Enantioselective Amination of 4-Substituted Pyrazolones Catalyzed by Oxindole-Containing Thioureas and by a Recyclable Linear-Polymer-Supported Analogue in a Continuous Flow Process.

A highly efficient organocatalytic amination of 4-substituted pyrazolones with azodicarboxylates mediated by a novel quinine-derived thiourea with a 3,3-diaryl-oxindole scaffold is reported. This synthetic method furnished 4-amino-5-pyrazolones in high yields and with excellent enantioselectivities (up to 97:3 er) at room temperature in short reaction times. Moreover, a linear-polymer-supported bifunctional thiourea, synthesized by reacting a bifunctional aromatic monomer (biphenyl) with isatin in superacidic media and further derivatization, was proven to be also an efficient heterogeneous organocatalyst for this α-amination reaction. The practical value of this process was demonstrated by the use of the immobilized catalyst in recycling experiments, maintaining the activity without additional reactivation, and in flow processes, allowing the synthesis of 4-amino-pyrazolone derivatives in a gram scale with high yield and enantioselectivity.

Access to Spiropyrazolone-butenolides through NHC-Catalyzed [3 + 2]-Asymmetric Annulation of 3-Bromoenals and 1H-Pyrazol-4,5-diones.

The stereoselective synthesis of spirocyclic pyrazolin-5-ones by N-heterocyclic carbene (NHC) organocatalysis has been less studied so far. For this reason and considering the interest of this class of compounds, here, we present the NHC-catalyzed [3 + 2]-asymmetric annulation of ß-bromoenals and 1H-pyrazol-4,5-diones that achieves to produce chiral spiropyrazolone-butenolides. The synthesis is general for aryl and heteroaryl ß-bromo-α,ß-unsaturated aldehydes and 1,3-disubstituted pyrazolones. The spirobutenolides have been obtained in good yields (up to 88%) and enantioselectivities (up to 97:3 er). This constitutes the first described example using pyrazoldiones as the starting materials for this class of spiro compounds.

Organocatalytic asymmetric synthesis of oxazolidino spiropyrazolinones via N,O-acetalization/aza Michael addition domino reaction between N-Boc pyrazolinone ketimines and γ-hydroxyenones.

A squaramide-catalyzed asymmetric N,O-acetalization/aza Michael addition domino reaction between N-Boc ketimines derived from pyrazolin-5-ones and γ-hydroxyenones has been developed for the construction of pyrazolinone embedded spirooxazolidines. A hydroquinine derived bifunctional squaramide catalyst was found to be the most effective for this cascade spiroannulation. This new protocol allows the generation of two stereocenters and the desired products are obtained in good yields with moderate to good diastereoselectivities (up to 3.3 : 1 dr) and high enantioselectivities (up to >99% ee) from a range of substituted N-Boc pyrazolinone ketimines and γ-hydroxyenones. The developed protocol is amenable for a scale-up reaction.

Squaramide-Catalyzed Asymmetric Mannich Reaction between 1,3-Dicarbonyl Compounds and Pyrazolinone Ketimines: A Pathway to Enantioenriched 4-Pyrazolyl- and 4-Isoxazolyl-4-aminopyrazolone Derivatives.

A series of N-Boc ketimines derived from pyrazolin-5-ones have been used as electrophiles in enantioselective Mannich reactions with different 1,3-dicarbonyl compounds. This method provides a direct pathway to access the 4-amino-5-pyrazolone derivatives bearing a quaternary substituted stereocenter and containing two privileged structure motifs, the ß-diketone and pyrazolinone substructures. The adducts were obtained in excellent yields (up to 90%) and enantioselectivities (up to 94:6 er) by employing a very low loading of 2 mol% of a quinine-derived bifunctional squaramide as an organocatalyst for a wide range of substrates. In addition, the utility of the obtained products was demonstrated through one step transformations to enantioenriched diheterocyclic systems (4-pyrazolyl-pyrazolone and 4-isoxazolyl-pyrazolone), potentially promising candidates for drug discovery.

Bifunctional thiourea-modified polymers of intrinsic microporosity for enantioselective α-amination of 3-aryl-2-oxindoles in batch and flow conditions.

