RESUMO
4-Phenyl-4-thiazoline-2-thiol is an active pharmaceutical compound, one of whose activities is as a human indolenamine dioxygenase inhibitor. It has been shown recently that in both the solid state and the gas phase, the thiazolinethione tautomer should be preferred. As part of both research on this lead compound and a medicinal chemistry program, a series of substituted arylthiazolinethiones have been synthesized. The molecular conformations and tautomerism of 4-(2-methoxyphenyl)-4-thiazoline-2-thione and 4-(4-methoxyphenyl)-4-thiazoline-2-thione, both C10H9NOS2, are reported and compared with the geometry deduced from ab initio calculations [PBE/6-311G(d,p)]. Both the crystal structure analyses and the calculations establish the thione tautomer for the two substituted arylthiazolinethiones. In the crystal structure of the 2-methoxyphenyl regioisomer, the thiazolinethione unit was disordered over two conformations. Both isomers exhibit similar hydrogen-bond patterns [R2(2)(8) motif] and form dimers. The crystal packing is further reinforced by short S...S interactions in the 2-methoxyphenyl isomer. The conformations of the two regioisomers correspond to stable geometries calculated from an ab initio energy-relaxed scan.
Assuntos
Tiazolidinas/química , Cristalografia por Raios X , Dimerização , Ligação de Hidrogênio , Isomerismo , Modelos Moleculares , Conformação MolecularRESUMO
Salification of new drug substances in order to improve physico-chemical or solid-state properties (e.g. dissolution rate or solubility, appropriate workup process, storage for further industrial and marketing development) is a well-accepted procedure. Amino acids, like aspartic acid, lysine or arginine take a great part in this process and are implicated in several different formulations of therapeutic agent families, including antibiotics (amoxicillin from beta lactam class or cephalexin from cephalosporin class), NSAIDs (ketoprofen, ibuprofen and naproxen from profen family, acetylsalicylic acid) or antiarrhythmic agents (e.g. ajmaline). Even if more than a half of known pharmaceutical molecules possess a salifiable moiety, what can be done for new potential drug entity that cannot be improved by transformation into a salt? In this context, after a brief review of pharmaceutical salts on the market and the implication of amino acids in these formulations, we focus on the advantage of using amino acids even when the target compound is not salifiable by exploiting their zwitterionic potentialities for cocrystal edification. We summarize here a series of new examples coming from literature to support the advantages of broadening the application of amino acids in formulation for new drug substances improvement research for non-salifiable molecules.
Assuntos
Aminoácidos/química , Preparações Farmacêuticas/química , Cristalização , Estrutura MolecularRESUMO
In this contribution different solid-state forms of the racemic compound (RS)-2-(2-oxo-pyrrolidin-1yl)-butyramide are studied from a structural and thermal point of view. Three different solid-state phases were identified, including two polymorphs and one hydrate phase. Comparison is made with the structure of the (S)-enantiomer, for which only one solid-state phase is known. The basic structural motif found in both polymorphs of the racemic compound is similar, but the basic motif observed for the hydrate differs. These synthons could in principle be used in future polymorph prediction studies to screen for possible alternative forms of the enantiopure compound. Based on the structure of the hydrate, further efforts should therefore be made in order to identify a hydrate structure of the enantiopure compound. Studying the different phases of a racemic compound can therefore help to guide polymorphic screening of an enantiopure compound.
Assuntos
Piracetam/análogos & derivados , Termodinâmica , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Levetiracetam , Modelos Moleculares , Estrutura Molecular , Piracetam/química , Difração de Pó , EstereoisomerismoRESUMO
Single crystals for two polymorphs of the ammonium carbamate self-derivative salt of prolinamide have been successfully obtained and characterized. Decarbonation of the carbamate salts was monitored by calorimetry, confirming stabilization of the reactive carbonated adducts in the solid state. Sublimation of the salts afforded crystals of prolinamide, leading to the first crystal structure of this otherwise common molecule. Reactivity of the ammonium carbamate self-derivative salt is further illustrated by the observation of a series of derived products, including dehydroprolinamide, a methylene-bridged prolinamide, and a bicyclic derivative. Crystal structures of these products display distinct amidic and/or non-amidic hydrogen bonding. This study emphasizes the reactivity of carbonated amines stabilized in the solid and opens perspectives for a systematic study of (solid-state) reactions involving these trapped reactive species.
