, sulfonates, or oxyphosphonium species; such methods involve hazardous reagents, generate stoichiometric waste streams, and often suffer from side reactions (such as overalkylation). We report here the first broad-scope nickel-catalysed direct amination of allyl alcohols: An inexpensive NiII/Zn couple enables the allylation of primary, secondary, and electron-deficient amines without the need for glove-box techniques. Under mild conditions, primary and secondary aliphatic amines react smoothly with a range of allyl alcohols, giving secondary and tertiary amines efficiently. This “totally catalytic” method can also be applied to electron-deficient nitrogen nucleophiles; the practicality of the process was demonstrated in an efficient, gram-scale preparation of the calcium antagonist drug substance flunarizine (Sibelium).
