New potential immunoenhancing compounds. Synthesis and pharmacological evaluation of new long-chain 2-amido-2-deoxy-D-glucose derivatives.

A series of long-chain fatty acids and the corresponding 2-hydroxy, 2-oxo, 3-hydroxy acid glucosamides were evaluated as immunomodulating compounds. In a preliminary screening, 2-[(2-ethoxycarbonyloxy)tetradecanoylamino]-2-deoxy-D-glucos e (2b) and 2-(3-hydroxydodecanoylamino)-2-deoxy-D-glucose (5a) resulted to be the most effective in enhancing the glucosamine activity. The findings of in vitro-ex vivo tests (unidirectional mixed lymphocyte culture reaction and primary antibody production) and in vivo tests (delayed type hypersensitivity, protection against bacterial or fungal infection and against Sarcoma 180 or Lewis lung carcinoma transplants) were very encouraging and allowed to assume for the two substances a protective activity, presumably through the ability of activating phagocytic and NK cells.

Synthesis and in vitro antibacterial activity of a new series of monobactam derivatives.

Using as a model monobactams with a substituted alpha-oxyimino moiety in the side chain (aztreonam), a series of 2-(2-aminothiazol-4-yl)-2-hydrazono-acetamido monobactam (II a, f) were prepared by condensation of the hydrazones (I a, e) (Z form) with tetrabutylammonium 3-amino-4-methyl-2-oxo-1-azetidin-sulphonate. Isomerization occurred during this synthesis and gave the E form of all compounds. Monobactams (II a, f) showed no significant in vitro antibacterial activity when compared with aztreonam and with some cephalosporins bearing the same E-hydrazono side chain.

Mass spectrometric identification of urinary and plasma metabolites of 9-hydroxy-19,20-bis-nor-prostanoic acid (rosaprostol).

9-Hydroxy-19,20-bis-nor-prostanoic acid (Rosaprostol) is an antiulcer compound with antisecretory and cytoprotective action. We studied the metabolites of Rosaprostol found in human plasma and in human and rat urine. Sixteen different metabolites were tentatively identified on the basis of their mass spectra. Two presumed metabolites were synthesized. To clarify the identities of some of them, deuterated Rosaprostol was administered to rats and mass spectra of the deuterated and protonated metabolites were examined. Rosaprostol is metabolized following three metabolic pathways leading, combined, to oxidized compounds with a lower number of carbons than the parent drug.

Synthesis and pharmacological evaluation of a new class of 2-(2-aminothiazol-4-yl)-2-hydrazonoacetamido cephalosporins.

A series of 2-(2-aminothiazol-4-yl)-2-hydrazonoacetamido cephalosporins 1a-h was prepared. Whenever possible, E and Z isomers were isolated, and their relative stabilities and their interconversions were tested. The antibacterial activity was tested against Gram-positive and Gram-negative bacteria. For compound 1c, whose Z and E forms do not interconvert rapidly, the Z form was the more active one. Among the other compounds, for which the E form is the only stable one for practical purposes, compound 1a was the most active. When compared with cefuroxime and cefotaxime, compound 1a showed slightly lower antibacterial activity but good serum level and half-life values.

Nonprotein sulfhydryls as possible components of the protective effect of rosaprostol on the rat gastric mucosa.

Experiments were designed to examine the possibility that nonprotein sulfhydryl groups of the gastric mucosa could participate in the protection of rat gastric mucosa by rosaprostol (the Na salt of 9-hydroxy-8,12 trans-19,20-bis-nor-prostanoic acid). Gastric mucosal lesions and the content of nonprotein sulfhydryls were evaluated after orally administered absolute ethanol. Pretreatment with rosaprostol by gavage prevented gastric lesions and reduced or prevented the decrease of mucosal nonprotein thiols. N-ethylmaleimide, a sulfhydryl blocker, worsened the ethanol-induced gastric lesions and lowered further the non protein thiols. Both variables were improved by the PG analogue and by PGE2. These results suggest a possible role of endogenous nonprotein sulfhydryl groups in the gastric protective effect of rosaprostol.

