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Xavier Florence - One of the best experts on this subject based on the ideXlab platform.
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influence of the alkylsulfonylamino substituent located at the 6 position of 2 2 dimethylchromans structurally related to cromakalim from potassium channel openers to calcium entry blockers
European Journal of Medicinal Chemistry, 2014Co-Authors: Xavier Florence, Pascal De Tullio, Bernard Pirotte, Vincent Desvaux, Eric Goffin, Philippe LebrunAbstract:The present study described the synthesis of original R/S-6-alkylsulfonylamino-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyrans bearing a 3- or 4-substituted phenylthiourea or phenylurea moiety at the 4-position. Their biological effects were evaluated both on insulin-secreting and smooth muscle cells and were compared to those of reference KATP channel activators such as (±)-cromakalim, diazoxide and previously synthesized cromakalim analogues. The study aimed at exploring the influence of the introduction of an alkylsulfonylamino substituent at the 6-position of 2,2-dimethylchromans in order to improve biological activity, tissue selectivity but also hydrophilicity of dihydroBenzopyran derivatives. Several compounds were found to be equipotent or even more potent than (±)-cromakalim and diazoxide at inhibiting the insulin releasing process. Most of the newly synthesized and more hydrophilic dihydroBenzopyrans also exhibited a marked vasorelaxant activity although they were less potent than (±)-cromakalim. Additional pharmacological and radioisotopic investigations suggested that R/S-N-3-chlorophenyl-N'-(3,4-dihydro-6-methylsulfonylamino-2,2-dimethyl-2H-1-Benzopyran-4-yl)thiourea (21) did not act as a potassium channel opener but rather as a Ca(2+) entry blocker.
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Modulation of the 6-position of Benzopyran derivatives and inhibitory effects on the insulin releasing process
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Xavier Florence, Pascal De Tullio, Bernard Pirotte, Sébastien Dilly, Philippe LebrunAbstract:The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyrans is described. All of these new Benzopyran derivatives were bearing, at the 4-position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electron-withdrawing group such as Cl or CN. The study aimed at exploring the influence of the nature of the substituent at the 6-position in order to develop new Benzopyran-type K(ATP) channel activators exhibiting an improved selectivity towards the insulin secreting cells. The original compounds were examined in vitro on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (vasorelaxant effect) and their activity was compared to that of the reference K(ATP) channel activators (±)-cromakalim, (±)-pinacidil, diazoxide and to previously synthesized cromakalim analogues. Structure-activity relationships indicated that the inhibitory effect on the insulin secreting cells was related to the lipophilicity of the molecules and to the size of the substituent located at the 6-position. A marked inhibitory activity on the insulin secretory process was obtained with molecules bearing a bulky tert-butyloxycarbonylamino group at the 6-position (20-23). The latter compounds were found to have the same efficacy on the pancreatic endocrine tissue than some previously described molecules. Lastly, radioisotopic experiments further identified R/S-N-4-chlorophenyl-N'-(6-tert-butyloxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyran-4-yl)thiourea (23) as a K(ATP) channel opener.
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development and validation of a nonaqueous capillary electrophoretic method for the enantiomeric purity determination of a synthetic intermediate of new 3 4 dihydro 2 2 dimethyl 2h 1 Benzopyrans using a single isomer anionic cyclodextrin derivative a
Journal of Chromatography A, 2010Co-Authors: Anne Rousseau, Xavier Florence, Bernard Pirotte, Anne Varenne, Pierre Gareil, Didier Villemin, Patrice Chiap, Jacques Crommen, Marianne Fillet, Annecatherine ServaisAbstract:Abstract The enantiomeric purity determination of a synthetic intermediate of new 3,4-dihydro-2,2-dimethyl-2 H -1-Benzopyrans, i.e. 4-amino-2,2-dimethyl-6-ethoxycarbonylamino-3,4-dihydro-2 H -1-Benzopyran, was successfully carried out using an anionic cyclodextrin (CD) derivative combined with a chiral ionic liquid (IL). In order to obtain high resolution and efficiency values, the addition of a chiral IL, i.e. ethylcholine bis(trifluoromethylsulfonyl)imide (EtChol NTf 2 ), to the background electrolyte containing heptakis(2,3-di- O -methyl-6- O -sulfo)-β-CD (HDMS-β-CD) was found to be essential. A simultaneous increase in separation selectivity and enantioresolution seems to indicate a synergistic effect of HDMS-β-CD and EtChol NTf 2 . The best enantioseparation of the key intermediate was achieved using a methanolic solution of 0.75 M formic acid, 10 mM ammonium formate, 1.5 mM HDMS-β-CD and 5 mM EtChol NTf 2 . Levamisole was selected as internal standard. The optimized conditions allowed the determination of 0.1% of each enantiomer in the presence of its stereoisomer using the method of standard additions. The NACE method was then fully validated with respect to selectivity, response function, trueness, precision, accuracy, linearity and limits of detection and quantification.
