- Substituted 1-methyl-4-phenylpyrrolidin-2-ones – Fragment-based design of N-methylpyrrolidone-derived bromodomain inhibitors
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N-Methylpyrrolidone is one of several chemotypes that have been described as a mimetic of acetyl-lysine in the development of bromodomain inhibitors. In this paper, we describe the synthesis of a 4-phenyl substituted analogue – 1-methyl-4-phenylpyrrolidin-2-one – and the use of aryl substitution reactions as a divergent route for derivatives. Ultimately, this has led to structurally complex, chiral compounds with progressively improved affinity as inhibitors of bromodomain-containing protein 4.
- Hilton-Proctor, J. P.,Ilyichova, O.,Jennings, I. G.,Johnstone, R. W.,Mountford, S. J.,Scanlon, M. J.,Shortt, J.,Thompson, P. E.,Zheng, Z.
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- Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut
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The two-step flow asymmetric synthesis of chiral γ-nitrobutyric acids as key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut is reported on a multigram scale. The telescoped process comprises an enantioselective Michael-type add
- ?tv?s, Sándor B.,Kappe, C. Oliver,Llanes, Patricia,Pericàs, Miquel A.
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p. 8122 - 8126
(2020/11/03)
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- Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design
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A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, A12, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure-activity relationship of compound A12, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.
- Dong, Xiaowu,Zhan, Wenhu,Zhao, Mengting,Che, Jinxin,Dai, Xiaoyang,Wu, Yizhe,Xu, Lei,Zhou, Yubo,Zhao, Yanmei,Tian, Tian,Cheng, Gang,Jin, Zegao,Li, Jia,Shao, Yanfei,He, Qiaojun,Yang, Bo,Weng, Qinjie,Hu, Yongzhou
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supporting information
p. 7264 - 7288
(2019/08/20)
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- New multicomponent reaction for the direct synthesis of β-aryl-γ-nitroesters promoted by hydrotalcite-derived mixed oxides as heterogeneous catalyst
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A new approach based on multicomponent/domino combined reactions for the synthesis of γ-nitroesters promoted by a mixed aluminium-magnesium oxides derived from hydrotalcite-like material was developed. Different γ-nitroesters were synthesized in 15-95percent yield using Meldrum's acid, aromatic aldehydes, nitromethane and different alcohols as reagents and solvents. The γ-aminobutyric acid derivatives, Phenibut and Baclofen, were prepared in 63 and 61percent overall yield, respectively, through a two steps synthetic strategy. A mechanistic pathway was proposed based on the gas chromatography mass spectrometry (GC-MS) and electrospray ionization mass spectrometry (ESI-MS) experiments.
- D'Oca, Caroline R. M.,Naciuk, Fabricio F.,Silva, Jéssica C.,Guedes, Esthéfani P.,Moro, Celso C.,D'Oca, Marcelo G. M.,Santos, Leonardo S.,Natchigall, Fabiane M.,Russowsky, Dennis
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p. 285 - 298
(2016/12/18)
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- A process for preparing 3 - phenyl - 4 - aminobutyric acid hydrochloride process (by machine translation)
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The present invention provides a process for preparing 3 - phenyl - 4 - aminobutyric acid hydrochloride of the process, the use of cinnamic acid methyl ester and nitromethane as the reaction substrate, nitromethane can be used as the reaction substrate bu
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Paragraph 0035; 0036; 0037
(2018/01/02)
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- Method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride
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The invention provides a method for synthesizing 4-amino-3-phenylbutyric acid hydrochloride. The synthetic method comprises the following steps: preparing methyl 4-nitro-3-phenyl butyrate, preparing methyl 4-amino-3-phenyl butyrate, and treating to obtain the product. According to the synthetic method disclosed by the invention, a complete process for synthesizing 4-amino-3-phenylbutyric acid hydrochloride is created, the synthetic method is simple in process, high in yield and low in cost, and the main problems that the initial raw materials used in the conventional process are high in price, the operation steps are onerous and pollution in the production process is severe are solved.