Two novel polymers of intrinsic microporosity decorated with chiral thioureas have been used as recoverable organocatalysts in enantioselective α-amination of 3-aryl-substituted oxindoles, creating a quaternary stereocenter. Both catalysts were able to promote the reaction in excellent yields and good enantioselection. Catalyst II, with a pyridyl nucleus, was used in recycling experiments maintaining the activity without additional reactivation, and in flow processes allowing the synthesis of the amination product in multigram scale.

'Apuntes en Neurología': una síntesis de la evidencia en trastornos neurológicos comunes paroxísticos y en trastornos neurodegenerativos / 'Apuntes en Neurología' (Notes in Neurology): a synthesis of the evidence on common paroxysmal neurological disorders and on neurodegenerative disorders

Apuntes en Neurología' es una iniciativa en la cual líderes de primera línea nacional e internacional, con amplio reconocimiento académico, se reunieron para sintetizar los aspectos clínicos más destacables dentro de su área de interés y acercar las novedades en una lengua más próxima. Entender los factores que afectan al inicio y progresión de cualquier enfermedad neurológica a través de una revisión es importante para el desarrollo de estrategias en pro de reducir la carga de estas enfermedades, y conocer los aspectos clínicos es esencial para poder resolver los problemas de la practica clínica diaria. Los datos aquí recogidos reflejan el peso de la evidencia y algunos de ellos anticipan un futuro prometedor en el tratamiento de estas enfermedades. Esta primera edición se centra en trastornos neurológicos comunes paroxísticos como la migraña, la epilepsia y las alteraciones del sueño, y en trastornos neurodegenerativos como la enfermedad de Parkinson y el deterioro cognitivo. Se trata de patologías claramente diferentes, si bien algunas de ellas, como la migraña y la epilepsia, pueden compartir sintomatología clínica. Los trastornos del sueño, por su parte, son manifestaciones importantes de enfermedades neurodegenerativas que, en ocasiones, son clínicamente evidentes mucho antes del inicio de otros síntomas neurológicos. Tras recordar la fisiopatología y el diagnostico, la revisión actual se centra en acercar los principales avances en cinco de las principales enfermedades neurológicas

Introduction. 'Apuntes en Neurologia' is an initiative in which prominent national and international leaders, with broad academic recognition, came together to synthesise the most outstanding clinical aspects within their area of interest and to discuss the latest developments in a more accessible language. Understanding the factors that affect the onset and progression of any neurological disease through a review is important to be able to develop strategies to reduce the burden of these diseases. Moreover, knowledge of the clinical aspects is essential to solve the problems of daily clinical practice. The data collected here reflect the weight of evidence and some of them anticipate a promising future in the treatment of these diseases. This first edition focuses on common paroxysmal neurological disorders such as migraine, epilepsy and sleep disorders, as well as neurodegenerative disorders such as Parkinson' disease and cognitive impairment. These are clearly different pathologies, although some of them such as migraine and epilepsy, may share clinical symptoms. Sleep disorders, however, are important manifestations of neurodegenerative diseases that are sometimes clinically apparent long before the onset of other neurological symptoms. After recalling pathophysiology and diagnosis, the current review focuses on bringing together the main advances in five of the major neurological diseases

Chiral Bifunctional Thioureas and Squaramides and Their Copolymers as Recoverable Organocatalysts. Stereoselective Synthesis of 2-Substituted 4-Amino-3-nitrobenzopyrans and 3-Functionalized 3,4-Diamino-4 H-Chromenes.

Novel styryl-substituted thioureas and squaramides were obtained in three steps from commercially available 4-hydroxy-3,5-dichloroaniline. These organocatalysts promote cascade reactions in high yields and excellent stereoselection. By using only a 5 mol % loading of catalyst, it is possible to obtain 2,3,4-trisubstituted benzopyrans by reaction of α-amido sulfones derived from salicyladehydes and nitrostyrenes or 2,3,4-trisubstituted 4 H-chromenes by reaction of the same α-amido sulfones with (phenylsulfonyl)acetonitrile in excellent diastereo- and enantioselectivities. Two polymeric thioureas and squaramides were prepared by copolymerization of the best monomeric catalysts with styrene and divinylbenzene and used for the same transformations. These polymers behave also as excellent stereoselective catalysts that can be recovered and reused for five cycles.