RESUMO
Pharmaceutical compounds are mostly developed as solid dosage forms containing a single-crystal form. It means that the selection of a particular crystal state for a given molecule is an important step for further clinical outlooks. In this context, piracetam, a pharmaceutical molecule known since the sixties for its nootropic properties, is considered in the present work. This molecule is analyzed using several experimental and theoretical approaches. First, the conformational space of the molecule has been systematically explored by performing a quantum mechanics scan of the two most relevant dihedral angles of the lateral chain. The predicted stable conformations have been compared to all the reported experimental geometries retrieved from the Cambridge Structural Database (CSD) covering polymorphs and cocrystals structures. In parallel, different batches of powders have been recrystallized. Under specific conditions, single crystals of polymorph (III) of piracetam have been obtained, an outcome confirmed by crystallographic analysis.
Assuntos
Fármacos Neuroprotetores/química , Piracetam/química , Teoria Quântica , Cristalografia por Raios X , Bases de Dados Factuais , Estrutura Molecular , Difração de PóRESUMO
THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND [SYSTEMATIC NAME: (2R)-3-(1H-indol-3-yl)-2-(4-nitro-1,3-dioxoisoindolin-2-yl)propanoic acid], C(19)H(13)N(3)O(6), an analogue of epigenetic modulator RG108, is constrained by strong hydrogen bonds between the indole N-H group and a carbonyl O atom of the phthalimide ring of a symmetry-related mol-ecule, and between the protonated O atom of the carboxyl group and a carbonyl O atom of the phthalimide ring. π-π stacking inter-actions with centroid-centroid distances of 3.638â (1) and 3.610â (1)â Å are also observed between indole and phthalimide rings.
RESUMO
Indoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC(50) values in the micromolar range in both tests. Introduction of small substituents in the 5- and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results.
Assuntos
Etano/química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indóis/química , Indóis/farmacologia , Domínio Catalítico , Linhagem Celular , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/química , Modelos Moleculares , Domínios e Motivos de Interação entre Proteínas , Relação Estrutura-AtividadeRESUMO
Cocrystallization (formation of a "cocrystal") is an emerging method to optimize physico-chemical properties of pharmaceutically active compounds. One elegant technique used to obtain such cocrystals is grinding the components together, either alone or in the presence of a small amount of solvent (so called solvent-drop grinding). Dry grinding has been used here to obtain cocrystals (actually a hydrated salt) of L-Proline and MnCl(2). In that context, a new crystalline structure of a multicomponent molecular complex composed of L-Proline and MnCl(2) is here reported. The complex was characterized by powder and single-crystal X-ray diffraction and differential scanning calorimetry. This study underlines the interest of grinding as a method to synthesize original solid-state complexes. It also emphasizes the advantage of combining calorimetric and X-ray diffraction to characterize the newly formed solids. Finally, our work provides structural basis for the role that L-Proline can play within multicomponent solid-state molecular complexes, in particular as a potential cocrystal former acting by both ionic and H-bond interactions when combined to molecules of pharmaceutical interest.
Assuntos
Química Farmacêutica/métodos , Cloretos/química , Cristalização/métodos , Compostos de Manganês/química , Prolina/química , Varredura Diferencial de Calorimetria , Cristalografia por Raios XRESUMO
Crystal structure of the three stereoisomers of 1,1'-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) hydrochloride after resolution by semi-preparative chiral HPLC establishes the absolute configuration and conformation.
Assuntos
Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/síntese química , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
The relative configuration of the endo isomer of the title compound, C(9)H(14)O(4)S, has been established and the conformation of the diastereoisomer is discussed. The five-membered ring adopts an envelope conformation. The conformation of the methane-sulfonate substituent is stabilized by inter-molecular C-Hâ¯O hydrogen bonds. The crystal packing results in alternating layers of polar methane-sulfonates and stacked bicyclo-hexa-nyl rings parallel to ab.
RESUMO
In the title compound, C(33)H(34)O(5)S·H(2)O, the mannopyran-oside ring adopts a chair conformation with the 2-α-thio-phenyl group occupying an axial position. One of the pendant benzyl groups is disordered over two sets of sites in a 0.5:0.5 ratio. In the crystal, the water mol-ecule makes two O-Hâ¯O hydrogen bonds to an adjacent sugar mol-ecule with the O atoms of the primary alcohol and ether groups acting as acceptors. At the same time, the OH group of the sugar makes a hydrogen bond to a water mol-ecule.
RESUMO
In the title compound, C18H27F3N5O3S+.Cl-, the guanidine group forms N-H...Cl hydrogen bonds, with four N...Cl distances in the range 3.164 (3)-3.337 (4) A. In the crystal packing, the cations are further linked by N-H...O and C-H...O interactions. The structure is compared with that of argatroban complexed with thrombin and is the subject of docking studies in the active site of thrombin.
Assuntos
Antitrombinas/química , Cloro/química , Guanidinas/química , Hidrogênio/química , Modelos Biológicos , Nitrogênio/química , Sulfonamidas/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Estrutura MolecularRESUMO
A concise and efficient asymmetric synthesis of ACNO analogues of morphine is reported.
