X-RAY CRYSTALLOGRAPHY OF SOME ANALGETIC PYRAZOLE DERIVATIVES AND FENAMATES

Abstract

This thesis reports the crystal structure investigations carried out by the author on five non-steroidal anti-inflammatory, antipyretic analgesic drugs as part of an ongoing programme in this laboratory. Two of these drugs are pyrazole derivatives, while the remaining three are fenamates. Like other non-narcotic anti-inflammatory analgesics, they are believed to act through the inhibition of prostaglandin biosynthesis.

The first chapter of the thesis gives an introductory survey of the chemistry, pharmacology, and crystallography of analgesic pyrazole derivatives and fenamates. The related topics discussed in this chapter include prostaglandins and their biosynthesis, the involvement of prostaglandins in inflammation, fever, and pain, and the structure–activity relations in analgesic pyrazole derivatives and fenamates.

Chapter 2 presents the crystal structure of metamizol monohydrate, the sodium salt of a sulfonate derivative of amidopyrine, which is perhaps the most widely used non-narcotic analgesic and anti-inflammatory pyrazolone derivative. The structure (space group P2?/c) was solved by direct methods and refined to an R value of 0.075 for 4466 observed reflections. The two crystallographically independent molecules have similar dimensions. The elongated molecules are hydrophobic at one end and hydrophilic at the other, with the middle portion partly hydrophobic and partly hydrophilic. The pyrazolone group has dimensions similar to those found in uncomplexed antipyrine and amidopyrine. The crystal structure consists of double layers of metamizol molecules stacked perpendicular to the b-axis, separated by layers of sodium ions and water molecules.

Chapter 3 reports the crystal structure of oxyphenbutazone monohydrate, a metabolite and perhaps the active form of phenylbutazone. The structure (space group P1) was solved by direct methods and refined to an R value of 0.107 for 1498 observed reflections. The butyl group is disordered, and the hydroxyl group occupies two sites with unequal occupancies. Due to asymmetry at two nitrogen atoms and one carbon atom in the central five-membered ring, the molecule can exist in eight isomeric states, of which four are sterically unfavourable. The disorder in the hydroxyl group position can be explained by the existence of the four sterically favourable isomers with unequal occupancies. Bond lengths and angles are similar to those in phenylbutazone. The crystal structure is stabilized by van der Waals interactions and O–H···O hydrogen bonds involving carbonyl, hydroxyl groups, and water molecules.

Chapter 4 presents the X-ray analysis of meclofenamic acid, niflumic acid, and a new crystal form of flufenamic acid. The crystal structures of flufenamic acid and niflumic acid (space groups P2?/c and P2?/n respectively) were solved straightforwardly using direct methods and refined to R factors of 0.070 and 0.080 for 2273 and 1426 observed reflections respectively. The disordered structure of meclofenamic acid (space group P1), which was more difficult to solve, was refined to an R value of 0.135 for 1062 observed reflections. The disorder is satisfactorily explained in terms of rotational isomerism of the (2,6-dichloro-3-methyl)phenyl group about the bond connecting it to the anthranilic acid moiety, with unequal occupancies of the disordered components based on packing considerations.

The structural characteristics of fenamates, obtained from the three X-ray analyses carried out by the author and two carried out elsewhere, are discussed in the final chapter. A common feature of all fenamates is the rigid planar geometry of the anthranilic acid or o-aminonicotinic acid moiety, stabilized by resonance interactions and an internal hydrogen bond. Conformational variety arises exclusively from differences in the orientation of the remaining phenyl ring relative to this rigid moiety. Another common feature is the formation of hydrogen-bonded dimers in the crystal structures.

Part of the work described in this thesis has already been reported in the following publications:

“Crystal Structure of Metamizol.” Current Science (1977) 46, 221–222 (with M. Vijayan).

“X-ray Studies on Analgetic Fenamates.” Acta Crystallographica (1978) A34, 880 (with M. Vijayan and T.N. Bhat).

“Structural Studies of Analgesics and Their Interactions. V. The Crystal and Molecular Structure of Metamizol Monohydrate.” Acta Crystallographica (1979) B35, 612–615 (with M. Vijayan and L. Brehm).

“Structural Studies of Analgesics and Their Interactions. VI. Niflumic Acid.” Acta Crystallographica (1979) B35, 262–263 (with M. Vijayan).

“Structural Studies of Analgesics and Their Interactions. VII. Stereoisomerism and Disorder in the Crystal Structure of Oxyphenbutazone Monohydrate.” Acta Crystallographica (in press) (with M. Vijayan).

“Structural Studies of Analgesics and Their Interactions. VIII. Rotational Isomerism and Disorder in the Crystal Structure of Meclofenamic Acid.” (submitted for publication) (with M. Vijayan).