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The synthesis of new N-substituted 4-hydroxy (III) and 4-acyloxy- or 4-alkoxy-2-pyrrolidinones (IV), as analogues of oxiracetam (III c), is reported. For this purpose, a convenient procedure for N-alkylation of the base-labile 4-hydroxy-2-pyrrolidinones (II a, c, d) was developed. Compounds (III) and (IV) were examined on phospholipid synthesis in brain microsomal membranes of rats, both in vivo and in vivo-in vitro, and on protein synthesis in brain slices. Results showed that only oxiracetam (III c), and to a lesser extent piracetam, are active both on phospholipid and brain protein synthesis.

The synthesis of 3-chloro-4-cyclopropylmethoxyphenylacetic acid (I) from 3-chloro-4-hydroxyacetophenone (III) by the etherification with cyclopropylmethyl bromide and by the Willgerodt reaction is described. The alpha-methyl homologue (II) was also prepared from 4-benzyloxy-3-chlorophenylacetate (VIII). The antiinflammatory, analgesic and antipyretic activities of the lysine salts of (I) (ISF 2508) and (II) (ISF 2606) were tested in comparison with alclofenac and phenylbutazone. The new ocmpounds compare favourably with the standards; in particular ISF 2508 was selected for further pharmacological studies.

As a part of a systematic research on new heterocyclic 3,4,5-trimethoxybenzamides with potential C.N.S. depressant activity, some derivatives of methyl- or dimethyloxazolidines were prepared. The results of preliminary pharmacological screening are reported in comparison with those of the model compound (I).

Within the framework of a research program on new compounds potentially active on learning and memory processes, some esters and amides of 2-oxo- and 2,5-dioxo-delta3-pyrroline-1-acetic acids were synthesized. Such compounds can be regarded either as dehydration products of the corresponding 4-hydroxy-2-pyrrolidinones or as cyclic derivatives of 4-aminoisocrotonic acid. Two approaches were used in an attempt to synthesize pyrrolinone derivatives. One method involved the direct alkylation with ethyl bromoacetate of 1,5-dihydro-2H-pyrrol-2-one (III b), obtained for the first time in pure form by cyclization of 4-amino-3-hydroxybutyric acid (GABOB). Another approach involved the preparation of the ethyl 3-bromo-2-oxo-1-pyrrolidineacetate (VI), by cyclization of N-(2,4-dibromobutyryl)glycine ethyl ester (V), and its 4-bromo isomer (X b) by bromination of ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate (X a). While the dehydrobromination of (VI) was unsuccessful, heating of (X b) with TEA afforded ethyl 2,5-dihydro-2-oxo-1H-pyrrole-1-acetate (IV a). Alternatively, (X a) was treated with methanesulfonyl chloride, then with TEA to give (IV a). Final ammonolysis of (IV a) provided the corresponding amide (IV b). For the synthesis of the maleimide analogue (XIII b), the N-(carboxymethyl)maleamic acid (XII a) was treated with PCl5 and then with anhydrous ammonia.

The synthesis of some alpha-hydrazinoarylacetic acids (I) by reaction of alpha-bromoarylacetic acids with hydrazine, alkylhydrazines and carbobenzyloxyhydrazines is described. Reduction of the hydrazones of 2- and 3-thienylglyoxylic acids provided a general and effective route to the thienylic series. In view of the use of compounds (I) for the preparation of new penicillins, the experimental conditions for their conversion into cyclohexylamides (XI) via the corresponding carbobenzyloxyderivatives (III) were also investigated.

The synthesis of some possible metabolites of trithiozine, a new antisecretory-antiulcer drug, is reported. The metabolite 4-(3,4,5-trimethoxybenzoyl)-2-morpholinol (III a) was prepared by oxidative cyclization of the corresponding diethanolamine derivative (II a). Similarly, 4-syringoyl-2-morpholinol (III c) was also obtained and both were converted into the methyl ethers (IV a, c), respectively. The same oxidative approach, starting from the alcohol (VII), afforded the isomeric 4-(3,4,5-trimethoxybenzoyl)-3-morpholinol (IX a) in low yields; therefore a four step process, involving the acid hydrolysis of the acetal intermediate (XII a) was preferred. In the course of the synthetic work 4-(3,4,5-trimethoxybenzoyl)-3-morpholone (V), a potential metabolite itself, was also prepared.

In the event that the GABA-GABOB system is involved in the initial phases of the learning and memory process, some new derivatives of 4-hydroxy-2-pyrrolidinone (I a) have been synthesized. The cyclic compounds of general formula (A) are more lipophilic than GABOB and should better enter brain fluids. The N-hydroxymethyl derivatives (II a...c) were prepared by addition of the suitable aldehydes to 4-acetoxy-2-pyrrolidinone (I b). In order to obtain the ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate (IV a) some synthetic routes starting from (I b), (III b) and from the 3-diazotetramic acid (V) were explored. However, the N-ethoxycarbonylmethyltetramic acid (X), obtained by Dieckmann cyclization of triester (VIII) and subsequent de-etho-xycarbonylation was reduced to (IV a). Ammonolysis of (IV a) afforded the acetamide (XI a). The O-acetyl derivatives (IV b) and (XI b) were also prepared.

A number of N-substituted 4-hydroxy-, 4-acyloxy- and 4-alkoxy-2-pyrrolidinones were examined by a screening method predictive of their activity on cognitive processes. The 1-aminocarbonylmethyl-substituted compounds showed a favorable effect on learning and memory, and among them the most active was the 4-hydroxy derivative, oxiracetam, which had a potency considerably higher than piracetam, used for comparison purposes.

Using as a model cephalosporins with an alpha-hydroxyimino moiety in the side chain, some new (E)-alpha-hydrazono and alpha-methylhydrazono benzyl cephalosporins were prepared. While the synthesis of methylhydrazono-derivatives (I a-d) involved direct condensation of the methylhydrazionacid (II a-b) with a protected 7-aminocephalosporanic derivative, the N-unsubstituted compounds (I e-f) had to be prepared from the N-acyl protected hydrazono acids (III a-d). The cephalosporin (I f) was also obtained as Z-isomer by condensation of the corresponding alpha-oxo compound with 4-nitrobenzyloxycarbonylhydrazine, chromatographic separation of the obtained E-Z mixture, and hydrogenolysis of the Z form. The in vitro antibacterial evaluation showed that N-methyl substitution is favorable among the E compounds, whereas among the N-unsubstituted hydrazono derivatives, the compound Z-(I f), although less stable, is much more potent than the corresponding E-isomer.