Co-crystals as a new approach to multimodal analgesia and the treatment of pain.

Pain is highly prevalent, but frequently untreated or under-treated, and health care professionals are faced with a range of treatment challenges. Multimodal therapy is recommended and can be achieved using open combinations (ie, concomitant administration) of individual agents, fixed-dose combinations (FDCs), or multimodal agents (ie, single agents with multiple mechanisms of action). Co-crystallization of active pharmaceutical ingredients (APIs) offers another approach, with the potential to provide drugs with unique properties and advantages for therapeutic applications compared to combinations.

Synthesis and crystal structure of 2,4,6,8-tetra-kis-(3,5-di--butyl-phen-oxy)pyrimido[5,4-]pyrimidine: expansion of the Piedfort concept.

The title host compound, CHNO, designed to self-assemble to form a new type of extended core Piedfort unit reminiscent of an eight-legged spider host, forms a number of crystalline inclusion compounds favouring oxygen-containing guest mol-ecules. We have established the presence of this unit in the unsolvated mol-ecular crystal at 100 K, which is monoclinic, space group 2/, with = 8. The new Piedfort unit is chiral and its core structure closely approximates to symmetry, with both enanti-omers present in the crystal.

Two polymorphic forms of the oxathiin systemic fungicide active carboxine.

Two polymorphic crystal forms of the title compound, CHNOS (systematic name: 6-methyl--phenyl-2,3-di-hydro-1,4-oxathiine-5-carboxamide), were isolated from a truncated, (12 solvent), polymorph screen on pure lyophillized material. Crystals of form 1 were obtained from all solvents included in the screen with the exception of methanol. As isolated from aceto-nitrile the crystals are triclinic, space group with = 2.

The first spontaneous resolution of a sulfoxide: Dianin's compound analogue, ()-4-(4-hy-droxy-phen-yl)-2,2,4-tri-methyl-thia-chroman-1-oxide.

The title sulfoxide, CHOS, was prepared by controlled oxidation of -Dianin's compound using hydrogen peroxide in glacial acetic acid. On recrystallization from glacial acetic acid, it was found to form unsolvated, spontaneously resolved crystals, the initial crystal structure analysis revealing the presence of both sulfoxide epimers in the crystal. On multiple recrystallization a single epimer was observed, with crystallization occurring in the unchanged ortho-rhom-bic space group 222, with = 1.

4-(4-Hy-droxy-phenyl)-2,2,4-trimethyl-7,8-benzo-thia-chroman, a fused-ring counterpart of -Dianin's compound.

The title compound, CHOS [systematic name: 4-(1,3,3-trimethyl-2,3-di-hydro-1-4-thia-phenanthren-1-yl)phenol], crystallizes unsolvated from nitro-methane as colourless prisms (m.p. 425-427 K) in the polar monoclinic space group with ' = 2 (mol-ecules and ).

Structure of Equilenin at 100 K: an estrone-related steroid.

The structure of the estrone-related steroid, Equilenin, CHO (systematic name 3-hy-droxy-13-methyl-11,12,13,14,15,16-hexa-hydro-cyclo-penta-[]phen-anthren-17-one), has been determined at 100 K. The crystals are ortho-rhom-bic, 222, and the absolute structure of the mol-ecule in the crystal has been determined by resonant scattering [Flack parameter = -0.05 (4)].

A metastable polymorphic form of the anti-fungal anilino-pyrimidine active pyrimethanil.

A second metastable form of the title compound, CHN (systematic name: 4,6-dimethyl--phenyl-pyrimidin-2-amine), was isolated from an attempted co-crystallization experiment with -erythriol in dimethyl sulfoxide (DMSO). The crystals of form 2 at 120 K are monoclinic, space group 2/ with ' = 4 compared to the previously reported triclinic form with ' = 2 [Sun (2011 ▸). , 1909-1914].

Crystal structure of 1-methylimidazole 3-oxide monohydrate.

1-Methylimidazole 3--oxide (NMI-O) crystallizes as a monohydrate, CHNO·HO, in the monoclinic space group 2 with ' = 2 (mol-ecules and ). The imidazole rings display a planar geometry (r.m.

Diels-Alder Reactions of α-Amido Acrylates with N-Cbz-1,2-dihydropyridine and Cyclopentadiene.

