196,289 research outputs found
SEARCH FOR SELECTIVE ANTAGONISTS AT α1-ADRENORECEPTOR SUBTYPES: WB-4101 RELATED COMPOUNDS
No full textThe development of subtype selective α1 ligands is intensively pursued in order to obtain more effective and safer agents for the treatment of cardiovascular pathologies such as hypertension and arrhythmia, but also and particularly of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).
One of the oldest and most potent α1 antagonists is represented by WB-4101, a 2-aminomethyl-1,4-benzodioxane derivative which is slightly selective for α1A and, to a minor extent, for α1D-ARs with respect to α1B-AR and 5-HT1A serotoninergic receptor. Many structural modifications of WB-4101 have been done to improve both affinity and selectivity.1-4 Some evidences, resulting from mutagenesis and docking studies, suggest that the benzodioxane moiety and the 2,6-dimethoxyphenoxy residue of WB-4101 are, respectively, involved in conferring α1a selectivity and high α1 affinity. Consistently with these findings, our recent researches have demonstrated that removal of one or both ortho-methoxy substituents adversely affects the affinity for the three α1-AR subtypes, but not that for the 5-HT1A receptor.3
On the basis of these indications, we synthesized a number of S and R analogues of WB-4101, characterized by different substitutions at the benzodioxane and/or phenoxy fragment, in order to modulate and, hopefully, to improve the activity and selectivity profile of the parent compound. In particular, we considered derivatives with benzodioxane 8-substituted with F,4 Cl, OH or OMe 4 or fused with a cyclohexane to give a tetrahydronaphthodioxane polycycle.2 On the other hand, 2,6-dimethoxyphenyl residue was replaced by ortho methoxy substituted 1-naphthyl 2 or biphenyl systems. Finally, hybrid structures were designed combining some of the above modifications. After binding assays, which demonstrated the better α1a, α1b, α1d and 5-HT1A affinity of the S enantiomers, these latter were tested in functional assays on isolated tissues, finding that almost all were able to discriminate among the α1-AR subtypes.
1. Bolognesi M.L., Budriesi R., Cavalli A., Chiarini A., Gotti R., Leonardi A., Minarini A., Poggesi E., Recanatini M., Rosini M., Tumiatti V., Melchiorre C. J.Med.Chem. 1999, 42, 4214-4224.
2. Bolchi C., Catalano P., Fumagalli L., Gobbi M., Pallavicini M., Pedretti A., Villa L., Vistoli G., Valoti E. Bioorg.Med.Chem. 2004, 12, 4937-51.
3. Fumagalli L., Bolchi C., Colleoni S., Gobbi M., Moroni B., Pallavicini M., Pedretti A., Villa L., Vistoli G., Valoti E. Bioorg.Med.Chem. 2005, 13, 2547-2559.
4. Valoti E., Pallavicini M., Villa L., Pezzetta D. J.Org.Chem. 2001, 66, 1018-1025
RESOLUTION VIA DIASTEREOMERIC AMIDES OF ENANTIOPURE 1,4-BENZOXATHIAN-2- AND 3-CARBOXYLIC ACIDS AND DETERMINATION OF THEIR CONFIGURATION
No full textThe 1,4-Benzoxathiane, 2- or 3-substituted, scaffold is an important moiety, present in a wide number of therapeutic agents. Despite its abundance in bioactive molecules, it is chemically unexploited and there are only a couple of examples in literature reporting the benzoxathiane in its enantiopure form.
In the present communication, taking advantage of the established synthetic method used for the synthesis of 1,4-benzodioxane carboxamides [1], we report a completely innovative and easy method for the preparation of both 2- and 3- substituted 2,3-dihydro-1,4-benzoxathiine [2]. By using the (S)-phenylethylamine, we defined for the first time the absolute configuration of each amide and, after hydrolysis, of its corresponding acid. This was possible thanks to the significant differences in terms of 1H-NMR spectra and of other physical chemical properties.