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new r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminothiocarbonylamino 2h 1 Benzopyrans structurally related to cromakalim as tissue selective pancreatic β cell katp channel openers
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Sophie Sebille, Pascal De Tullio, Xavier Florence, Bernard Pirotte, B Becker, Mariehelene Antoine, Catherine Michaux, Johan Wouters, Philippe LebrunAbstract:The present work was aimed at exploring a series of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-Benzopyrans structurally related to (+/-)-cromakalim and differently substituted at the 4- and 6-positions. The biological effects of these putative activators of ATP-sensitive potassium channels (K(ATP)) were characterized in vitro on the pancreatic endocrine tissue (inhibition of insulin release) and on the vascular smooth muscle tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine atom on the C-4 phenyl ring, independently of the nature of the halogen atom at the 6-position of the Benzopyran nucleus. Most original dimethylchroman thioureas were more potent than their 'urea' homologues and even more potent than diazoxide at inhibiting insulin release. Moreover, and unlike (+/-)-cromakalim or (+/-)-pinacidil, such compounds appeared to be highly selective towards the pancreatic tissue. Radioisotopic and fluorimetric investigations indicated that the new drugs activated pancreatic K(ATP) channels. Lastly, conformational studies suggested that the urea/thiourea dimethylchromans can be regarded as hybrid compounds between cromakalim and pinacidil.
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design synthesis and pharmacological evaluation of r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminocarbonylamino 2h 1 Benzopyrans toward tissue selective pancreatic beta cell katp channel openers structurally related to cromakalim
Journal of Medicinal Chemistry, 2006Co-Authors: Sophie Sebille, David Gall, Pascal De Tullio, Xavier Florence, Philippe Lebrun, Bernard PirotteAbstract:In the search of a novel series of Benzopyrans structurally related to (+/-)-cromakalim and acting as pancreatic beta-cell potassium channel openers, several R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-Benzopyrans with or without a substituent on the phenyl ring in the 4-position were synthesized. Their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K(ATP) channel activators (+/-)-cromakalim, diazoxide, (+/-)-pinacidil, and compound 4. Structure-activity relationships indicated that the most pronounced inhibitory activity on the pancreatic tissue was obtained by introducing a meta- or para-electron-withdrawing group (a chlorine atom) on the C-4 phenyl ring (drugs 37-42). Such molecules, unlike the parent compound (+/-)-cromakalim, also exhibited a high selectivity for the pancreatic tissue versus the vascular tissue. Radioisotopic and electrophysiological investigations performed with R/S-6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyran (38) confirmed that the drug activated pancreatic KATP channels.
Philippe Lebrun - One of the best experts on this subject based on the ideXlab platform.
