Short communicationSynthesis and pharmacological study of ethyl 1-methyl-5-(substituted 3,4-dihydro-4-oxoquinazolin-3-yl)-1H-pyrazole-4-acetates
Introduction
Our research group has long been interested in the chemistry and pharmacology of 4(3H)-quinazolinones bearing a heterocyclic nucleus such as pyrazole, isoxazole and indazole. These compounds showed analgesic, antiinflammatory [1], [2], [3], [4], [5], [6] and antineoplastic [7], [8], [9] activities.
Among the pyrazole derivatives, some have the structure of type I bearing the ethoxycarbonylmethyl group at the C-4 position of the pyrazole nucleus, presenting the structural feature of the heteroarylalkanoic esters (see figure 1). These compounds showed remarkable analgesic activity associated with appreciable antiexudative properties and very reduced ulcerogenic effects and systemic toxicity [5].
It is reported that heteroarylalkanoic esters could afford in vivo the related acids [10] which are a well-established class of non-steroidal antiinflammatory agents (NSADs), therapeutically useful in the treatment of acute as well as chronic inflammatory conditions [10].
In particular, Lonazolac-Ca, the active principle of the antiinflammatory and antirheumatic agent Irritren®, is the calcium salt of 1-phenyl-3-(p-chlorophenyl)-1H-pyrazole-4-acetic acid [11], [12], [13], [14]. It shows a very good proportion of clinical efficacy and gastroduodenal side effects.
In order to improve the properties of the 5, 6, 7 and 8 unsubstituted quinazolinones (I), we prepared a new series of compounds which are substituted on the quinazolinone nucleus with groups that have similar lipophylic character but exert opposite electronic effects.
Section snippets
Chemistry
The synthesis of the quinazoline derivatives 2d–p was carried out following figure 2.
The amino derivatives 1a–c [15] were reacted with ethyl orthoacetates to produce the desired quinazolinones 2d–p.
The structures of compounds 2 were assigned on the basis of analytical as well as spectroscopic data. The IR spectra exhibited bands in the 1670–1750 cm−1 region, due to the endocyclic and ester carbonyl groups. The 1H-NMR spectra indicated hindered internal rotation about the bond that links the
Pharmacology
All the new quinazolinones were screened in order to evaluate their analgesic and antiinflammatory activities, behavioural effect, acute toxicity and, lastly, ulcerogenic potential. Indomethacin (INDO) and phenylbutazone (PBZ) were tested in all the assays as reference standards.
Results and discussion
Pharmacological data are reported in table I.
Conclusions
The pharmacological data obtained for compounds 2d–p were compared with those previously reported for the unsubstituted analogues of type 2 [5]. It seems that 6-Cl, 7-Cl and 8-CH3 substitution does not generally show any advantage for the analgesic activity, whereas it allows obtaining in some cases higher inhibition values in the carrageenin paw oedema test and the acetic acid peritonitis test. The above substitutions influenced the studied activities following different trends. Finally,
Chemistry
All melting points were taken in a Büchi-530 capillary apparatus and are uncorrected. IR spectra were recorded in a JASCO IR-810 spectrometer as Nujol mulls. 1H-NMR spectra were obtained in DMSO-d6 or CDCl3 solutions in a Brüker AC-E 250 MHz spectrometer using tetramethylsilane as internal reference. Microanalyses were performed in the laboratories of the Dipartimento di Scienze Farmaceutiche, University of Catania, Italy, and were within ±0.4% of theoretical values.
Acknowledgements
Financial support from MURST is gratefully acknowledged.
References (20)
- et al.
Eur. J. Med. Chem.
(1994) - et al.
Immunopharmacology
(1990) - et al.
Il Farmaco
(1998) - et al.
Eur. J. Med. Chem.
(1986) - et al.
Il Farmaco
(1990) - et al.
Il Farmaco
(1992) - et al.
Il Farmaco
(1994) - et al.
Arch. Pharm. Pharm. Med. Chem.
(1999) - et al.
Heterocycles
(1996) - et al.
Pharmazie
(1999)
Cited by (109)
Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives as potential inhibitors of TNF-α
2023, Journal of Molecular StructureArylpyrazole as selective anti-enterococci; synthesis and biological evaluation of novel derivatives for their antimicrobial efficacy
2023, Journal of Heterocyclic ChemistryRegiodivergent Synthesis of 3,4- and 4,5-Disubstituted N-Methylpyrazoles from 4-Acyl-1 H-pyrrole-2,3-dione and Methylhydrazine
2022, Journal of Organic ChemistryOne-pot synthesis of some new regioselective 4β-pyrazolepodophyllotoxins as DNA topoisomerase-II targeting anticancer agents
2022, Journal of Molecular StructureCitation Excerpt :Pyrazole derivatives have wide-ranging of pharmacological activities like antimicrobial [13], anti-inflammatory [14], antidepressant [15], antioxidant [16], antimycobacterial [17], antiviral [18], anticonvulsant [19] and insecticidal [20] activities. In specific, the antitumor activity of pyrazole derivative was first evaluated in phase I studies in man in 1960s [21]. Later, 1-carboxamidopyrazole and 1-thiocarbamoylpyrazole were prepared which exhibited substantial anticancer results on animal trials [22,23].