RESUMEN
The reaction between two equivalents of {(Me3Si)2CH}(Ph)PH(BH3) (1) and Bu2Mg, followed by two equivalents of BH3·SMe2, gives the corresponding phosphido-bis(borane) complex, which may be crystallised as two distinct chemical species: the complex [{(Me3Si)2CH}(Ph)P(BH3)2]2Mg(THF)4·THF (2a), and two different THF solvates (1 : 1 and 1 : 2) of the solvent-separated ion triples [{(Me3Si)2CH}(Ph)P(BH3)2]2[Mg(THF)6]·THF (2b) and [{(Me3Si)2CH}(Ph)P(BH3)2]2[Mg(THF)6]·2THF (2c). Similar reactions between two equivalents of 1 and either (4-tBuC6H4CH2)2Ca(THF)4 or [(Me3Si)2CH]2Sr(THF)2, followed by two equivalents of BH3·SMe2, give the heavier alkali metal complexes [{(Me3Si)2CH}(Ph)P(BH3)2]2M(THF)4 [M = Ca (3), Sr (4)]. Surprisingly, compounds 2a, 3 and 4 adopt almost identical structures in the solid state, which differ only in the geometrical arrangement of the phosphido-bis(borane) ligands and the hapticity of the borane groups.
RESUMEN
Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.
Asunto(s)
Compuestos de Bencidrilo/farmacocinética , Nootrópicos/farmacocinética , Compuestos de Fenilurea/farmacocinética , Inhibidores de Fosfodiesterasa 4/farmacocinética , Administración Intravenosa , Regulación Alostérica , Animales , Área Bajo la Curva , Compuestos de Bencidrilo/administración & dosificación , Estudios Cruzados , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Evaluación Preclínica de Medicamentos , Femenino , Macaca fascicularis , Nootrópicos/administración & dosificación , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Rolipram/farmacologíaRESUMEN
Structurally well-defined bimetallic titanium(IV) (salen) and monometallic vanadium(V) (salen) complexes have been used as catalysts for the asymmetric addition of trimethylsilyl cyanide to ß-nitroalkenes to produce chiral nitronitriles with ee values in the range of 79-89 % and conversions up to 100 % at 0 °C. The reaction conditions (solvent, temperature, time and vanadium complex counter-ion) were optimised, and it was shown that the catalyst loading could be significantly reduced (20 to 2 mol %) and the reaction temperature increased (-40 to 0 °C) compared to previous studies that used an in situ prepared catalyst. The results are compared and contrasted with previous results obtained by using the same catalysts for the asymmetric addition of trimethylsilyl cyanide to aldehydes, and a transition-state structure for the asymmetric addition of trimethylsilyl cyanide to nitroalkenes is proposed to account for the observed stereochemistry.
RESUMEN
Treatment of the secondary phosphine {(Me(3)Si)(2)CH}(Ph)PH with BH(3)·SMe(2) yields the phosphine-borane {(Me(3)Si)(2)CH}(Ph)PH(BH(3)) (12) as colorless crystals. The reactions between 12 and n-BuLi, PhCH(2)Na or PhCH(2)K yield the corresponding phosphido-borane complexes [[{(Me(3)Si)(2)CH}(Ph)P(BH(3))]Li(THF)(2)](∞) (13), [{(Me(3)Si)(2)CH}(Ph)P(BH(3))][Na(12-crown-4)(2)] (14), or [[{(Me(3)Si)(2)CH}(Ph)P(BH(3))]K(pmdeta)](2) (15), respectively, after crystallization in the presence of the appropriate co-ligand. While 13 crystallizes as a chain polymer, 14 crystallizes as a separated ion pair and 15 as a dimer. In both 13 and 15 the phosphido-borane ligands bind the alkali metal cations via both P-M and B-H···M contacts. Unexpectedly, NMR spectroscopy suggests that the separated ion pair 14 undergoes rapid inversion at phosphorus, while 13 and 15 do not. The phosphido-bis(borane) complexes [{(Me(3)Si)(2)CH}(Ph)P(BH(3))(2)]Li(12-crown-4) (16b), [[{(Me(3)Si)(2)CH}(Ph)P(BH(3))(2)]Na(THF)(2)](2) (17), and [[{(Me(3)Si)(2)CH}(Ph)P(BH(3))(2)]K(THF)(0.5)](∞) (18a) were prepared by treatment of the corresponding in situ-generated phosphido-borane complexes with BH(3)·SMe(2) and crystallization in the presence of the appropriate co-ligand. Compound 16b crystallizes as a monomer, while 17 crystallizes as a dimer and 18a crystallizes as a ribbon polymer. These crystallographic studies reveal entirely new binding modes for both phosphido-borane and phosphido-bis(borane) ligands and allow a direct comparison between these two ligand types.
Asunto(s)
Boranos/química , Metales Alcalinos/química , Compuestos Organometálicos/química , Fosfinas/química , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis químicaRESUMEN
Treatment of the secondary phosphine {(Me(3)Si)(2)CH}PH(C(6)H(4)-2-SMe) with BH(3)·SMe(2) gives the corresponding phosphine-borane {(Me(3)Si)(2)CH}PH(BH(3))(C(6)H(4)-2-SMe) (9) as a colourless solid. Deprotonation of 9 with n-BuLi, PhCH(2)Na or PhCH(2)K proceeds cleanly to give the corresponding alkali metal complexes [[{(Me(3)Si)(2)CH}P(BH(3))(C(6)H(4)-2-SMe)]ML](n) [ML = Li(THF), n = 2 (10); ML = Na(tmeda), n = ∞ (11); ML = K(pmdeta), n = 2 (12)] as yellow/orange crystalline solids. X-ray crystallography reveals that the phosphido-borane ligands bind the metal centres through their sulfur and phosphorus atoms and through the hydrogen atoms of the BH(3) group in each case, leading to dimeric or polymeric structures. Compounds 10-12 are stable towards both heat and ambient light; however, on heating in toluene solution in the presence of 10, traces of free phosphine-borane 9 are slowly converted to the free phosphine {(Me(3)Si)(2)CH}PH(C(6)H(4)-2-SMe) (5) with concomitant formation of the corresponding phosphido-bis(borane) complex [{(Me(3)Si)(2)CH}P(BH(3))(2)(C(6)H(4)-2-SMe)]Li (14).