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influence of the alkylsulfonylamino substituent located at the 6 position of 2 2 dimethylchromans structurally related to cromakalim from potassium channel openers to calcium entry blockers
European Journal of Medicinal Chemistry, 2014Co-Authors: Xavier Florence, Pascal De Tullio, Bernard Pirotte, Vincent Desvaux, Eric Goffin, Philippe LebrunAbstract:The present study described the synthesis of original R/S-6-alkylsulfonylamino-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyrans bearing a 3- or 4-substituted phenylthiourea or phenylurea moiety at the 4-position. Their biological effects were evaluated both on insulin-secreting and smooth muscle cells and were compared to those of reference KATP channel activators such as (±)-cromakalim, diazoxide and previously synthesized cromakalim analogues. The study aimed at exploring the influence of the introduction of an alkylsulfonylamino substituent at the 6-position of 2,2-dimethylchromans in order to improve biological activity, tissue selectivity but also hydrophilicity of dihydroBenzopyran derivatives. Several compounds were found to be equipotent or even more potent than (±)-cromakalim and diazoxide at inhibiting the insulin releasing process. Most of the newly synthesized and more hydrophilic dihydroBenzopyrans also exhibited a marked vasorelaxant activity although they were less potent than (±)-cromakalim. Additional pharmacological and radioisotopic investigations suggested that R/S-N-3-chlorophenyl-N'-(3,4-dihydro-6-methylsulfonylamino-2,2-dimethyl-2H-1-Benzopyran-4-yl)thiourea (21) did not act as a potassium channel opener but rather as a Ca(2+) entry blocker.
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Modulation of the 6-position of Benzopyran derivatives and inhibitory effects on the insulin releasing process
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Xavier Florence, Pascal De Tullio, Bernard Pirotte, Sébastien Dilly, Philippe LebrunAbstract:The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyrans is described. All of these new Benzopyran derivatives were bearing, at the 4-position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electron-withdrawing group such as Cl or CN. The study aimed at exploring the influence of the nature of the substituent at the 6-position in order to develop new Benzopyran-type K(ATP) channel activators exhibiting an improved selectivity towards the insulin secreting cells. The original compounds were examined in vitro on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (vasorelaxant effect) and their activity was compared to that of the reference K(ATP) channel activators (±)-cromakalim, (±)-pinacidil, diazoxide and to previously synthesized cromakalim analogues. Structure-activity relationships indicated that the inhibitory effect on the insulin secreting cells was related to the lipophilicity of the molecules and to the size of the substituent located at the 6-position. A marked inhibitory activity on the insulin secretory process was obtained with molecules bearing a bulky tert-butyloxycarbonylamino group at the 6-position (20-23). The latter compounds were found to have the same efficacy on the pancreatic endocrine tissue than some previously described molecules. Lastly, radioisotopic experiments further identified R/S-N-4-chlorophenyl-N'-(6-tert-butyloxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyran-4-yl)thiourea (23) as a K(ATP) channel opener.
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new r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminothiocarbonylamino 2h 1 Benzopyrans structurally related to cromakalim as tissue selective pancreatic β cell katp channel openers
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Sophie Sebille, Pascal De Tullio, Xavier Florence, Bernard Pirotte, B Becker, Mariehelene Antoine, Catherine Michaux, Johan Wouters, Philippe LebrunAbstract:The present work was aimed at exploring a series of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-Benzopyrans structurally related to (+/-)-cromakalim and differently substituted at the 4- and 6-positions. The biological effects of these putative activators of ATP-sensitive potassium channels (K(ATP)) were characterized in vitro on the pancreatic endocrine tissue (inhibition of insulin release) and on the vascular smooth muscle tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine atom on the C-4 phenyl ring, independently of the nature of the halogen atom at the 6-position of the Benzopyran nucleus. Most original dimethylchroman thioureas were more potent than their 'urea' homologues and even more potent than diazoxide at inhibiting insulin release. Moreover, and unlike (+/-)-cromakalim or (+/-)-pinacidil, such compounds appeared to be highly selective towards the pancreatic tissue. Radioisotopic and fluorimetric investigations indicated that the new drugs activated pancreatic K(ATP) channels. Lastly, conformational studies suggested that the urea/thiourea dimethylchromans can be regarded as hybrid compounds between cromakalim and pinacidil.