Two peculiar synthetic pathways were developed and followed for the achievement of the two regioisomeric carboxamides, due to the liability of the 3- substituted moiety. To do so, we also considered how the regioselectivity in the benzoxathiane ring closure strongly relies on the nature of both solvent and substrate [3]. 2-Mercaptophenol was ad hoc condensed, achieving the two enantiopure amides, which were further hydrolyzed in acid conditions, letting to the achievement of the corresponding 1,4-benzoxathian carboxylic acids.
[1] Fumagalli L, Bolchi C, Bavo F, Pallavicini M., Tetrahedron Lett. 2016;57(18):2009-2011.
[2] Straniero V, Lodigiani G, Suigo L, Valoti E., Chirality., 2022;34(8):1053‐1064.
[3] Casiraghi A, Valoti E, Suigo L, Artasensi A, Sorvillo E, Straniero V. J Org Chem. 2018;83(21):13217-13227
Resolution of ortho- and meta-substituted 1-phenylethylamines with isopropylidene glycerol
No full textAbstract—The hydrogen phthalate of isopropylidene glycerol 1, previously reported as an efficient resolving agent of p-substituted 1-phenylethylamines, was also found to resolve selected o- and m-isomers. In particular, the (S)-enantiomers of 1-(2-
methylphenyl)ethylamine 2, 1-(3-methylphenyl)ethylamine 3, 1-(2-chlorophenyl)ethylamine 4 and 1-(3-methoxyphenyl)ethylamine
5 were obtained in good yields and very high enantiomeric excess (e.e.) by selective crystallization of the respective salts with (S)- or (R)-1. The e.e.s of the resolved substrates were determined by chiral HPLC analysis. The (S)-configuration of (−)-3 was established according to Raban’s procedure. Optical rotations of non-racemic free amines 2 and 3 are reported. The success of the resolutions presented and of the precedent ones using 1 indicate that the position of the substituent on the 1-phenylethylamine framework does not affect the resolution, showing the uncommon versatility of 1 in the resolution of monosubstituted 1-phenylethylamines
Heteroaryl-substituted phenols as potential antioxidants
No full textA series of O-heteroaryl phenols have been synthesised and structurally characterised. Photo-Fries rearrangement of these compounds represents a useful way to access the corresponding C-heteroaryl derivatives. The activity of the new phenolic compounds as radical scavengers towards the 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonate) (ABTS+•) has been evaluated. 2-tert-Butyl-4-(4-phenyl-isoxazol-3-ylmethoxy)-phenol (compound 3c) showed the highest scavenger activity (IC50 value (i.e. the concentration that scavenged 50% of the radicals) 3.17 × 10-6 M), which was one order of magnitude greater than that of the corresponding lead compound tert-butylhydroxy-anisole (BHA) (IC50 1.04 × 10-5 M). In further experiments, compound 3c showed dose-dependent inhibition of the oxidation of linoleic acid, as well as methaemoglobin formation, promoted by the presence of the radical generator 2,2′-azobis(amidino-propane) hydrochloride (AAPH) and it was markedly more potent than BHA in these assays. © 2007 The Authors
Synthesis of N,N'-dibenzylethylenediamine via palladium-carbon-catalysed reductive alkylation
No full textReductive alkylation of ethylenediamine with benzaldehyde and hydrogen in the presence of Pd-C has been investigated in order to optimize the synthesis of N,N'-dibenzylethylenediamine; the efficiency of the procedure has been improved by minimizing undesired competing reactions of cyclization and hydrogenolysis
FOLATES, COMPOSITIONS AND USES THEREOF
No full textThe present invention relates to folates, compositions and uses thereof, in particular, the invention describes a crystalline or amorphous compound which is unsubstituted folate or reduced folate, or the natural or unatural isomers thereof, of at least one organic base, as well ac compositions and uses thereof. The compounds of the invention show a long lasting stability as well as a peculiarly high water-solubility
Perivascular adipose tissue modulates the effects of flavonoids on rat aorta rings: role of superoxide anion and β3 receptors