Chiral Bifunctional Thioureas and Squaramides Grafted into Old Polymers of Intrinsic Microporosity for Novel Applications.

We have prepared different polymeric chiral bifunctional thioureas and squaramides by modification of the very well-known polymers of intrinsic microporosity (PIM), specifically PIM-1 and PIM-CO-1, to be used as recoverable organocatalysts. The installation of the chiral structures into the polymers has been done in two or three steps in high yields. The catalytic activity of the resulting materials has been proved in the stereoselective nitro-Michael addition and in a cascade process, which allows the synthesis of enantioenriched 4H-chromene derivatives. Squaramide II and thiourea III have been used in six cycles maintaining their activity.

Diastereo- and Enantioselective Syntheses of Trisubstituted Benzopyrans by Cascade Reactions Catalyzed by Monomeric and Polymeric Recoverable Bifunctional Thioureas and Squaramides.

4-Vinylphenyl-substituted squaramides have been tested as organocatalysts for the diastereo- and enantioselective synthesis of trisubstituted benzopyrans via an oxa-Michael intramolecular nitro-Michael cascade reaction. Both the enantio- and diastereoselection were good to moderate, depending on the nature of the chiral scaffold in the catalyst. The diastereoselection is better for the most active catalyst because the final products epimerize at C-3 along the time. Supported squaramide sq-9 prepared by copolymerization of sq-4 with styrene and divinylbenzene is also effective in promoting the cascade reaction, and it is recoverable and reusable for five cycles maintaining the activity.

Supported and Unsupported Chiral Squaramides as Organocatalysts for Stereoselective Michael Additions: Synthesis of Enantiopure Chromenes and Spirochromanes.

Novel supported chiral bifunctional squaramides have been easily prepared starting from diamines derived from natural amino acids and commercially available aminoalkyl polystyrene resins. These squaramides behave as excellent stereoselective recoverable organocatalysts in different Michael additions, in neat conditions at room temperature. The reaction on 2-(2-nitrovinyl) phenol as electrophile lead, in excellent yields and enantioselectivities, to intermediates that can be easily transformed into 4H-chromenes, and spirochromanones.

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions.

The catalytic activity of different supported bifunctional thioureas on sulfonylpolystyrene resins has been studied in the nitro-Michael addition of different nucleophiles to trans-ß-nitrostyrene derivatives. The activity of the catalysts depends on the length of the tether linking the chiral thiourea to the polymer. The best results were obtained with the thiourea derived from (L)-valine and 1,6-hexanediamine. The catalysts can be used in only 2 mol % loading, and reused for at least four cycles in neat conditions. The ball milling promoted additions also worked very well.

Bottom-Up Synthesis of Supported Thioureas and Their Use in Enantioselective Solvent-Free Aza-Henry and Michael Additions.

Two sets of supported chiral thioureas, which differ in the length of the tether that connects the chiral appendage to the polymer structure and the effective functionalization, have been prepared by copolymerization of styrene, novel styryl thioureas derived from l-valine, and divinylbenzene. The efficiency of these polymeric thioureas has been tested in two different enantioselective transformations, namely, aza-Henry and nitro-Michael reactions, in neat reaction conditions. The obtained results show that it is possible to recycle the thiourea, and they are able to promote the reactions with good enantioselectivity at a low catalyst loading.

