In the search for new antiinflammatory drugs: synthesis and antiinflammatory activity of some Thiazolo(3,2-a)pyrimidine derivatives containing a thioether group.

Our strategy for the exploration of new NSAIDs starts on the synthesis of derivatives of 5-oxo-5H-Thiazolo [3,2-a] pyrimidines. The compounds were achieved by the following methods: (a) condensation of 2-amino-4-alkylthiomethilthiazole with ethyl 4-chloro-3-oxobutanoate (PPA method), (b) triphenyl phosphonium salts preparation, (c) Wittig-reaction of the salts with suitable aldehyde. Synthesized compounds were screened for antiinflammatory activity in the carrageenin rat paw oedema assay according to Winter et al. Some of the new synthesize compounds, at the dose used (50 mg/Kg) reduced meaningfully the oedema. The pharmacological effect varies according to the administration time.

Synthesis and antiulcer activity of some (1S, 5R)-2-thiabicyclo (3, 3, 0) oct-5-ene derivatives.

The preparation of (1S,5R)-2-Thiabicyclo[3,3,0]oct-6-ene derivatives (Sn;n=0,1,2) is described. Spectral and optical data (IR, NMR, Mass, alphaD20) are reported. These compounds can be considered as thiaprostacyclin-like derivatives. Studies of anti-ulcer activity in comparison with two reference compounds (cimetidine, pirenzipine) have shown that all the new compounds own a good anti-ulcer activity. Further studies are in progress to establish the mechanisms of their action.

Synthesis of some 5-azaflavones.

Within a plan of researches concerning drugs with anti-ulcer activity, a series of 5-azaflavones has been prepared. In this first communication we report the relevant synthesis obtained by cyclization of appropriate beta-diketones in HCOOH at the boiling point. The beta-diketones have been obtained by Claisen condensation, starting from methyl 3-hydroxypicolinate and from appropriate aromatic or heterocyclic methylketone, using NaH as base.

Antiulcer activity of some PG-like derivatives and their intermediates.

During a search on PG-like compounds as antiulcer drugs we synthetized some hetherocyclic derivatives. Some compounds of this series were found to be effective after oral administration in inhibiting restraint induced ulcers in the rat. Three of the most active compounds showed fairly good antiinflammatory activity in the carrageenin-induced rat paw oedema test and in the RPAR test.

Effects of metoxibutropate, ibuprofen and guaiacol on the gastrointestinal system.

In previous studies we have shown that ibuprofen, guaiacol and the guaiacol ester of ibuprofen (I.N.N. metoxibutropate) are able to inhibit in-vitro prostaglandin synthesis. In the present study we have evaluated the effect of ibuprofen, guaiacol and metoxibutropate on the gastrointestinal system. Oral treatment with equimolar increasing doses of the three drugs produced a progressive inhibition of prostaglandin biosynthesis in the intestinal tract, without any effect on the rate of intestinal propulsion. Further studies evaluated the gastric tolerance of a molar dose of ibuprofen causing ulceration in 50% of the animals. After single and repeated administration of guaiacol and of the guaiacol ester of ibuprofen, the percentage of animals with gastric damage was very low and the index of ulceration seemed rather moderate. Our results show that although guaiacol is able to inhibit prostaglandin biosynthesis like a classic NSAID, it does not induce gastric damage. For these reasons it is justified to combine guaiacol with ibuprofen in order to reduce gastric erosions induced by a classic antiinflammatory drug.

[Use of the "Sartorius" cutaneous absorption simulator for transdermal pharmaceutical forms of NSAIDs]. / Utilizzazione del simulatore di assorbimento cutaneo "Sartorius" per la messa a punto di forme farmaceutiche transdermiche contenenti FANS.

We report the results of the in vitro-release of the active ingredients (flurbiprofen and ibuprofen) from dermal form obtained by the Sartorius Absorption simulator SM16750. The results show that the choice of the excipients is basic. Using NSAID, the aqueous gel can be considered the suitable formulation to obtained a good in vitro-release. The quantities of the active ingredients released during the time are plotted in diagrams.

Prostaglandins intermediates. Reduction of (E)-oxolactone by means of a chiral phase transfer catalyst.

Preparation of (15 S)-hydroxy derivative (1-b), a key intermediate in the synthesis of PG like compounds, by reduction the corresponding enone (2), is described. High yields in (S)-isomer was obtained by means of chiral phase-transfer catalyst: (-)-N-(1-dodecyl)-N-methylephedrinium bromide. Eleven ammonium quaternary salts derived from (-)-N-methylephedrine were prepared and tested as catalyst in the reduction of enone (2) with NaBH4. Synthesis of enone (2), from phosphonate (6) (via Wadsworth-Emmons reaction) is also described.

Synthesis and antiinflammatory activity of 5-oxo-5H-1,3,4- thiadiazolo[3,2-a]pyrimidine-6-carboxamides.

A series of 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-carboxamides were synthesized and evaluated for antiinflammatory activity in the carrageenin oedema test and in RPAR in the rat. Some proved active in both tests. Two compounds, namely 2-(3-pyridyl)- and 2-morpholino-5-oxo-5H- 1,3,4-thiadiazole[3,2-a]pyrimidine-6-N-(2-pyridyl)carboxamide were particularly interesting.

Synthesis and antiulcer activity of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo [1,5-a]pyrimidine-7-ones.

A series of (E)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo-[1,5-a]pyrimidine-7-ones were synthesized and evaluated for the inhibition of stress-induced gastric ulcers in the rat after oral administration. Several molecules were found to be very active. The particularly interesting compound (E)-1-(3-chlorophenyl)-5-[2-(3-pyridyl)ethenyl]-1H,7H-pyrazolo[1,5-a]- pyrimidine-7-one was chosen for wider pharmacological investigation.

7-trans-(2-Pyridylethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-ones: synthesis and pharmacological activity.

A series of 7-trans-(2-pyridylethenyl)-5H-thiazolo[3,2-a]pyrimidine-5-ones was synthesized and evaluated for their pharmacological activity. Some compounds were found to be effective in inhibiting restraint ulcers in the rat. Two of them also showed interesting antiinflammatory activity.

Synthesis and antiinflammatory activity of 7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-N-pyridylcarboxamides.

A series of 7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-N-pyridylcarboxamides was synthesized and assayed in the carrageenin-induced paw oedema test in the rat. Some compounds showed moderate antiinflammatory activity.

New derivatives of pyrrolo and pyrido[2,1-b] quinazoline as antiulcer agents.

A series of 3-benzylidene-1,2,3,9-tetrahydro-9-oxopyrrolo-[2,1-b] quinazolinecarboxylic acids and 6-benzylidene-6,7,8,9-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazolinecarboxylic acid was synthesized and evaluated for their antiulcer activity by the test of inhibition of restraint ulcers in the rat, and for gastric antisecretory activity using the technique of Shay. Some compounds appear potentially useful for therapeutic application.

Synthesis of new 2-(2-phenylethenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acids.

New 2-(2-phenylethenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acids with a hydroxy or alkoxy substituent in the 3-position were synthesized as potential antiallergic agents. None of them was effective in passive cutaneous anaphylactic reaction test in the rat.