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design synthesis and pharmacological evaluation of r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminocarbonylamino 2h 1 Benzopyrans toward tissue selective pancreatic beta cell katp channel openers structurally related to cromakalim
Journal of Medicinal Chemistry, 2006Co-Authors: Sophie Sebille, David Gall, Pascal De Tullio, Xavier Florence, Philippe Lebrun, Bernard PirotteAbstract:In the search of a novel series of Benzopyrans structurally related to (+/-)-cromakalim and acting as pancreatic beta-cell potassium channel openers, several R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-Benzopyrans with or without a substituent on the phenyl ring in the 4-position were synthesized. Their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K(ATP) channel activators (+/-)-cromakalim, diazoxide, (+/-)-pinacidil, and compound 4. Structure-activity relationships indicated that the most pronounced inhibitory activity on the pancreatic tissue was obtained by introducing a meta- or para-electron-withdrawing group (a chlorine atom) on the C-4 phenyl ring (drugs 37-42). Such molecules, unlike the parent compound (+/-)-cromakalim, also exhibited a high selectivity for the pancreatic tissue versus the vascular tissue. Radioisotopic and electrophysiological investigations performed with R/S-6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyran (38) confirmed that the drug activated pancreatic KATP channels.
Bernard Pirotte - One of the best experts on this subject based on the ideXlab platform.
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influence of the alkylsulfonylamino substituent located at the 6 position of 2 2 dimethylchromans structurally related to cromakalim from potassium channel openers to calcium entry blockers
European Journal of Medicinal Chemistry, 2014Co-Authors: Xavier Florence, Pascal De Tullio, Bernard Pirotte, Vincent Desvaux, Eric Goffin, Philippe LebrunAbstract:The present study described the synthesis of original R/S-6-alkylsulfonylamino-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyrans bearing a 3- or 4-substituted phenylthiourea or phenylurea moiety at the 4-position. Their biological effects were evaluated both on insulin-secreting and smooth muscle cells and were compared to those of reference KATP channel activators such as (±)-cromakalim, diazoxide and previously synthesized cromakalim analogues. The study aimed at exploring the influence of the introduction of an alkylsulfonylamino substituent at the 6-position of 2,2-dimethylchromans in order to improve biological activity, tissue selectivity but also hydrophilicity of dihydroBenzopyran derivatives. Several compounds were found to be equipotent or even more potent than (±)-cromakalim and diazoxide at inhibiting the insulin releasing process. Most of the newly synthesized and more hydrophilic dihydroBenzopyrans also exhibited a marked vasorelaxant activity although they were less potent than (±)-cromakalim. Additional pharmacological and radioisotopic investigations suggested that R/S-N-3-chlorophenyl-N'-(3,4-dihydro-6-methylsulfonylamino-2,2-dimethyl-2H-1-Benzopyran-4-yl)thiourea (21) did not act as a potassium channel opener but rather as a Ca(2+) entry blocker.
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Modulation of the 6-position of Benzopyran derivatives and inhibitory effects on the insulin releasing process
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Xavier Florence, Pascal De Tullio, Bernard Pirotte, Sébastien Dilly, Philippe LebrunAbstract:The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyrans is described. All of these new Benzopyran derivatives were bearing, at the 4-position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electron-withdrawing group such as Cl or CN. The study aimed at exploring the influence of the nature of the substituent at the 6-position in order to develop new Benzopyran-type K(ATP) channel activators exhibiting an improved selectivity towards the insulin secreting cells. The original compounds were examined in vitro on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (vasorelaxant effect) and their activity was compared to that of the reference K(ATP) channel activators (±)-cromakalim, (±)-pinacidil, diazoxide and to previously synthesized cromakalim analogues. Structure-activity relationships indicated that the inhibitory effect on the insulin secreting cells was related to the lipophilicity of the molecules and to the size of the substituent located at the 6-position. A marked inhibitory activity on the insulin secretory process was obtained with molecules bearing a bulky tert-butyloxycarbonylamino group at the 6-position (20-23). The latter compounds were found to have the same efficacy on the pancreatic endocrine tissue than some previously described molecules. Lastly, radioisotopic experiments further identified R/S-N-4-chlorophenyl-N'-(6-tert-butyloxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyran-4-yl)thiourea (23) as a K(ATP) channel opener.