Synthesis and antiviral activities of 2-substituted azino-3-(D-arabinofuranosyl)-5-carboxymethylene-thiazolidine-4-ones.

2-(1-Isopropylidene)azino-3-beta and 3-alpha-D-arabinofuranosyl-5-methoxycarbonylmethylenethiazolidine-4-ones (III) and (IV) have been synthesized by condensation of benzylated alpha-chloro-D-arabinofuranose (V) with o-(trimethylsilyl)-2-(1-isopropilidene)azino-5-methoxycarbonylmethylen- thiazolidine-4-one (VI) in the presence of SnCl4 or molecular sieves. Condensation of benzoylated alpha, beta-bromo-D-arabinose (VII) with (VI) led exclusively to the alpha anomer (VIII). 2-(1-Isopropylidene)azino-3-alpha-D-arabinofuranosyl-5-carbamoylmethylene- thiazolidine-4-one (IX) has been synthesized from (IV) (R, R1, R2 = CH3). 1H-N.M.R. and 13C-N.M.R. data confirmed the structures of (III) and (IV) (R, R1, R2 = CH3 and R, R1 = CH3, R2 = Ph). Antiviral activities were tested on monolayer cultures of KB-cells. Whereas previously tested beta-D-ribofuranosyl derivatives had moderate activity, alpha and/or beta-D-arabinofuranosyl derivatives are totally inactive against herpes simplex and poliovirus.

Gastric antisecretory, antiulcer and cytoprotective properties of 9-hydroxy-19,20-bis-nor-prostanoic acid in experimental animals.

9-Hydroxy-19,20-bis-nor-prostanoic acid (IBI-C83) was evaluated on gastric acid secretion and gastric lesions induced in laboratory animals by a variety of experimental conditions: compound IBI-C83 is proved effective in decreasing basal, histamine- and pentagastrin-stimulated total acid output in rats and in pentagastrin perfused dogs. The concentration of N-acetylneuraminic acid in the gastric fluid, a marker of mucus secretion, is enhanced in rats by IBI-C83. This drug prevents gastric damage induced by non-steroidal antiinflammatory compounds such as acetylsalicylic acid, indometacin and phenylbutazone, gastric ulcers following pylorus ligation, and facilitates healing of the gastric ulcers evoked by subserosal injection of acetic acid. A prominent feature of IBI-C83 is its capacity to protect the rat from gastric damage elicited by necrotizing agents such as absolute ethanol, hydrochloric acid and hypertonic saline. This property, called "cytoprotection" and common to naturally occuring prostaglandins, is independent on the antisecretory activity of IBI-C83 and is not shared, at least in the reported experimental models, by the H2-receptor antagonist cimetidine. In spite of the prostaglandin-like properties displayed in its cytoprotective activity, compound IBI-C83 does not affect cardiovascular functions, gastrointestinal transit and uterine motility.

Synthesis and biological activity of digitoxigenin aminoesters.

A series of 3 beta-esters of digitoxigenin (3 beta-hydroxy-14 beta-hydroxy-5 beta-card-20(22)-enolide) with alpha-aminoacids, were synthesized and tested for inotropic activity on the guinea-pig isolated heart and by slow infusion in the cat in comparison with digitoxigenin, Lanatoside C and Strophantin K. Esterification of the 3 beta-hydroxy group of digitoxigenin with various amino acids led to compounds still retaining inotropic activity with low in vivo potency and short duration of action. The compounds are inactive when administered orally.

Chemical modifications in the tetracycline series.

