Lina M. Acosta

Three styryl-substituted tetrahydro-1,4-epoxy-1-benzazepines: configurations, conformations and hydrogen-bonded chains

(2SR,4RS)-7-Chloro-2-exo-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(18)H(16)ClNO, (I), crystallizes as a racemic twin in the space group P2(1) and the molecules are linked into a chain of edge-fused R(3)(3)(9) rings by a combination of C-H...O and C-H...N hydrogen bonds. The diastereoisomer (2RS,4RS)-7-chloro-2-endo-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (II), also crystallizes as a racemic twin, but in the space group P2(1)2(1)2(1), and a two-centre C-H...N hydrogen bond and a three-centre C-H...(O,N) hydrogen bond combine to link the molecules into a complex chain of rings. In (2R,4R)-7-fluoro-2-endo-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(18)H(16)FNO, (III), which is not isomorphous with (II), the molecules are linked by a single C-H...O hydrogen bond into simple chains, but the molecular arrangements in (II) and (III) are nonetheless very similar. The significance of this study lies in its observation of the variations in molecular configuration and conformation, and in the variation in the supramolecular aggregation, consequent upon modest changes in the peripheral substituents.

4-Hydroxy-2-vinyl-2,3,4,5-tetrahydro-1-benzazepine and its 7-fluoro and 7-chloro analogues are isomorphous but not strictly isostructural

4-Hydroxy-2-vinyl-2,3,4,5-tetrahydro-1-benzazepine, C(12)H(15)NO, (I), and its 7-fluoro and 7-chloro analogues, namely 7-fluoro-4-hydroxy-2-vinyl-2,3,4,5-tetrahydro-1-benzazepine, C(12)H(14)FNO, (II), and 7-chloro-4-hydroxy-2-vinyl-2,3,4,5-tetrahydro-1-benzazepine, C(12)H(14)ClNO, (III), are isomorphous, but with variations in the unit-cell dimensions which preclude in compound (III) one of the weaker intermolecular interactions found in compounds (I) and (II). Thus the compounds are not strictly isostructural in terms of the structurally significant intermolecular interactions, although the corresponding atomic coordinates are very similar. The azepine rings adopt chair conformations. The molecules are linked by a combination of N-H...O and O-H...N hydrogen bonds into chains of edge-fused R(3)(3)(10) rings, which in compounds (I) and (II) are further linked into sheets by a single C-H...pi(arene) hydrogen bond. The significance of this study lies in its observation of isomorphism in compounds (I)-(III), and its observation of a sufficient variation in one of the cell dimensions effectively to alter the range of significant hydrogen bonds present in the crystal structures.

Five closely related 4-chloro-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepines: similar molecular structures but different supramolecular assemblies.

Dibenz[b,f]azepine (DBA) is a privileged 6-7-6 tricyclic ring system of importance in both organic and medicinal chemistry. Benzo[b]pyrimido[5,4-f]azepines (BPAs), which also contain a privileged 6-7-6 ring system, are less well investigated, probably because of a lack of straightforward and versatile methods for their synthesis. A simple and versatile synthetic approach to BPAs based on intramolecular Friedel-Crafts alkylation has been developed. A group of closely-related benzo[b]pyrimido[5,4-f]azepine derivatives, namely (6RS)-4-chloro-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C14H14ClN3, (I), (6RS)-4-chloro-8-hydroxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C14H14ClN3O, (II), (6RS)-4-chloro-8-methoxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C15H16ClN3O, (III), and (6RS)-4-chloro-8-methoxy-6,11-dimethyl-2-phenyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C21H20ClN3O, (IV), has been prepared and their structures compared with the recently published structure [Acosta-Quintero et al. (2015). Eur. J. Org. Chem. pp. 5360-5369] of (6RS)-4-chloro-2,6,8,11-tetramethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, (V). All five compounds crystallize as racemic mixtures and they have very similar molecular conformations, with the azepine ring adopting a boat-type conformation in each case, although the orientation of the methoxy substituent in each of (III) and (IV) is different. The supramolecular assemblies in (II) and (IV) depend upon hydrogen bonds of the O-H...N and C-H...π(arene) types, respectively, those in (I) and (V) depend upon π-π stacking interactions involving pairs of pyrimidine rings, and that in (III) depends upon a π-π stacking interaction involving pairs of phenyl rings. Short C-Cl...π(pyrimidine) contacts are present in (I), (II) and (IV) but not in (III) or (V).