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development and validation of a nonaqueous capillary electrophoretic method for the enantiomeric purity determination of a synthetic intermediate of new 3 4 dihydro 2 2 dimethyl 2h 1 Benzopyrans using a single isomer anionic cyclodextrin derivative a
Journal of Chromatography A, 2010Co-Authors: Anne Rousseau, Xavier Florence, Bernard Pirotte, Anne Varenne, Pierre Gareil, Didier Villemin, Patrice Chiap, Jacques Crommen, Marianne Fillet, Annecatherine ServaisAbstract:Abstract The enantiomeric purity determination of a synthetic intermediate of new 3,4-dihydro-2,2-dimethyl-2 H -1-Benzopyrans, i.e. 4-amino-2,2-dimethyl-6-ethoxycarbonylamino-3,4-dihydro-2 H -1-Benzopyran, was successfully carried out using an anionic cyclodextrin (CD) derivative combined with a chiral ionic liquid (IL). In order to obtain high resolution and efficiency values, the addition of a chiral IL, i.e. ethylcholine bis(trifluoromethylsulfonyl)imide (EtChol NTf 2 ), to the background electrolyte containing heptakis(2,3-di- O -methyl-6- O -sulfo)-β-CD (HDMS-β-CD) was found to be essential. A simultaneous increase in separation selectivity and enantioresolution seems to indicate a synergistic effect of HDMS-β-CD and EtChol NTf 2 . The best enantioseparation of the key intermediate was achieved using a methanolic solution of 0.75 M formic acid, 10 mM ammonium formate, 1.5 mM HDMS-β-CD and 5 mM EtChol NTf 2 . Levamisole was selected as internal standard. The optimized conditions allowed the determination of 0.1% of each enantiomer in the presence of its stereoisomer using the method of standard additions. The NACE method was then fully validated with respect to selectivity, response function, trueness, precision, accuracy, linearity and limits of detection and quantification.
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new r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminothiocarbonylamino 2h 1 Benzopyrans structurally related to cromakalim as tissue selective pancreatic β cell katp channel openers
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Sophie Sebille, Pascal De Tullio, Xavier Florence, Bernard Pirotte, B Becker, Mariehelene Antoine, Catherine Michaux, Johan Wouters, Philippe LebrunAbstract:The present work was aimed at exploring a series of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-Benzopyrans structurally related to (+/-)-cromakalim and differently substituted at the 4- and 6-positions. The biological effects of these putative activators of ATP-sensitive potassium channels (K(ATP)) were characterized in vitro on the pancreatic endocrine tissue (inhibition of insulin release) and on the vascular smooth muscle tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine atom on the C-4 phenyl ring, independently of the nature of the halogen atom at the 6-position of the Benzopyran nucleus. Most original dimethylchroman thioureas were more potent than their 'urea' homologues and even more potent than diazoxide at inhibiting insulin release. Moreover, and unlike (+/-)-cromakalim or (+/-)-pinacidil, such compounds appeared to be highly selective towards the pancreatic tissue. Radioisotopic and fluorimetric investigations indicated that the new drugs activated pancreatic K(ATP) channels. Lastly, conformational studies suggested that the urea/thiourea dimethylchromans can be regarded as hybrid compounds between cromakalim and pinacidil.
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design synthesis and pharmacological evaluation of r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminocarbonylamino 2h 1 Benzopyrans toward tissue selective pancreatic beta cell katp channel openers structurally related to cromakalim
Journal of Medicinal Chemistry, 2006Co-Authors: Sophie Sebille, David Gall, Pascal De Tullio, Xavier Florence, Philippe Lebrun, Bernard PirotteAbstract:In the search of a novel series of Benzopyrans structurally related to (+/-)-cromakalim and acting as pancreatic beta-cell potassium channel openers, several R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-Benzopyrans with or without a substituent on the phenyl ring in the 4-position were synthesized. Their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K(ATP) channel activators (+/-)-cromakalim, diazoxide, (+/-)-pinacidil, and compound 4. Structure-activity relationships indicated that the most pronounced inhibitory activity on the pancreatic tissue was obtained by introducing a meta- or para-electron-withdrawing group (a chlorine atom) on the C-4 phenyl ring (drugs 37-42). Such molecules, unlike the parent compound (+/-)-cromakalim, also exhibited a high selectivity for the pancreatic tissue versus the vascular tissue. Radioisotopic and electrophysiological investigations performed with R/S-6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyran (38) confirmed that the drug activated pancreatic KATP channels.