Recambio plasmático terapéutico: aplicaciones en neurología / Therapeutic plasma exchange: applications in neurology

Introducción. El recambio plasmático es una técnica utilizada en el tratamiento de algunas enfermedades neurológicas de base autoinmune desde los años ochenta, especialmente en situaciones agudas. En los últimos años se han publicado nuevos datos sobre su empleo en numerosas entidades con base autoinmune, ampliando, con ello, el espectro de utilización. Objetivo. Actualizar las indicaciones de esta técnica en el tratamiento de las enfermedades neurológicas. Desarrollo. Se ha realizado una revisión exhaustiva de todos los artículos publicados desde los años ochenta sobre la eficacia del recambio plasmático en el tratamiento de las diferentes enfermedades neurológicas. También se ha efectuado un análisis detallado de las recomendaciones y evidencias de la utilización de este procedimiento por parte de las diferentes sociedades científicas. Conclusiones. El recambio plasmático ha demostrado ser una alternativa eficaz con evidencia científica de primer nivel en enfermedades como el síndrome de Guillain-Barré, la polineuropatía desmielinizante inflamatoria crónica o la miastenia grave. Ha mostrado ser eficaz en el tratamiento de episodios desmielinizantes agudos sin respuesta a otras terapias, en los brotes de neuromielitis óptica y en otras enfermedades del sistema nervioso central producidas por anticuerpos. En los estudios comparativos con inmunoglobulinas intravenosas, la eficacia de ambas terapias es similar. Es preciso seguir realizando estudios comparativos para conocer mejor los mecanismos y establecer indicaciones prioritarias y comparar la relación coste-eficacia de ambos procedimientos (AU)

Introduction. Plasma exchange is a technique used in the treatment of some neurological autoimmune disorders since the 80s, especially in acute conditions. In recent years new data about it use has been published in many diseases with autoimmune basis, expanding the range of use of this technique. Aim. To update the current indications of this technique in the treatment of neurological diseases. Development. We conducted a thorough review of all articles about the efficacy of plasma exchange in the treatment of different neurological diseases published since the 80s. We have also carried out a detailed analysis of recommendations and evidence of the use of this procedure by analyzing the guidelines of different scientific societies. Conclusions. Plasma exchange has proven to be an effective alternative treatment with high grade scientific evidence in diseases such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis. It has been effective in treating acute demyelinating episodes unresponsive to other therapies, neuromyelitis optica relapses and other central nervous system diseases induced by antibodies. In comparative studies with intravenous immunoglobulin efficacy of both therapies is similar. Comparative studies should continue to be conducted in order to better understand the mechanisms of action, prioritize indications and compare the cost-effectiveness ratio of both procedures (AU)

[Therapeutic plasma exchange: applications in neurology]. / Recambio plasmático terapéutico: aplicaciones en neurología.

INTRODUCTION: Plasma exchange is a technique used in the treatment of some neurological autoimmune disorders since the 80s, especially in acute conditions. In recent years new data about it use has been published in many diseases with autoimmune basis, expanding the range of use of this technique. AIM: To update the current indications of this technique in the treatment of neurological diseases. DEVELOPMENT: We conducted a thorough review of all articles about the efficacy of plasma exchange in the treatment of different neurological diseases published since the 80s. We have also carried out a detailed analysis of recommendations and evidence of the use of this procedure by analyzing the guidelines of different scientific societies. CONCLUSIONS: Plasma exchange has proven to be an effective alternative treatment with high grade scientific evidence in diseases such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis. It has been effective in treating acute demyelinating episodes unresponsive to other therapies, neuromyelitis optica relapses and other central nervous system diseases induced by antibodies. In comparative studies with intravenous immunoglobulin efficacy of both therapies is similar. Comparative studies should continue to be conducted in order to better understand the mechanisms of action, prioritize indications and compare the cost-effectiveness ratio of both procedures.

TITLE: Recambio plasmatico terapeutico: aplicaciones en neurologia.Introduccion. El recambio plasmatico es una tecnica utilizada en el tratamiento de algunas enfermedades neurologicas de base autoinmune desde los años ochenta, especialmente en situaciones agudas. En los ultimos años se han publicado nuevos datos sobre su empleo en numerosas entidades con base autoinmune, ampliando, con ello, el espectro de utilizacion. Objetivo. Actualizar las indicaciones de esta tecnica en el tratamiento de las enfermedades neurologicas. Desarrollo. Se ha realizado una revision exhaustiva de todos los articulos publicados desde los años ochenta sobre la eficacia del recambio plasmatico en el tratamiento de las diferentes enfermedades neurologicas. Tambien se ha efectuado un analisis detallado de las recomendaciones y evidencias de la utilizacion de este procedimiento por parte de las diferentes sociedades cientificas. Conclusiones. El recambio plasmatico ha demostrado ser una alternativa eficaz con evidencia cientifica de primer nivel en enfermedades como el sindrome de Guillain-Barre, la polineuropatia desmielinizante inflamatoria cronica o la miastenia grave. Ha mostrado ser eficaz en el tratamiento de episodios desmielinizantes agudos sin respuesta a otras terapias, en los brotes de neuromielitis optica y en otras enfermedades del sistema nervioso central producidas por anticuerpos. En los estudios comparativos con inmunoglobulinas intravenosas, la eficacia de ambas terapias es similar. Es preciso seguir realizando estudios comparativos para conocer mejor los mecanismos y establecer indicaciones prioritarias y comparar la relacion coste-eficacia de ambos procedimientos.