New tetracycline analogs modified at position 5, 6 and 2 were synthetized. The 5-deoxy-5-oxo-derivatives, 2a and 3a, were obtained by DMSO/acetic anhydride oxidation of doxycycline (2) and methacycline (3), respectively; the 6-demethyl-6-hydroxymethyl-6-alpha-hydroxyoxytetracycline (3b) by methacycline oxidation with the KCIO3/OsO4 system and the 6-hydroxyanhydrooxytetracycline (4) treating 3b with periodic acid. The 2-ethoxycarbonyl-2-decarboxamidodoxycycline (2b), was synthesized by treating doxycycline nitrile (2c) with EtOH and anhydrous HCl, 2-thiocarboxamide-2-decarboxamidodoxycycline (2d) by reaction of doxycycline with P2S5 in dioxane and 2-aminomethyl-2-decarboxamidodoxycycline (2e) by RANEY-Nickel reduction of 2d. All the synthetized compounds proved to be almost inactive on agar plates both on Gram-positive and Gram-negative bacteria.

Synthesis and antibacterial activity of some ureido cephalexin and cefadroxil derivatives.

The antibacterial activity of some ureido, acylureido and carbamoylureido derivatives of cephalexin and cefadroxil, prepared in our laboratories, as compared to parent compounds is reported. Only the 7-[D-alpha-(imidazolidin-2-one-1-ylcarbonylamino)-alpha-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid (IV d) and the 7-[D-alpha-(imidazolidin-2-one-1-ylcarbonylamino)-alpha-p-hydroxyphenylacetamido]-3-methyl-3-cephem-4-carboxylic acid (V c) showed some antibiotic activity. However we found no activity improvement against Pseudomonas strains (contrary to the results obtained in similar penicillin derivatives) and a lower beta-lactamase resistance.

Metabolic pathway of the diethylamide of trans-3-methyl-4-phenyl-3-butenoic acid, an hypolipemic agent, in the rabbit.

The metabolism of the hypolipemic agent 3-methyl-4-phenyl-3-butenoic acid diethylamide (I) after oral administration to rabbits has been qualitatively investigated. Four main metabolites were identified in the urine of animals deriving from three different metabolic processes: aromatic hydroxylation, lactonization and N-dealkylation. All metabolites occured in free forms, were pharmacologically inactive and the unchanged starting drug was never recovered. The metabolic pathway of compound I was also compared with that of the parent non-substituted amide, 3-methyl-4-phenyl-3-butenamide (II). The fate of the two structurally related drugs was similar, except for hydroxylation of the carbon in the alpha position to the amidic group, occuring in compound II but not in compound I.

Synthesis of 6alpha-methyldigitoxigenin 3-acetate.

In order to determine the influence of a 6alpha-methyl group activity, the 6alpha-methyl derivative of digitoxigenin 3-acetate 14 was prepared and pharmacologically tested in comparison with digitoxigenen 3-acetate. The synthesis of 6alpha-methyldigitoxigenin 3-acetate (14) was performed starting from 21-hydroxy-4-pregnene-3,20-dione (1). According to the cardiac activity determined on guinea-pig isolated heart and by slow infusion in the cat, the 6alpha-methyldigitoxigenin 3-acetate (14) is not more active than digitoxigenin 3-acetate.

Microbiologic and pharmacologic properties of a new ampicillin derivative: Ampicillin-guaiacolsulfonate.

Ampicillin-guaiacolsulfonate, a new derivative of ampicillin, preserves the antibacterial properties of ampicillin, is suitable for infection owing to its good water solubility and it has far higher stability in dry state than has sodium ampicillin. Ampicillin-guaiacolsulfonate is better orally absorbed in rabbit than is ampicillin. In vitro experiments carried out with the model system by Rosano and Schulman, and measurements of the intestinal absorption in the everted sac jejunal preparation, carried out with 14C-labelled compounds, demonstrate that the new ampicillin derivative is better absorbed by the intestine because of an increase in the intestinal permeability of the molecule itself.

A new product of rearrangement of penicillin V (S)-sulphoxide.

Penicillin V (S)-sulphoxide (I), treated with methanesulphonic acid in benzene and dimethylacetamide, gives the decarboxylated increment3-cephem compound (IV) and a new product of rearrangement to which the structure of the 4-[N-(1'-carboxy-2'-methylenepropyl)carbamoyl]-2-phenoxymethylthiazole (VIII) is ascribed.