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Paragraph 0015; 0019
(2017/10/07)
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- Chemical assembly systems: Layered control for divergent, continuous, multistep syntheses of active pharmaceutical ingredients
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While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels - choice of starting material, reagent, or order of reaction modules - enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, β-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49-75%).
- Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
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p. 678 - 682
(2015/03/04)
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- Synthesis of functionalized γ-lactone via Sakurai exo -cyclization/rearrangement of 3,3-bis(silyl) enol ester with a tethered acetal
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An efficient synthesis of functionalized γ-lactones has been developed involving Sakurai exo-cyclization/rearrangement of 3,3-bis(silyl) enol esters with a tethered acetal. While the steric and electronic effects of geminal bis(silane) favor the desired Sakurai pathway, the methoxy species formed in the deprotection step also facilitates both cyclization and rearrangement. The synthetic value of this approach has been demonstrated by efficiently transforming the E-vinylsilane into enyne and the γ-lactone moiety into multisubstituted THF.
- Yin, Zhiping,Liu, Zengjin,Huang, Zhenggang,Chu, Yang,Chu, Zhiwen,Hu, Jia,Gao, Lu,Song, Zhenlei
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supporting information
p. 1553 - 1556
(2015/03/30)
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- Polystyryl-BEMP as an efficient recyclable catalyst for the nucleophilic addition of nitroalkanes to α,β-unsaturated carbonyl compounds under solvent-free conditions
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2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3, 2-diazaphosphorine supported on polystyrene (PS-BEMP) is an efficient catalyst for the addition of nitroalkanes (1-1.5 equiv.) to α,β-unsaturated carbonyl compounds (1.0 equiv.) in the absence of a reaction medium (solvent-free conditions). The corresponding γ-nitro carbonyl compounds have been isolated in excellent yields but the catalyst can be satisfactorily recovered and used for only 3 times due to the magnetic stirring which caused crunching of the catalyst beads thus hampering its complete recovery. To optimize the catalyst's reuse and improve the environmental efficacy of solvent-free conditions, the first solvent-free cyclic continuous-flow reactor has been set up. This reactor has allowed the product to be isolated in an almost quantitative yield by using a very small amount of organic solvent, making the recovery and reuse of the catalyst efficient and reproducible.
- Ballini,Barboni,Castrica,Fringuelli,Lanari,Pizzo,Vaccarob
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supporting information; experimental part
p. 1218 - 1224
(2009/05/30)
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- 2-(CYCLIC AMINO)-PYRIMIDONE DERIVATIVES AS TPK1 INHIBITORS
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A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof (I) wherein R2 represents a hydrogen or the like; R3 represents methyl group or the like; R20 represents a halogen atom or the like; q represents an integer of 0 to 3; Z represent nitrogen atom, CH, or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents a substituted alkyloxy and the like; p represents an integer of 0 to 3; X represents bond, CH2, oxygen atom, NH, or the like; any one or more of R5 and R6, R5 and R4, R6 and R4, X and R5, X and R4, X and R6, and R6 and R6 may combine to each other to form a ring, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).
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Page/Page column 204
(2008/06/13)
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- NOVEL AMINO- AND IMINO-ALKYLPIPERAZINES
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Described are novel amino- and iminoalkyl piperazines having affinity for serotonergic receptors and pharmacological compositions thereof. These compounds and their isomers, including optical isomers, enantiomers, diastereomers, N-oxides, polymorphs, hydr
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Page/Page column 28
(2010/11/29)
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- A short and convenient chemoenzymatic synthesis of both enantiomers of 3-phenylGABA and 3-(4-chlorophenyl)GABA(Baclofen)
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Both enantiomers of the pharmacologically active GABA analogues 4-amino-3-phenyl and 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) with high enantiomeric excesses were synthesized by a chemoenzymatic method involving α-chymotrypsin mediated kinetic resolutions of the corresponding 3-phenyl- and 3-(4-chlorophenyl)-4-nitrobutyric acid methyl ester precursors.
