3753-59-1Relevant academic research and scientific papers
Efficient α-Alkylation of Arylacetonitriles with Secondary Alcohols Catalyzed by a Phosphine-Free Air-Stable Iridium(III) Complex
Panda, Surajit,Saha, Ratnakar,Sethi, Subrat,Ghosh, Rahul,Bagh, Bidraha
, p. 15610 - 15621 (2020/12/01)
A well-defined and readily available air-stable dimeric iridium(III) complex catalyzed α-alkylation of arylacetonitriles using secondary alcohols with the liberation of water as the only byproduct is reported. The α-alkylations were efficiently performed at 120 °C under solvent-free conditions with very low (0.1-0.01 mol %) catalyst loading. Various secondary alcohols including cyclic and acyclic alcohols and a wide variety of arylacetonitriles bearing different functional groups were converted into the corresponding α-alkylated products in good yields. Mechanistic study revealed that the reaction proceeds via alcohol activation by metal-ligand cooperation with the formation of reactive iridium-hydride species.
Identification of novel small-molecule inhibitors targeting menin-MLL interaction, repurposing the antidiarrheal loperamide
Yue, Liyan,Du, Juanjuan,Ye, Fei,Chen, Zhifeng,Li, Lianchun,Lian, Fulin,Zhang, Bidong,Zhang, Yuanyuan,Jiang, Hualiang,Chen, Kaixian,Li, Yuanchao,Zhou, Bing,Zhang, Naixia,Yang, Yaxi,Luo, Cheng
supporting information, p. 8503 - 8519 (2016/09/28)
Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the menin-MLL interaction (IC50 = 69 ± 3 μM). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC-YM21, DC-YM25 and DC-YM26 displayed better activities with IC50 values of 0.83 ± 0.13 μM, 0.69 ± 0.07 μM and 0.66 ± 0.05 μM, respectively. Further treatment with DC-YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.
MUSCARINIC RECEPTOR ANTAGONISTS
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Page/Page column 28, (2008/12/04)
The present invention relates to muscarinic receptor antagonists, which are useful, among other uses, for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors. The invention also relates to the process for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and the methods for treating diseases mediated through muscarinic receptors. Also provided herein are pharmaceutical compositions comprising one or more muscarinic receptor antagonists and at least one or more therapeutic agent selected from histamine antagonists, corticosteroids, beta agonists, leukotriene antagonists, EGFR kinase inhibitors, PAF antagonists, 5-lipoxygenase inhibitors, chemokine inhibitors, PDE-4 inhibitors or p38 MAP Kinase inhibitors.
Nucleophile-catalyzed asymmetric acylations of silyl ketene imines: Application to the enantioselective synthesis of verapamil
Mermerian, Ara H.,Fu, Gregory C.
, p. 949 - 952 (2007/10/03)
All-carbon quaternary stereocenters are generated with good enantioselectivity through a nucleophile-catalyzed acylation reaction of silyl ketene imines (see scheme, TBS = tert-butyldimethylsilyl). The method is applied to the first catalytic asymmetric synthesis of the drug verapamil.
Syntheses and pharmacological characterization of achiral and chiral enantiopure C/Si/Ge-analogous derivatives of the muscarinic antagonist cycrimine: A study on C/Si/Ge bioisosterism
Tacke, Reinhold,Kornek, Thomas,Heinrich, Tilman,Burschka, Christian,Penka, Martin,Pülm, Melanie,Keim, Christine,Mutschler, Ernst,Lambrecht, Günter
, p. 140 - 165 (2007/10/03)
The C/Si/Ge-analogous compounds rac-Ph(c-C5H9)El(CH2OH)CH2CH 2NR2 (NR2=piperidino; El=C, rac-3a; El=Si, rac-3b; El=Ge, rac-3c) and (c-C5H9)2El(CH2OH)CH 2CH2NR2 (NR2=piperidino; El=C, 5a; El=Si, 5b; El=Ge, 5c) were prepared in multi-step syntheses. The (R)- and (S)-enantiomers of 3a-c were obtained by resolution of the respective racemates using the antipodes of O,O′-dibenzoyltartaric acid (resolution of rac-3a), O,O′-di-p-toluoyltartaric acid (resolution of rac-3b), or 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (resolution of rac-3c). The enantiomeric purities of (R)-3a-c and (S)-3a-c were ≥98% ee (determined by 1H-NMR spectroscopy using a chiral solvating agent). Reaction of rac-3a-c, (R)-3a-c, (S)-3a-c, and 5a-c with methyl iodide