No full text: Several studies demonstrate the beneficial effects of dietary flavonoids on the cardiovascular system. Since perivascular adipose tissue (PVAT) plays an active role in the regulation of vascular tone in both health and diseases, the present study aimed to assess the functional interaction between PVAT and flavonoids in vitro on rat aorta rings. Several flavonoids proved to display both antispasmodic and spasmolytic activities towards noradrenaline-induced contraction of rings deprived of PVAT (-PVAT). However, on PVAT-intact (+PVAT) rings, both actions of some flavonoids were lost and/or much decreased. In rings-PVAT, the superoxide donor pyrogallol mimicked the effect of PVAT, while in rings+PVAT the antioxidant mito-tempol restored both activities of the two most representative flavonoids, namely apigenin and chrysin. The Rho-kinase inhibitor fasudil, or apigenin and chrysin concentration-dependently relaxed the vessel active tone induced by the Rho-kinase activator NaF; the presence of PVAT counteracted apigenin spasmolytic activity, though only in the absence of mito-tempol. Similar results were obtained in rings pre-contracted by phenylephrine. Finally, when β3 receptors were blocked by SR59230A, vasorelaxation caused by both flavonoids was unaffected by PVAT. These data are consistent with the hypothesis that both noradrenaline and apigenin activated adipocyte β3 receptors with the ensuing release of mitochondrial superoxide anion, which once diffused toward myocytes counteracted flavonoid vasorelaxant activity. This phenomenon might limit the beneficial health effects of dietary flavonoids in patients affected by either obesity and/or other pathological conditions characterized by sympathetic nerve overactivity
2-Hydroxymethyl-1,4-dioxane: synthesis, resolution and determination of the absolute configurations of the enantiomers
No full text2-Hydroxymethyl-1, 4-dioxane 3 was resolved via salt formation between its hydrogen phthalate and (R)- or (S)-1-phenylethylamine, selective crystallization of the resultant diastereomeric mixtures and subsequent recovery of its enantiomers by saponification. The progress of the resolution was followed by chiral HPLC and the absolute stereochemistry of the two enantiomers determined by comparison of their specific rotations with that of (R)-3 synthesized from enantiomerically pure (R)-1-O-benzylglycerol. The results of the synthesis of 3 and of its resolution are discussed and compared with those previously obtained for 1,2-isopropylidene glycerol evaluating the consequences of replacement of ispropylidene with an ethylene bridge
Process for the diastereoisomeric resolution of 5-Methyltetrahydrofolic acid
No full textThe invention relates to a process for the distereoisomeri resolution of 5-Methyltetrahydrofolic acid; it discloses also a cristalline amine salt of 5-Methyltetrahydrofolic acid and is furthe directed to a process for the transformation of the single diastereoisomers of the 5-Methyltetrahydrofolic amine salts obtained by the process of the invnetion into the corresponding free acid or into an alkaline earth matal salt. The inventio provides a simple, economically advantageous and efficient process and allows to obtain stable and pure (6R) and (6S)- diastereoisomers of 5-Methyltetrahydrofolic acid in good yield and diastereoisomeric putity
Diastereomeric 2-aminomethyl-1,4-benzodioxane mandelates : phase diagrams and resolution
No full textThe diastereomeric salts of (R)- and (S)-2-aminomethyl-1,4-benzodioxane with unichiral mandelic acid form a simple eutectic, whose binary phase melting point diagram shows the unique eutectic at 0.35 M ratio of the less soluble diastereomer. Such an eutectic composition, near to 0.5, is consistent with the modest efficiency previously reported for their separation via crystallization from ethanol/ethyl acetate. However, the ternary solubility phase diagram, obtained from solubility measurements in methanol, shifts the eutectic to a lower molar ratio (0.10) of the less soluble diastereomer, thus indicating an optimal resolvability of the diastereomeric mandelates. This was confirmed by the highly efficient resolution of racemic 2-aminomethyl-1,4-benzodioxane with (R)-mandelic acid via a single crystallization from methanol. The ready availability of both the racemic substrate and the resolving acid makes this simple and efficient resolution procedure very attractive to obtain the enantiomers of 2-aminomethyl-1,4-benzodioxane, which are important synthetic intermediates
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