Insights into the crystal structure, polymorphism and thermal behavior of menthol optical isomers and racemates

International audienceThe physico-chemical properties of the levo- and dextrorotatory menthol isomers as well as the corresponding racemic compound were studied using X-ray single-crystal or powder diffraction and differential scanning calorimetry experiments. As a result, the not yet determined crystal structure of DL-menthol was solved. Moreover, the stable and metastable experimental temperature-composition phase diagrams of the L-menthol/D-menthol binary system were determined. The thermodynamic relative stability of the different menthol polymorphs was also established. The present paper provides new physical, chemical and thermodynamic data of L-, D- and DL-menthol and offers new insight into their polymorphism as well as into the levorotatory-dextrorotatory menthol interactions. Both the thermodynamic and crystallographic approaches demonstrate unambiguously that racemic menthol is a racemate

Comprehensive determination of the solid state stability of bethanechol chloride active pharmaceutical ingredient using combined analytical tools

International audienceThe use of an integrative analytical approach allowed us to establish the intrinsic solid state stability of bethanechol chloride (BC), an active pharmaceutical ingredient used in the treatment of urinary retention. First, the crystal structure of the monoclinic form has been described using single crystal X-ray diffraction studies. Second, thermal analyses revealed that the compound degrades upon melting, with an apparent melting temperature estimated to be 231 °C. No transition from the monoclinic to the orthorhombic form has been observed, suggesting that the monoclinic form is the stable one. Third, the two-step melting–decomposition process has been elucidated by liquid chromatography and thermogravimetry coupled to mass spectrometry. The first step corresponds to the sample liquefaction, which consists of the gradual dissolution of bethanechol chloride in its liquid degradant, i.e. betamethylcholine chloride. This step is in agreement with Bawn kinetics and the activation energy of the reaction has been estimated at 35.5 kcal mol−1. The second step occurs with accelerated degradation in the melt. Elucidation of secondary decomposition pathways evidenced autocatalytic properties conferred by the formation of both isocyanic acid and methyl chloride. Finally, dynamic water vapor sorption analysis showed a substantial hygroscopicity of the drug substance. A deliquescent point has been determined at 56% relative humidity at 25 °C

rac-(3S,4S)-3-Hy­droxy-4-phenyl-1-[(S)-(3-phenyl-4,5-dihydro-1,2-oxazol-5-yl)meth­yl]-4,5-dihydro-1H-1,5-benzo­diazepin-2(3H)-one

In the title compound, C25H23N3O3, the seven-membered diazepine ring adopts a boat conformation with the hydroxy-substituted C atom at the prow and fused-ring C atoms at the stern. The crystal packing features C—H⋯O, C—H⋯π and N—H ⋯π inter­action

Synthèse de nouvelles xanthines, dérivées de 2-amino-2-oxazolines, antagonistes potentiels des récepteurs de l'adenosine

Ce travail de thèse nous a permis de synthétiser un grand nombre de nouveaux dérivés de type 1- ou 3-[2-hydroxy-3-aryloxypropyl]xanthines. Ces composés ont été obtenus à partir d'un synthon original de type amidine, les 2-amino-2-oxazolines. Les différentes voies réaxtionnelles nous ont conduit à des diaminouraciles intermédiaires diversement substitués dont les possibilités réactionnelles nous ont permis l'accès à plus de 60 nouvelles xanthines et analogues. Différentes stratégies de synthèse ont été développées pour accéder à de nouvelles xanthines 3 différemment substituées en position 1 et 7. L'ensemble de ces composés originaux a fait l'objet d'études de liaison en tant qu'antagonistes potentiels vis-vis des récepteurs de l'adénosine. Ces tests ont pu êttre réalisés grâce à une collaboration établie avec l'équipe du professeur C. Muller de l'Institut Pharmaceutique de l'Université de Bonn. Ces études pharmacologiques nous ont permis de déceler de nouveaux dérivés possédant une affinité de l'ordre de 30 à 100 nM et présentant, pour certains, une sélectivité notable vis-à-vis des récepteurs de l'adénosine A1 ou A2A. Ainsi, un groupement cycloalkyle, de type cyclopentyle ou noradamantyle, substitué en position 8 et associé à une chaîne propylique en position 1 (xanthines 3e et 3g) semble constituer un bon pharmacophore pour l'affinité vis-à-vis du récepteur de l'adénosine A1. De plus, ce modèle de xanthine ne présente pas de substitution en position 7. Par ailleurs, les motifs xanthines présentant un groupement méthoxystyryle en position 8 associé à une chaîne propargyle en position 1 (composé 3f) et un groupe méthyle en position 7 (composé 3k) ont révélé une affinité remarquable vis-à-vis du récepteur A2A.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Intramolecular Michael Additions in Uridine Derivatives: Isolation of the Labile 5′O-C6 Cyclonucleoside

International audienceUridine derivatives undergo a diastereospecific intramolecular hetero Michael addition onto uracil C6 to give cyclo-adducts. In contrast to the potent amine and thiol nucleophiles at the 5′ position of ribose, which readily give the N-and S-cyclonucleosides in good yields, the cyclization reaction from the "natural" 5′-hydroxyl is tedious and has so far been overlooked most probably because of the thermodynamic instability of the O-cyclo-adduct. Here, we show that the O-cyclonucleoside 1 can be isolated, although in low isolated yields, in acidic conditions following an original mechanism. Whether such cyclization reactions occur from biologically relevant pyrimidine-based nucleosides is an open question of interest. Given the structures of thymidine-based antiviral drugs, our results suggest a new hypothetical mode of action for these drugs

Efficient one-pot microwave-assisted synthesis of 3-(thien-3-yl)imidazolidine-2,4-dione analogs

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Synthesis of [7]Helicene Enantiomers and Exploratory Study of Their Conversion into Helically Chiral Iodoarenes and Iodanes

International audienc

Relative helix-helix conformations in branched aromatic oligoamide foldamers.

International audienceThe de novo design and synthesis of large and well-organized, tertiary-like, α-peptidic folded architectures is difficult because it relies on multiple cooperative interactions within and between secondary folded motifs of relatively weak intrinsic stability. The very stable helical structures of oligoamides of 8-amino-2-quinoline carboxylic acid offer a way to circumvent this difficulty thanks to their ability to fold into predictable and stable secondary motifs. Branched architectures comprised of two pairs of tetrameric (1), pentameric (2), or octameric (3) oligomers connected via an ethylene glycol spacer were designed and synthesized. The short spacer holds two helices in close proximity, thus enabling interactions between them. Degrees of freedom allowed in the system are well-defined: the relative P or M handedness of the two helices; the relative orientation of the helix axes; and the gauche or anti conformation of the ethylene spacer. Investigating the structures of 1-3 in the solid state and in solution allowed a detailed picture to be drawn of their conformational preferences and dynamics. The high variability of the solid state structures provides many snapshots of possible solution conformations. Helix-helix handedness communication was evidenced and shown to depend both on solvent and on a defined set of side chains at the helix-helix interface. Interdigitation of the side chains was found to restrict free rotation about the ethylene spacer. One solid state structure shows a high level of symmetry and provides a firm basis to further design specific side chain/side chain directional interactions