An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors.

Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.

A three-dimensional hydrogen-bonded framework in (2S*,4R*)-7-fluoro-2-exo-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine.

Molecules of the title compound, C(18)H(16)FNO, are linked into a three-dimensional framework structure by a combination of two C-H...O hydrogen bonds and three C-H...pi(arene) hydrogen bonds. Comparisons are made with the (2R,4R) diastereoisomer and with the corresponding pair of diastereoisomeric 7-chloro analogues.

Hydrogen-bonded dimers, chains and rings in six differently substituted 2-vinyltetrahydro-1,4-epoxy-1-benzazepines.

In (2SR,4RS)-2-exo-vinyl-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(12)H(13)NO, (I), the molecules are linked by two independent C-H...pi(arene) hydrogen bonds to form sheets, such that all of the molecules in a given sheet are of the same configuration. The molecules of (2SR,4RS)-7-chloro-2-exo-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(14)H(16)ClNO, (II), are linked by a C-H...O hydrogen bond into C(4) chains, where all the molecules in a given chain are of the same configuration, whereas the molecules of (2SR,4RS)-8-chloro-9-methyl-2-exo-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(15)H(18)ClNO, (III), are linked into centrosymmetric dimers by pairs of symmetry-related C-H...pi(arene) hydrogen bonds. (2RS,4RS)-8-Chloro-9-methyl-2-endo-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(15)H(18)ClNO, (IV), is a diastereoisomer of (III) and, as for (II), a single C-H...O hydrogen bond links the molecules into C(4) chains, each containing molecules of a single configuration. The structure of (2SR,4RS)-8-chloro-9-methyl-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(14)H(16)ClNO, (V), contains a C-H...O hydrogen bond which links pairs of molecules into centrosymmetric R(2)(2)(6) dimers. (2SR,4RS)-7,9-Dichloro-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(13)H(13)Cl(2)NO, (VI), is an inversion twin containing both the (2S,4R) and (2R,4S) enantiomers in the space group P2(1), and a C-H...O hydrogen bond links molecules of a given configuration into simple C(3) chains.

Six closely related 4,6‐disubstituted 2‐amino‐5‐formylpyrimidines: different ring conformations, polarized electronic structures, and hydrogen‐bonded assembly in zero, one, two and three dimensions

In each of ethyl N-{2-amino-5-formyl-6-[methyl(phenyl)amino]pyrimidin-4-yl}glycinate, C(16)H(19)N(5)O(3), (I), N-{2-amino-5-formyl-6-[methyl(phenyl)amino]pyrimidin-4-yl}glycinamide, C(14)H(16)N(6)O(2), (II), and ethyl 3-amino-N-{2-amino-5-formyl-6-[methyl(phenyl)amino]pyrimidin-4-yl}propionate, C(17)H(21)N(5)O(3), (III), the pyrimidine ring is effectively planar, but in each of methyl N-{2-amino-6-[benzyl(methyl)amino]-5-formylpyrimidin-4-yl}glycinate, C(16)H(19)N(5)O(3), (IV), ethyl 3-amino-N-{2-amino-6-[benzyl(methyl)amino]-5-formylpyrimidin-4-yl}propionate, C(18)H(23)N(5)O(3), (V), and ethyl 3-amino-N-[2-amino-5-formyl-6-(piperidin-4-yl)pyrimidin-4-yl]propionate, C(15)H(23)N(5)O(3), (VI), the pyrimidine ring is folded into a boat conformation. The bond lengths in each of (I)-(VI) provide evidence for significant polarization of the electronic structure. The molecules of (I) are linked by paired N-H···N hydrogen bonds to form isolated dimeric aggregates, and those of (III) are linked by a combination of N-H···N and N-H···O hydrogen bonds into a chain of edge-fused rings. In the structure of (IV), molecules are linked into sheets by means of two hydrogen bonds, both of N-H···O type, in the structure of (V) by three hydrogen bonds, two of N-H···N type and one of C-H···O type, and in the structure of (VI) by four hydrogen bonds, all of N-H···O type. Molecules of (II) are linked into a three-dimensional framework structure by a combination of three N-H···O hydrogen bonds and one C-H···O hydrogen bond.