- Felluga, Fulvia,Gombac, Valentina,Pitacco, Giuliana,Valentin, Ennio
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p. 1341 - 1345
(2007/10/03)
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- Evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase
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Syntheses and evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2- imines as inhibitors of nitric oxide synthase (NOS) are discussed. An extensive SAR was established for pyrrolidin-2-imines class of compounds. The amidines came out as the most potent inhibitors in addition to displaying selectivity.
- Shankaran,Donnelly, Karla L.,Shah, Shrenik K.,Guthikonda, Ravindra N.,MacCoss, Malcolm,Humes, John L.,Pacholok, Stephen G.,Grant, Stephan K.,Kelly,Wong
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p. 4539 - 4544
(2007/10/03)
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- Synthesis of β-functionalized α,β-unsaturated oximes via silylation of nitro compounds
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A general method for the synthesis of conjugated enoximes 2 via silylation of functionalized aliphatic nitro compounds 1 has been elaborated. The configuration of obtained products has been determined by NMR spectroscopy.
- Danilenko, Vitaly M.,Tishkov, Alexander A.,Ioffe, Sema L.,Lyapkalo, Ilya M.,Strelenko, Yury A.,Tartakovsky, Vladimir A.
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p. 635 - 647
(2007/10/03)
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- Radical cyclization in heterocycle synthesis. II. Total synthesis of (±)-anantine and (±)-isoanantine
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(+)-Anantine, (±)-isoanantine and related compounds were synthesized via two key reactions, sulfanyl radical addition-cyclization and stereoselective construction of the E-benzylidene moiety.
- Naito, Takeaki,Honda, Yuko,Bhavakul, Vanida,Yamaguchi, Sayaka,Fujiwara, Azusa,Miyata, Okiko,Ninomiya, Ichiya
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p. 1932 - 1939
(2007/10/03)
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- Inhibition of cyclic adenosine-3',5'-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogues
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Rolipram [(R,S)-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone] has been shown to inhibit selectively the cAMP phopshodiesterase (PDE) of vascular smooth muscle. In order to further explore the structural requirements for selective PDE inhibition, we synthesized a series of rolipram derivatives differently substituted either at the pyrrolidinone or at the aromatic ring. Among these compounds, rolipram was the most active compound. Semirigid analogues were prepared and used for an evaluation of the active conformation of rolipram. Structural comparison with two other potent and chemically different smooth muscle cAMP-PDE inhibitors, trequinsin and Ro 20-1724, allows us to propose a first topological model of the smooth muscle cAMP-PDE pharmacophore.
- Marivet,Bourguignon,Lugnier,Mann,Stoclet,Wermuth
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p. 1450 - 1457
(2007/10/02)
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- (Substituted-phenyl)-5-oxo-2-pyrrolidinepropanoic acids and esters thereof, and use for reversing electroconvulsive shock-induced amnesia
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Certain 5-oxo-3-(unsubstituted-phenyl)- or 5-oxo-3-(substituted phenyl)-2-pyrrolidinepropanoic acids and 5-oxo-β-(unsubstituted-phenyl)- or 5-oxo-β-(substituted-phenyl)-2-pyrrolidinepropanoic acids, their pharmaceutically acceptable esters and metal and amine cation salts, pharmaceutical compositions employing these compounds, and a method of treating senility or of reversing amnesia are disclosed.
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- 1-(Substituted-aryl)-dihydro-1H-pyrrolizine-3,5-[2H,6H-]diones and use for reversing amnesia
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1-(Substituted-aryl)-dihydro-1H-pyrrolizine-3,5-[2H,6H]-diones are effective cognition activating agents for the treatment of senility and for reversing amnesia. Pharmaceutical compositions containing these compounds and a method of treating senility or of reversing amnesia are also disclosed.
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