Jean Pierre Bazureau - One of the best experts on this subject based on the ideXlab platform.
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an efficient and concise synthesis of n 3 substituted 9 methoxy 4h 1 Benzopyrano 2 3 d pyrimidine 4 5h imines and form amidine derivatives from methyl n 3 cyano 8 methoxy 4h 1 Benzopyran 2 yl methanimidate
Synthesis, 2017Co-Authors: A Bouattour, Mehdi Fakhfakh, Souhir Abid, Ludovic Paquin, Houcine Ammar, Jean Pierre BazureauAbstract:A four-step microwave-assisted reaction of N-3-susbstituted 4 H -[1]-Benzopyrano[2,3- d ]pyrimidine-4(5 H )-imines and formamidine derivatives was successfully developed from primary amines, cyclic secondary amines, and methyl N -(3-cyano-8-methoxy-4 H -[1]-Benzopyran-2-yl)methanimidate as key intermediate. The simplicity of the microwave protocols gave facile possibilities of isolation of the desired products by simple filtration. The synthesized compounds were obtained in good yields and purity, and characterized by 1 H, 13 C NMR, IR, and HRMS analyses.
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An Efficient and Concise Synthesis of N-3-Substituted 9-Methoxy-4 H -[1]-Benzopyrano[2,3- d ]pyrimidine-4(5 H)-imines and Formamidine Derivatives from Methyl N -(3-Cyano-8-methoxy-4 H -[1]-Benzopyran-2-yl)methanimidate
SYNTHESIS, 2017Co-Authors: A Bouattour, Mehdi Fakhfakh, Souhir Abid, Ludovic Paquin, Houcine Ammar, Jean Pierre BazureauAbstract:A four-step microwave-assisted reaction of N-3-susbstituted 4 H -[1]-Benzopyrano[2,3- d ]pyrimidine-4(5 H)-imines and formamidine derivatives was successfully developed from primary amines, cyclic secondary amines, and methyl N -(3-cyano-8-methoxy-4 H -[1]-Benzopyran-2-yl)methanimidate as key intermediate. The simplicity of the microwave protocols gave facile possibilities of isolation of the desired products by simple filtration. The synthesized compounds were obtained in good yields and purity, and characterized by 1 H, 13 C NMR, IR, and HRMS analyses. © Georg Thieme Verlag Stuttgart - New York.
Pascal De Tullio - One of the best experts on this subject based on the ideXlab platform.
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influence of the alkylsulfonylamino substituent located at the 6 position of 2 2 dimethylchromans structurally related to cromakalim from potassium channel openers to calcium entry blockers
European Journal of Medicinal Chemistry, 2014Co-Authors: Xavier Florence, Pascal De Tullio, Bernard Pirotte, Vincent Desvaux, Eric Goffin, Philippe LebrunAbstract:The present study described the synthesis of original R/S-6-alkylsulfonylamino-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyrans bearing a 3- or 4-substituted phenylthiourea or phenylurea moiety at the 4-position. Their biological effects were evaluated both on insulin-secreting and smooth muscle cells and were compared to those of reference KATP channel activators such as (±)-cromakalim, diazoxide and previously synthesized cromakalim analogues. The study aimed at exploring the influence of the introduction of an alkylsulfonylamino substituent at the 6-position of 2,2-dimethylchromans in order to improve biological activity, tissue selectivity but also hydrophilicity of dihydroBenzopyran derivatives. Several compounds were found to be equipotent or even more potent than (±)-cromakalim and diazoxide at inhibiting the insulin releasing process. Most of the newly synthesized and more hydrophilic dihydroBenzopyrans also exhibited a marked vasorelaxant activity although they were less potent than (±)-cromakalim. Additional pharmacological and radioisotopic investigations suggested that R/S-N-3-chlorophenyl-N'-(3,4-dihydro-6-methylsulfonylamino-2,2-dimethyl-2H-1-Benzopyran-4-yl)thiourea (21) did not act as a potassium channel opener but rather as a Ca(2+) entry blocker.