gave the corresponding methylammonium iodides rac-4a-c, (R)-4a-c, (S)-4a-c, and 6a-c (3a-c→4a-c; 5a-c→6a-c). The absolute configuration of (S)-3a was determined by a single-crystal X-ray diffraction analysis of its (R,R)-O,O′-dibenzoyltartrate. The absolute configurations of the silicon analog (R)-4b and germanium analog (R)-4c were also determined by single-crystal X-ray diffraction. The chiroptical properties of the (R)- and (S)-enantiomers of 3a-c, 3a-c·HCl, and 4a-c were studied by ORD measurements. In addition, the C/Si/Ge analogs (R)-3a-c, (S)-3a-c, (R)-4a-c, (S)-4a-c, 5a-c, and 6a-c were studied for their affinities at recombinant human muscarinic M1, M2, M3, M4, and M5 receptors stably expressed in CHO-K1 cells (radioligand binding experiments with [3H]N-methylscopolamine as the radioligand). For reasons of comparison, the known C/Si/Ge analogs Ph2El(CH2OH)CH2CH2NR2 (NR2=piperidino; El=C, 7a; El=Si, 7b; El=Ge, 7c) and the corresponding methylammonium iodides 8a-c were included in these studies. According to these experiments, all the C/Si/Ge analogs behaved as simple competitive antagonists at M1-M5 receptors. The receptor subtype affinities of the individual carbon, silicon, and germanium analogs 3a-8a, 3b-8b, and 3c-8c were similar, indicating a strongly pronounced C/Si/Ge bioisosterism. The (R)-enantiomers (eutomers) of 3a-c and 4a-c exhibited higher affinities (up to 22.4 fold) for M1-M5 receptors than their corresponding (S)-antipodes (distomers), the stereoselectivity ratios being higher at M1, M3, M4, and M5 than at M2 receptors, and higher for the methylammonium compounds (4a-c) than for the amines (3a-c). With a few exceptions, compounds 5a-c, 6a-c, 7a-c, and 8a-c displayed lower affinities for M1-M5 receptors than the related (R)-enantiomers of 3a-c and 4a-c. The stereoselective interaction of the enantiomers of 3a-c and 4a-c with M1-M5 receptors is best explained in terms of opposite binding of the phenyl and cyclopentyl ring of the (R)- and (S)-enantiomers. The highest receptor subtype selectivity was observed for the germanium compound (R)-4c at M1/M2 receptors (12.9-fold).
Phenyl-substituted normethadones: Synthesis and pharmacology
Mbela,Poupaert,Cumps,Moussebois,Haemers,Borloo,Dumont
, p. 237 - 242 (2007/10/02)
Phenyl-substituted normethadone derivatives were synthesized and their affinity (IC50) for opioid receptors was determined by displacement of the specific binding sites of [3H]sufentanyl on rat brain preparations. Substitution resulted in a decrease of affinity in-vitro. These results suggest that normethadone-like compounds may interact with the P subsite of the μ-opioid receptor and that the P subsite has a well-defined cavity shape of stringent dimensions.
Synthesis and aromatase inhibition of 3-cycloalkyl-substituted 3-(4- aminophenyl)piperidine-2,6-diones
Hartmann,Batzl,Pongratz,Mannschreck
, p. 2210 - 2214 (2007/10/02)
The synthesis of 3-cycloalkyl-substituted 3-(4-aminophenyl)piperidine-2,6- diones is described [cyclopentyl (1), cyclohexyl (2)]. The enantiomers of 2 were separated either by using HPLC on optically active sorbent or by crystallization of the brucine salt of the phthalamic acid of 2. The absolute configuration of the (+)- and (-)-enantiomers of 2 were assigned as S and R, respectively, by comparing the CD spectra to those of the enantiomers of aminoglutethimide (AG, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione). The compounds were tested in vitro for inhibition of human placental aromatase, the cytochrome P450-dependent enzyme which is responsible for the conversion of androgens to estrogens. Compounds 1 and 2 inhibited aromatase by 50% at 1.2 and 0.3 μM, respectively (IC50 AG = 37 μM). According to the findings with AG, the (+)-enantiomer of 2 was responsible for the inhibitory activity, being a 240-fold more potent aromatase inhibitor in vitro than racemic AG. On the other hand, (+)-2 displayed a strongly reduced inhibition of desmolase (cholesterol side-chain cleavage enzyme) compared to AG (relative activity = 0.3). Thus (+)-2 is of interest as a potential drug for the treatment of estrogen-dependent diseases, e.g. mammary tumors.