Assuntos
Morfina/química , Morfina/síntese química , Compostos Policíclicos/síntese química , Ciclização , Compostos Policíclicos/química , EstereoisomerismoRESUMO
The title compound, C30H34FNO7S, is a key intermediate in the design of dual 5-LOX (5-lipoxygenase)/COX-2 (cyclooxygenase-2) inhibitors. The compound crystallizes as a racemate. Linear hydrogen-bonded chains are aligned along the [201] direction, and stacked pi-pi interactions and C-H...O contacts stabilize the crystal structure.
Assuntos
Inibidores de Ciclo-Oxigenase/química , Inibidores de Lipoxigenase/química , Morfolinas/química , Ácidos Sulfínicos/química , Cristalografia por Raios X , Inibidores de Ciclo-Oxigenase/farmacologia , Ligação de Hidrogênio , Inibidores de Lipoxigenase/farmacologia , Modelos Moleculares , Estrutura MolecularRESUMO
The structures of three compounds, namely 7-methoxy-2-[3-(trifluoromethyl)phenyl]-9H-indeno[1,2-c]pyridazin-9-one, C19H11F3N2O2, (Id), 6-methoxy-2-[3-(trifluoromethyl)phenyl]-9H-indeno[1,2-c]pyridazin-9-one, C19H11F3N2O2, (IId), and 2-methyl-6-(4,4,4-trifluorobutoxy)-9H-indeno[1,2-c]pyridazin-9-one, C16H13F3N2O2, (IIf), which are potent reversible type-B monoamine oxidase (MAO-B) inhibitors, are presented and discussed. Compounds (Id) and (IId) crystallize in a nearly planar conformation. The crystal structures are stabilized by weak C-H...O hydrogen bonds. The packing is dominated by pi-pi stacking interactions between the heterocyclic central moieties of centrosymmetrically related molecules. In compound (IIf), the trifluoroethyl termination is almost perpendicular to the plane of the ring.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Indenos/química , Inibidores da Monoaminoxidase/química , Piridazinas/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura MolecularRESUMO
Three related compounds containing a pyrazole moiety with vicinal phenyl rings featuring a methylsulfonyl substituent are described, namely 3-methyl-1-[4-(methylsulfonyl)phenyl]-5-phenyl-1H-pyrazole, C17H16N2O2S, ethyl 1-[4-(methylsulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-carboxylate, C19H18N2O4S, and 1-[4-(methylsulfonyl)phenyl]-3-[3-(morpholino)phenoxymethyl]-5-phenyl-1H-pyrazole, C27H27N3O4S. The design of these compounds was based on celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in order to study the influence of various substituents on COX-2 and 5-lipoxygenase (5-LOX) inhibition.
RESUMO
[reaction: see text] A new access to benzhydryl-phenylureas is described. These new interesting urea derivatives were obtained by reaction of substituted benzils with substituted phenylureas under microwave irradiation. Phenylthiourea, when reacted with benzil, gave 3-phenyl-thiohydantoin. Moreover, benzylurea, as phenethylurea, gave the corresponding 3-substituted hydantoin derivatives, demonstrating that only phenylurea derivatives can result in benzhydryl-phenylureas under the applied conditions. This new reaction proved to be an easy access to substituted 1-benzhydryl-3-phenyl-ureas.
RESUMO
The title compound (BM531), C(17)H(26)N(4)O(5)S, has been designed for use as both a thromboxane synthase inhibitor (TXSI) and a thromboxane receptor antagonist (TXRA). We report here the X-ray crystal structure determination of the compound.
Assuntos
Receptores de Tromboxanos/antagonistas & inibidores , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Conformação Molecular , Estrutura MolecularRESUMO
The crystal structures of 4-methyl-2-[N-(3,4-methylenedioxybenzylidene)hydrazino]thiazole, C(12)H(11)N(3)O(2)S, and its reduction product 4-methyl-2-[N-(3,4-methylenedioxybenzylidene)hydrazono]-4,5-dihydrothiazole, C(12)H(13)N(3)O(2)S, have been determined and compared. In the reduction product, the tautomer observed bears an H atom on the exocyclic N atom. Both compounds form hydrogen-bonded dimers over centers of inversion.
RESUMO
The title compound, C(12)H(12)N(2)O(3)S, is a strict pyridine analogue of nimesulide, a selective inhibitor of cyclooxygenase-2. The structure is characterized by a pyridinium ring with a deprotonated sulfonamide group. An intermolecular charge-assisted hydrogen bond between these two groups is observed within the crystal packing, linking the molecules into an infinite chain running along the b-axis direction.