One-pot sequential organocatalytic Michael-Tishchenko-lactonization reactions. Synthesis of enantioenriched 4,5,6-trisubstituted δ-lactones.

Enantioenriched trisubstituted lactones were obtained in good yields and moderate to very good enantioselectivities in one-pot process, which implies a sequential organocatalyzed Michael addition of ketones to enals, followed by catalytic intramolecular diastereoselective Tishchenko reaction and lactonization. The final lactones were obtained as single diastereoisomers, demonstrating that the mixture of the anti and syn diastereomers epimerized to the syn hydroxy ester during the oxido-reduction step.

Diferencias entre ganadores y perdedores en la utilización de posiciones y espacios de juego en rugby internacional / Differences between winners and losers in the use of positions and spaces play in international rugby

El objetivo de este estudio fue determinar diferencias en la utilización de las distintas posiciones de juego y los espacios de juego entre equipos ganadores y perdedores en rugby internacional desde una perspectiva cualitativa. Para ello, se recogieron los datos de los partidos disputados en la Copa del Mundo de Rugby 2007 (n=48). Los resultados muestran como los equipos ganadores utilizan más jugadores combinan el juego de delanteros y tres cuartos. Estos resultados pueden indicar que los jugadores delanteros de equipos ganadores, además de participar en la obtención de los balones tienen mayor protagonismo en el juego abierto (AU)

The objective of this study was to determine differences in the use of the different positions of play and play spaces between winning and losing teams in World Cup 2007 from a qualitative perspective. To do this, we collected data from games played in the (..) (AU)

[Onabotulinumtoxin A in the treatment of chronic migraine]. / Onabotulinumtoxin A en el tratamiento de la migraña crónica.

INTRODUCTION. Chronic migraine is the most frequent complication of migraine. Its management is complex and difficult, and is based essentially on preventive measures. AIM. To analyse the development of the use of Onabotulinumtoxin A (OnabotA) in migraine, especially in its chronic form, the method of administration, its mechanism of action, its safety profile and its possible indications in clinical practice. DEVELOPMENT. The study conducts a thorough review of all the clinical trials in the literature that have used OnabotA in the prevention of migraine, both in its episodic and its chronic forms, and the outcomes in the chronic form are analysed in detail. CONCLUSIONS. In studies in phase III, OnabotA has proved to be effective in the treatment of patients with chronic migraine, with significant reductions in the mean frequency of days with headaches, the number of headache episodes, the days with migraine or the proportion of patients with severe disability, in addition to other parameters. It is also effective in the subgroup of patients with symptomatic headache due to medication abuse. OnabotA has proved to be safe and well tolerated in this indication, with foreseeable, usually mild or moderate, transitory side effects. In sum, OnabotA is a safe, well-tolerated alternative in the preventive treatment of chronic migraine.