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Modulation of the 6-position of Benzopyran derivatives and inhibitory effects on the insulin releasing process
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Xavier Florence, Pascal De Tullio, Bernard Pirotte, Sébastien Dilly, Philippe LebrunAbstract:The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyrans is described. All of these new Benzopyran derivatives were bearing, at the 4-position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electron-withdrawing group such as Cl or CN. The study aimed at exploring the influence of the nature of the substituent at the 6-position in order to develop new Benzopyran-type K(ATP) channel activators exhibiting an improved selectivity towards the insulin secreting cells. The original compounds were examined in vitro on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (vasorelaxant effect) and their activity was compared to that of the reference K(ATP) channel activators (±)-cromakalim, (±)-pinacidil, diazoxide and to previously synthesized cromakalim analogues. Structure-activity relationships indicated that the inhibitory effect on the insulin secreting cells was related to the lipophilicity of the molecules and to the size of the substituent located at the 6-position. A marked inhibitory activity on the insulin secretory process was obtained with molecules bearing a bulky tert-butyloxycarbonylamino group at the 6-position (20-23). The latter compounds were found to have the same efficacy on the pancreatic endocrine tissue than some previously described molecules. Lastly, radioisotopic experiments further identified R/S-N-4-chlorophenyl-N'-(6-tert-butyloxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyran-4-yl)thiourea (23) as a K(ATP) channel opener.
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new r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminothiocarbonylamino 2h 1 Benzopyrans structurally related to cromakalim as tissue selective pancreatic β cell katp channel openers
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Sophie Sebille, Pascal De Tullio, Xavier Florence, Bernard Pirotte, B Becker, Mariehelene Antoine, Catherine Michaux, Johan Wouters, Philippe LebrunAbstract:The present work was aimed at exploring a series of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-Benzopyrans structurally related to (+/-)-cromakalim and differently substituted at the 4- and 6-positions. The biological effects of these putative activators of ATP-sensitive potassium channels (K(ATP)) were characterized in vitro on the pancreatic endocrine tissue (inhibition of insulin release) and on the vascular smooth muscle tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine atom on the C-4 phenyl ring, independently of the nature of the halogen atom at the 6-position of the Benzopyran nucleus. Most original dimethylchroman thioureas were more potent than their 'urea' homologues and even more potent than diazoxide at inhibiting insulin release. Moreover, and unlike (+/-)-cromakalim or (+/-)-pinacidil, such compounds appeared to be highly selective towards the pancreatic tissue. Radioisotopic and fluorimetric investigations indicated that the new drugs activated pancreatic K(ATP) channels. Lastly, conformational studies suggested that the urea/thiourea dimethylchromans can be regarded as hybrid compounds between cromakalim and pinacidil.
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design synthesis and pharmacological evaluation of r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminocarbonylamino 2h 1 Benzopyrans toward tissue selective pancreatic beta cell katp channel openers structurally related to cromakalim
Journal of Medicinal Chemistry, 2006Co-Authors: Sophie Sebille, David Gall, Pascal De Tullio, Xavier Florence, Philippe Lebrun, Bernard PirotteAbstract:In the search of a novel series of Benzopyrans structurally related to (+/-)-cromakalim and acting as pancreatic beta-cell potassium channel openers, several R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminocarbonylamino)-2H-1-Benzopyrans with or without a substituent on the phenyl ring in the 4-position were synthesized. Their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K(ATP) channel activators (+/-)-cromakalim, diazoxide, (+/-)-pinacidil, and compound 4. Structure-activity relationships indicated that the most pronounced inhibitory activity on the pancreatic tissue was obtained by introducing a meta- or para-electron-withdrawing group (a chlorine atom) on the C-4 phenyl ring (drugs 37-42). Such molecules, unlike the parent compound (+/-)-cromakalim, also exhibited a high selectivity for the pancreatic tissue versus the vascular tissue. Radioisotopic and electrophysiological investigations performed with R/S-6-chloro-4-(3-chlorophenylaminocarbonylamino)-3,4-dihydro-2,2-dimethyl-2H-1-Benzopyran (38) confirmed that the drug activated pancreatic KATP channels.