Thermal Diels-Alder reactions of α-amido acrylates with N-Cbz-1,2-dihydropyridine and cyclopentadiene have been explored to investigate the factors influencing the endo/exo selectivity. For the dihydropyridine, steric factors allowed the diastereoselectivity to be modulated to favor either endo- or exo-ester adducts. For cyclopentadiene, the endo-ester adducts were favored regardless of steric perturbation, although catalysis by bulky Lewis acids increased the proportion of exo-ester adducts in some cases.

Methanesulfonic acid salt forms of carbamazepine and 10,11-dihydrocarbamazepine.

New methanesulfonic acid salt forms of the anticonvulsant and analgesic active pharmaceutical ingredient carbamazepine and its closely related structural analogue 10,11-dihydrocarbamazepine have been prepared and characterized by single-crystal X-ray diffraction at 120 and 100 K, respectively {namely [(5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium methanesulfonate, C15H13N2O(+)·CH3SO3(-), and [(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)(hydroxy)methylidene]azanium methanesulfonate, C15H15N2O(+)·CH3SO3(-)}. In light of the structural information obtained, the crystal structure of the carbamazepine trifluoroacetic acid monosolvate [dibenzo[b,f]azepine-5-carboxamide-trifluoroacetic acid (1/1), C15H12N2O·CF3COOH] was redetermined at 100 and 270 K, and from this data it was concluded that the protonation state for this solvate species is best described as in an `intermediate state' with the acidic proton located almost at the mid-point between the acid and base.

Structural assignment of a bis-cyclopentenyl-β-cyanohydrin formed via alkene metathesis from either a triene or a tetraene precursor.

The identity of the major product of Ru-catalysed alkene metathesis of two polyene substrates has been determined using density functional theory (DFT) NMR prediction, a (1)H-(1)H Total Correlated Spectroscopy (TOCSY) NMR experiment and ultimately by single-crystal X-ray crystallography. The substrates were designed as those that would potentially allow expedient access to the trans-decalin skeleton of the natural product (-)-euonyminol, but the product was found to be a bis-cyclopentenyl-β-cyanohydrin [1-(1-hydroxycyclopent-3-en-1-yl)cyclopent-3-ene-1-carbonitrile, C11H13NO] rather than the trans-2,3,6,7-dehydrodecalin-β-cyanohydrin.

Engineering robust polar chiral clathrate crystals.

The R-(+)-enantiomeric form of Dianin's compound and the S-(+)-enantiomeric form of its direct thiachroman analogue both obtained chromatographically employing a cellulose tris(3,5-dimethylphenylcarbamate) column, are shown to undergo supramolecular assembly to form a polar clathrate lattice which is stable even in the absence of a consolidating guest component.

Towards the enantioselective synthesis of (-)-euonyminol--preparation of a fully functionalised lower-rim model.

The development of a stereoselective total synthesis of β-dihydroagarofuran 4 is described. This compound contains the same oxygenation pattern on its 'lower-rim' as found in the natural sesquiterpene (-)-euonyminol (1) and it is expected that the route described should be applicable to the synthesis of that complex natural product. (-)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesquiterpenoids isolated from the Celastraceae which possess interesting biological activities (e.

Synthesis of anti and syn hydroxy-iso-evoninic acids.

The first synthesis of hydroxy-iso-evoninic acid (2), a pyridyl diacid found as a macrodilactone bridging ligand in bioactive Celastraceae sesquiterpenoid-based natural products, has been achieved in 9 steps and an overall yield of 26%. The synthesis utilizes a benzilic ester rearrangement (BER) and a late stage benzylic oxidation to give access to all four stereoisomers whose absolute stereochemistry was assigned following chromatographic separation and anomalous dispersion X-ray crystallography.

(R)-4-(4-Aminophenyl)-2,2,4-trimethylchroman and (S)-4-(4-aminophenyl)-2,2,4-trimethylthiachroman.

The title compounds, C(18)H(21)NO and C(18)H(21)NS, in their enantiomerically pure forms are isostructural with the enantiomerically pure 4-(4-hydroxyphenyl)-2,2,4-trimethylchroman and 4-(2,4-dihydroxyphenyl)-2,2,4-trimethylchroman analogues and form extended linear chains via N-H···O or N-H···S hydrogen bonding along the [100] direction. The absolute configuration for both compounds was determined by anomalous dispersion methods with reference to both the Flack parameter and, for the light-atom compound, Bayesian statistics on Bijvoet differences.