Onabotulinumtoxin A en el tratamiento de la migraña crónica / Onabotulinumtoxin A in the treatment of chronic migraine

Introducción. La migraña crónica constituye la complicación más frecuente de la migraña. Su manejo es complejo y difícil y se basa fundamentalmente en la profilaxis. Objetivo. Analizar el desarrollo de la utilización de Onabotulinumtoxin A (OnabotA) en la migraña, especialmente en su forma crónica, el modo de administración, su mecanismo de acción, el perfil de seguridad y sus posibles indicaciones en la práctica clínica. Desarrollo. Se realiza una revisión exhaustiva de todos los ensayos clínicos publicados que han utilizado OnabotA en la prevención de la migraña, tanto en su forma episódica como crónica, y se analizan detalladamente los resultados en la forma crónica. Conclusiones. En los estudios en fase III, la OnabotA ha demostrado ser eficaz en el tratamiento de pacientes con migraña crónica al reducir significativamente la frecuencia media de días de dolor de cabeza, los episodios de dolor de cabeza, los días de migraña o la proporción de pacientes con discapacidad grave, además de otros parámetros. Es eficaz también en el subgrupo de pacientes con cefalea por abuso de medición sintomática. La OnabotA se ha mostrado segura y bien tolerada en esta indicación, con efectos adversos previsibles, habitualmente leves o moderados, y pasajeros. En definitiva, la OnabotA constituye una alternativa eficaz y bien tolerada en el tratamiento preventivo de la migraña crónica (AU)

Introduction. Chronic migraine is the most frequent complication of migraine. Its management is complex and difficult, and is based essentially on preventive measures. Aim. To analyse the development of the use of Onabotulinumtoxin A (OnabotA) in migraine, especially in its chronic form, the method of administration, its mechanism of action, its safety profile and its possible indications in clinical practice. Development. The study conducts a thorough review of all the clinical trials in the literature that have used OnabotA in the prevention of migraine, both in its episodic and its chronic forms, and the outcomes in the chronic form are analysed in detail. Conclusions. In studies in phase III, OnabotA has proved to be effective in the treatment of patients with chronic migraine, with significant reductions in the mean frequency of days with headaches, the number of headache episodes, the days with migraine or the proportion of patients with severe disability, in addition to other parameters. It is also effective in the subgroup of patients with symptomatic headache due to medication abuse. OnabotA has proved to be safe and well tolerated in this indication, with foreseeable, usually mild or moderate, transitory side effects. In sum, OnabotA is a safe, well-tolerated alternative in the preventive treatment of chronic migraine (AU)

Enantioselective conjugate addition of nitro compounds to α,ß-unsaturated ketones: an experimental and computational study.

A series of chiral thioureas derived from easily available diamines, prepared from α-amino acids, have been tested as catalysts in the enantioselective Michael additions of nitroalkanes to α,ß-unsaturated ketones. The best results are obtained with the bifunctional catalyst prepared from L-valine. This thiourea promotes the reaction with high enantioselectivities and chemical yields for aryl/vinyl ketones, but the enantiomeric ratio for alkyl/vinyl derivatives is very modest. The addition of substituted nitromethanes led to the corresponding adducts with excellent enantioselectivity but very poor diastereoselectivity. Evidence for the isomerization of the addition products has been obtained from the reaction of chalcone with [D(3)]nitromethane, which shows that the final addition products epimerize under the reaction conditions. The epimerization explains the low diastereoselectivity observed in the formation of adducts with two adjacent tertiary stereocenters. Density functional studies of the transition structures corresponding to two alternative activation modes of the nitroalkanes and α,ß-unsaturated ketones by the bifunctional organocatalyst have been carried out at the B3LYP/3-21G* level. The computations are consistent with a reaction model involving the Michael addition of the thiourea-activated nitronate to the ketone activated by the protonated amine of the organocatalyst. The enantioselectivities predicted by the computations are consistent with the experimental values obtained for aryl- and alkyl-substituted α,ß-unsaturated ketones.

Highly diastereo- and enantioselective direct Barbas-List aldol reactions promoted by novel benzamidoethyl and benzamidopropyl prolinamides in water.

Four novel benzamido-functionalized prolinamides have been prepared and tested as organocatalysts for enantioselective aldol reaction of aldehydes and cyclic ketones in water. In particular, prolinamide derived from achiral ethylene diamine was the best catalyst leading to anti aldols in excellent diastereomeric (up to 98/2) and enantiomeric (up to 99/1) ratios, thereby showing that lateral amide functionalities might be a key issue for facilitating "in water" chemistry. These catalysts are cheaper and easier to prepare than those previously described.