- Preparation method of N-(aryl/heteroaryl) alkyl-diamide
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The invention relates to a preparation method of N-(aryl/heteroaryl)alkyl- diamide, which comprises the following steps: under the protection of nitrogen, sequentially adding transition metal, phosphine or nitrogen ligand, cocatalyst, alkali, solvent, Nhalogenated cyclodiamide, alkyl aromatic ring or alkyl heteroaromatic ring compound into a reaction container, carrying out oxidative amination reaction at 80-140 DEG C, and till the reaction concludes after 6-48 hours, evaporating and drying a solvent and carrying out column chromatography separation to obtain an N (aryl/heteroaryl) alkyl diamide compound. The invention is simple in synthesis process, mild in reaction condition, high in yield and easy to industrialize.
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Paragraph 0040-0041
(2020/12/29)
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- Phenylpiperazine 5,5-dimethylhydantoin derivatives as first synthetic inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis
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Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1-15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure-activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 μM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter.
- ?es?awska, Ewa,Chudzik, Anna,Czekajewska, Joanna,Handzlik, Jadwiga,Kaczor, Aneta,Karczewska, El?bieta,Kie?-Kononowicz, Katarzyna,Latacz, Gniewomir,Nitek, Wojciech,Witek, Karolina
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- Synthesis of hydantoins and dihydrouracils via thermally-promoted cyclization of ureidoacetamides
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The synthesis of hydantoins and dihydrouracils from ureidoacetamides has been carried out at high temperature in glycol solvents. A series of substrates were prepared and examined to determine the effect of substrate structure, N-acyl substitution (X), and solvent on the course of the reaction. A dramatic effect was observed when using ureidoacetamides (e.g., X=N-methyl-N-phenyl), which led to higher yields, faster reaction times, and lower racemization of chiral substrates. The rate of racemization of a chiral hydantoin in the presence of dibenzylamine and N-methyl aniline has also been determined. The thermal cyclization methodology has been applied to the preparation of a complex hydantoin.
- Hillier, Michael C.,Gong, Hai-Hua,Clyne, Dean S.,Babcock, Martin J.
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p. 9413 - 9420
(2015/03/05)
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- SAR-studies on the importance of aromatic ring topologies in search for selective 5-HT7 receptor ligands among phenylpiperazine hydantoin derivatives
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The current study is focused on newly developed phenylpiperazine derivatives of aromatic methylhydantoin differing in mutual positions of methyl and phenyl moieties. The new compounds were synthesized using Bucherer-Bergs reaction, two-phase alkylation, Mitsunobu reaction and/or an alkylation under microwave irradiation. The compounds developed were assessed on their affinity for serotoninergic receptors 5-HT1A, 5-HT6, 5-HT 7 and α1-ARs in radioligand binding assays. Selected compounds were tested on their inhibitory effect at human 5-HT3A expressed in Xenopus Oocytes as well as on their activity at α1-adrenoceptor subtypes in functional and electrophysiological bioassays, respectively. Most of investigated compounds exhibited affinities for α1-ARs, 5-HT1A, 5-HT7 (Ki ~ 0.8-353 nM) significantly higher than those for 5-HT6 receptors. Very weak inhibitory effect at 5-HT3A accompanied with high activity at α1D-AR subtypes were observed for selected representative compounds. Among the current series, particularly 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl) -5-methylimidazolidine-2,4-dione hydrochloride (25a) displayed the highest 5-HT7 affinity with Ki = 3 nM and selectivity with 40-3600 fold towards 5-HT1A, 5-HT6, and α1-ARs.
- Handzlik, Jadwiga,Bojarski, Andrzej J.,Sata?a, Grzegorz,Kubacka, Monika,Sadek, Bassem,Ashoor, Abrar,Siwek, Agata,Wi?cek, Ma?gorzata,Kucwaj, Katarzyna,Filipek, Barbara,Kie?-Kononowicz, Katarzyna
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p. 324 - 339
(2014/04/17)
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- Regioselective synthesis of 7,8-dihydroimidazo [5,1-c][1,2,4]triazine-3, 6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold
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Dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives were prepared by successive N3- and N1-alkylation of hydantoins, followed by regioselective thionation and subsequent cyclization under mild conditions. In a final alkylation step a further substituent may be introduced. The synthetic strategy allows broad structural variation of this new drug-like heterobicyclic scaffold. In addition to extensive NMR and MS analyses, the structure of one derivative was confirmed by X-ray crystallography.
- Tzvetkov, Nikolay T.,Euler, Harald,Mueller, Christa E.
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supporting information
p. 1584 - 1593
(2012/11/07)
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- Propanoic acid derivatives that inhibit the binding of integrins to their receptors
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A compound of the structure A method for the inhibition of the binding of α4β1integrin to its receptors, for example VCAM-1(vascular cell adhesion molecule-1) and fibronectin; pharmaceutically active compositions comprising these compounds; and the use of these compounds for the control or prevention of diseases states in which α4β1is involved are also disclosed.
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Page column 49
(2008/06/13)
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- Propanoic acid derivatives that inhibit the binding of integrins to their receptors
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A method for the inhibition of the binding of α4β1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds (I) that inhibit this binding; pharmaceutically active compositions comprising such compounds; and the use of such compounds either as above, or in formulations for the control or prevention of diseases states in which α4β1 is involved. All substituents are as defined in the application.
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- Ring-Transformation of Imidazolidine-2,4-diones ( = Hydantoins ) to 4H-Imidazoles in the Reaction with 3-(Dimethylamino)-2,2-dimethyl-2H-azirines
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At ca. 70 deg C, 3-(dimethylamino)-2,2-dimethyl-2H-azirine (1) and 5,5-disubstituted hydantoins 4 in MeCN or i-PrOH give 2-(1-aminoalkyl)-5-(dimethylamino)-4,4-dimethyl-4H-imidazoles 5 in good yield (Scheme 2).These products are decarboxylated 1:1 adducts of 1 and 4.A reaction mechanism is suggested in analogy to the previously reported reactions of 1 and NH-acidic heterocycles containing the CO-NH-CO-NH moiety (Scheme 5).The formation of ureas 6 and 7 can be rationalized by trapping the intermediate isocyanate F by an amine.No reaction is observed between 1 and 1,5,5- or 3,5,5-trisubstituted hydantoins in refluxing MeCN or i-PrOH, but an N-isopropylation of 1,5,5-trimethylhydantoin (8b) occurs in the presence of morpholine (Scheme 3).The reaction of the bis(azirine)dibromozink complex 11 and hydantoines 4 in refluxing MeCN yields zink complexes 12 of the corresponding 2-(1-aminoalkyl)-4H-imidazoles 5 (Scheme 4).
- Schlaepfer-Daehler, Marlise,Mukherjee-Mueller, Gabriele,Heimgartner, Heinz
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p. 1251 - 1261
(2007/10/02)
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- Method of treating asthma with alkyl, alkylidene and alkylene hydantoins
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Pharmaceutical formulations are described, which comprise a hydantoin of formula (I): STR1 wherein R1 is C1-4 alkyl, R2 is hydrogen or C1-4 alkyl; or R1 and R2 taken together either represent a C4-6 alkylene group or a group of formula: STR2 where R5 and R6 independently represent hydrogen or C1-4 alkyl; R3 is C1-6 alkyl or benzyl; R4 is hydrogen or C1-6 alkyl; provided that R2 and R4 cannot both be hydrogen; or R1 and R4 taken together represent a C2-4 alkylene group; associated with a pharmaceutically-acceptable carrier therefor. The compounds, some of which are novel, are useful in the treatment of immediate hypersensitivity diseases such as asthma.
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