Elsevier

Il Farmaco

Volume 59, Issue 1, January 2004, Pages 25-31
Il Farmaco

Synthesis and COX-2 inhibitory properties of N-phenyl- and N-benzyl-substituted amides of 2-(4-methylsulfonylphenyl)cyclopent-1-ene-1-carboxylic acid and of their pyrazole, thiophene and isoxazole analogs

https://doi.org/10.1016/j.farmac.2003.09.003Get rights and content

Abstract

Some N-phenyl- (7a–10a) and N-benzyl-substituted (7b–10b) amido analogs of cyclooxygenase (COX-2) selective tricyclic non-steroidal anti-inflammatory drugs have been synthesized with the aim to obtain information on the structural requirements for the COX-inhibitory activity. Compounds 7–10 were tested in vitro for their inhibitory properties only towards COX-2 enzyme by measuring prostaglandin E2 (PGE2) production on activated J774.2 macrophages. Some of the new compounds (7a, 8a, 9a and 9b) showed a modest activity, with percentage inhibition values near 30% at a concentration of 10 μM. These data have been tentatively explained by a conformational study which indicates that at least the N-phenyl-substituted amides 7a–9a present steric hindrances which may prevent a good interaction with COX-2 active site.

Introduction

Prostaglandins are endogenous substances involved in different processes of physiological nature, and are potent mediators of inflammation. Prostaglandins are produced, together with other prostanoids, in the arachidonic acid metabolism, whose first step, consisting of the oxidative conversion of arachidonic acid into prostaglandin H2, is catalyzed by cyclooxygenase (COX) [1], [2]. This enzyme exists at least as two isoforms, one constitutive (COX-1) and the other inducible (COX-2) [2], [3]. Thus, while COX-1 is constitutively expressed and is involved in the synthesis and supply of the necessary arachidonic acid metabolites for a maintenance of gastric and renal functions as well as for an adequate vascular homeostasis, COX-2 is expressed only after an inflammatory stimulus, releasing metabolites that are used to induce inflammation and pain [4], [5], [6]. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) act by reducing prostaglandin biosynthesis through the inhibition of the COX reaction [7], [8]. In spite of their beneficial action, their activity is associated with deleterious side effects, and continuous administration of these drugs leads to nefrotoxicity and gastric ulcerations [9], [10]. The therapeutic anti-inflammatory action of NSAIDs is produced by inhibition of COX-2, while the unwanted side effects arise from the inhibition of COX-1 activity. Recently, some new NSAIDs possessing a good selectivity towards COX-2 have been described. The common structural backbone of these COX-2 selective inhibitors (A, Fig. 1 ) consists of two aryl groups linked to adjacent atoms of a central ring (X) which may be homocyclic or heteroaromatic, one of which is substituted in the p-position with either an aminosulfonyl (Y = NH2) or a methylsulfonyl (Y = Me) group. There are also examples of potent COX-2 inhibitors that possess cycloalkyl [11], alkoxy [12] or phenoxy [12], [13] moieties in the non-sulfonyl containing ‘aryl’ region. The central rings most commonly found within this class of molecules are cyclopentene (1) [11], thiophene (2) [14], pyrazole (3) [15], [16] and isoxazole (4) [17] (Fig. 1).

The limited chemical diversity of these molecules prompted us to search for new structures which, even though different from that of the COX-2 tricyclic inhibitors of type A, may possess analogs biopharmacological properties [18], [19], [20], [21]. Therefore, some type B compounds were synthesized which may be viewed as analogs of 1,2-diarylsubstituted NSAIDs of type A (Fig. 2 ) in which the non-sulfurated aromatic ring is replaced with a methyleneaminoxymethyl moiety (MAOMM). This kind of group (b in Fig. 3 ) was previously described as bioequivalent of aryls (a in Fig. 3) in many other classes of drugs in which this aromatic system is considered important for the activity [21], [22], [23], [24], [25], [26], [27]. Some of the new oxime-ethers of type B in which X = cyclopentene (5) or thiophene (6) showed COX-2 inhibitory properties, with satisfactory level of activity and COX-2 vs. COX-1 selectivity [18], [20].

These results suggested to widen the study of the effects on the inhibitory activity towards COX enzymes due to a further chemical manipulation at level of the non-sulfurated aromatic ring of compounds of type A. The amido group (c in Fig. 3) seemed to be suitable for this purpose since, as an aryl ring, it presents a nearly planar geometry; furthermore, the amido-moiety possess a π-system which may partially simulate the electronic system of an aryl.

On the basis of these considerations, we have designed and synthesized some compounds of type C (Fig. 2) in which the central core may be the cyclopentene (7) as in SC57666 (1), the thiophene (8) as in Dup697 (2), the pyrazole (9) as in celecoxib (3) or the isoxazole (10) as in valdecoxib (4) (Fig. 4 ). As R substituent we have chosen the phenyl (a) or the benzyl (b) group which have been resulted important for the activity as substituents of the oximic oxygen in type B compounds (Fig. 2).

Section snippets

Chemistry

As far as the N-phenyl- (7a) and the N-benzyl-substituted (7b) cyclopentene amides are concerned, they were prepared as reported in Scheme 1 . The cross-coupling reaction between the 2-bromocyclopent-1-ene-1-carbaldehyde 11 [18] with p-thiomethylphenylboronic acid in toluene–EtOH solution in the presence of Pd(PPh3)4 and aqueous Na2CO3 afforded the 2-[4-(methylthio)phenyl]cyclopent-1-ene-1-carbaldehyde 12. Compound 12 was oxidized in CH3CN by a one-step procedure both at level of methylthio-

Biological results and conclusion

For the new compounds 7–10 the inhibitory activity towards COX-2, which constitutes the ideal target of an anti-inflammatory drug, was evaluated in vitro by measuring the PGE2 production on activated J774.2 macrophages. The results were reported in Table 1 together with those obtained in the same type of test with celecoxib (3) and with the previously studied cyclopentenyl and thienyl oxime-ethers 5 and 6. As it can be seen, only compounds 7a, 8a, 9a and 9b, at a concentration of 10 μM showed a

Chemistry

Melting points were determined on a Kofler hot-stage apparatus and are uncorrected. 1H NMR spectra of all compounds were obtained with a Gemini 200 spectrometer operating at 200 MHz, in a ca. 2% solution of CDCl3. Analytical TLCs were carried out on 0.25 mm layer silica gel plates containing a fluorescent indicator; spots were detected under UV light (254 nm). Column chromatographies were performed using 70–230 mesh silica gel. Mass spectra were detected with a Hewlett Packard 5988A

Acknowledgements

We would like to thank Dr. Claudio Milanese of ACRAF-Angelini Ricerche for the enzyme assays.

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