The use of dynamic vapour sorption methods for the characterisation of water uptake in amorphous trehalose.

Water uptake by amorphous sugars is an issue of high importance for the food and pharmaceutical industries. However, while the processes associated with sorption-induced crystallisation have been widely studied, little is known regarding the uptake mechanisms associated with pre-crystallisation water levels. In the present investigation we use dynamic vapour sorption to study the water uptake mechanisms associated with amorphous trehalose.

Blind crystal structure prediction of a novel second polymorph of 1-hydroxy-7-azabenzotriazole.

The commercially available peptide coupling reagent 1-hydroxy-7-azabenzotriazole has been shown to crystallize in two polymorphic forms. The two polymorphs differ in their hydrogen-bonding motif, with form I having an R(2)(2)(10) dimer motif and form II having a C(5) chain motif. The previously unreported form II was used as an informal blind test of computational crystal structure prediction for flexible molecules.

Diastereoselective synthesis of atropisomers containing two non-biaryl stereogenic axes: stereochemical relay through stereogenic centres in dihydrostilbene-2,2'-dicarboxamides.

Addition of laterally lithiated tertiary aromatic amides to benzaldimines controls the formation of a new stereogenic centre adjacent to the benzaldimine aromatic ring. Drawing on the fact that such amino-substituted stereogenic centres may themselves control the conformation of amides, with amido-substituted benzaldimines we found it becomes possible to relay stereochemistry from one amide to another via this intervening stereogenic centre. A group of dihydrostilbene-2,2'-dicarboxamide derivatives bearing one or two stereogenic axes are made by this method, which demonstrates the use of combined kinetic and thermodynamic control for the relay of stereochemical information.

The synthesis of water soluble decalin-based thiols and S-nitrosothiols--model systems for studying the reactions of nitric oxide with protein thiols.

The syntheses of three decalin-based tert-thiols displaying varying degrees of solubility in aqueous milieu are described. The S-nitroso derivatives of these compounds have also been prepared and the structures of two of these determined by single crystal X-ray diffraction. These compounds have been designed for studying the interaction of nitric oxide (NO) with thiols under physiological conditions.

Phosphaadamantanes as ligands for palladium catalyzed cross-coupling chemistry: library synthesis, characterization, and screening in the Suzuki coupling of alkyl halides and tosylates containing beta-hydrogens with boronic acids and alkylboranes.

A 15-member library of phosphaadamantane ligands has been prepared via P-arylation of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phosphaadamantane. Screening of this tertiary phosphine collection has allowed for the rapid determination of the most suitable ligand, specifically 1,3,5,7-tetramethyl-6-(2,4-dimethoxyphenyl)-2,4,8-trioxa-6-phosphaadamantane, for facilitating Suzuki-type couplings of alkyl halides or tosylates containing beta-hydrogens with either boronic acids or alkylboranes.

Palladium complexes of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane: synthesis, crystal structure and use in the Suzuki and Sonogashira reactions and the alpha-arylation of ketones.

Palladium complexes of 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane were prepared and characterized with Pd[1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane](2).dba shown to be an effective catalyst for use in the Suzuki and Sonogashira reactions and the alpha-arylation of ketones. Couplings using this versatile complex proceeded in excellent yields under mild conditions.

Structure of bis(2-acetylpyridine 3-hexamethyleneiminylthiosemicarbazonato) palladium II, a potential antitumor complex.

The crystal structure of the potential antitumor complex bis(2-acetyppyridine 3-hexamethyleneiminylthiosemicarbazonato)palladium(II) has been solved. The palladium(II) atom is in a square planar environment surrounded by two cis nitrogen atoms and two cis sulfur atoms. The ligands are not equivalent, one being tridentate with (N,N,S) donation, the other being monodentate using only the sulfur atom to coordinate to the metal.

Structure, Electrochemistry, and Properties of Bis(ferrocenecarboxylato)(phthalocyaninato)silicon(IV) and Its Implications for (Si(Pc)O)(n)() Polymer Chemistry.

The crystal and molecular structure of bis(ferrocenecarboxylato)(phthalocyaninato)silicon(IV) (1) is reported. The structure is compared to the only other two fully solved Si(Pc) structures. The size of the Si atom is shown to vary with the nature of the axial ligands.