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The synthesis of different anthracyclines of the daunorubicin family, fluorinated at position 8 or 10 is described. The 8-fluoroderivatives ( 2a-c ) were obtained by glycosylation of the corresponding fluorinated aglycones. The 10-fluoroderivatives ( 2d-g ) were synthesized directly from daunorubicin ( 1a ) and idarubicin ( 1c ) following a non deglycosidative approach. 8-( S )-Fluorodoxorubicin was obtained from 8-( S )-fluorodaunorubicin, although in very low yield.

New pyridobenzo-and dipyridothiadiazepindioxides 3–5 and two isomers 13–14 were synthetized and their anti HIV-1 activity and the cytotoxicity were evaluated in vitro . A good antiviral activity was shown by pyridobenzothiadiazepindioxides 4 , compound 4a being the best.

The new penem antibiotic Men 10700 (3), bearing an amino acid derived amide as C-2 side chain, was synthesized. Men 10700 exhibited high potency and a broad spectrum of activity against Gram positive and Gram negative microorganisms.

A short synthesis of a cyclic constrained analogue 1 of the potent Substance P antagonist (±) CP-96345 is described. The key feature is the formation of the benzo[b]-1,5-naphthyridine system at the very last step of the synthesis throught an intramolecular arylation of an amine promoted by a strong base. If the tricyclic system was synthesized first, 2-methoxy benzylation of both the nitrogen atoms occurred.

Penem dithiocarbamates, 10 were synthesized from the alcohol 6 , in high yields and favourable ratio between the penem and the undesired penam isomers. In vitro antibacterial activity showed a dependence on polarity and steric hindrance of the side chain at C-2. Best results were obtained with the piperazino derivatives 10 l–n , while catechol 10 p did not show the expected improvements in anti-pseudomonal activity.

8-(S)-fluoro-daunomycinone is obtained from daunomycinone in 5 synthetic steps and coupled with daunosamine to give, after two further deprotection steps, 8-(S)-fluorodaunorubicin. DAST [(diethylamino)sulfur trifluoride] accomplishes the fluorodehydroxylation reaction in the ring-A of a protected anthracyclinone with retention of configuration.

Two new tetracyclic structures, containing the diazepine ring, were synthesized: 5,6-dihydro-12H-benzofuro[3,2-b][1,5]benzodiazepin-6-one and 5,6-dihydro-12H-benzofuro[3,2-b]pyrido[3,2-f][1,5]diazepin-6-one. Thus N-(2-haloaryl)-2-[(2-cyanophenyl)oxy]acetamides were cyclized to the corresponding N-(2-haloaryl)-3-amino-2-benzofurancarboxamides and then, through the formation of the central diazepine ring, to the title compounds. Formation of the diazepine ring took place only when an electron-withdrawing group was present in the molecule to facilitate the nucleophilic attack of an amine in the benzofuran intermediate.

Three new tetracyclic structures, containing the azepine ring, were synthesized: 11,12-dihydro-6H-benzofuro[3,2-c][2]benzoazepine-6,11-dione, 5,6,11,12-tetrahydroindolo[3,2-c][2]benzoazepine-6,11-dione and 11,12-dihydro-6H-benzofuro[3,2-c][2]benzoazepin-6-one.

A new series of 11-[(aminoalkyl) carbonyl] derivatives of 6,11-dihydrobibenzo [c,f] [1,2,5] thiadiazepine 5,5-dioxide (10-39) were synthesized and evaluated for potential antidepressant activity in the apomorphine-induced hypothermia (Apo 16) tests. Effects on reserpine-induced hypothermia and toxicity for the most potent antagonists of Apo 16 hypothermia were also studied. Structure-activity relationships are reported. Anticholinergic effects were evaluated for compound 12, identified as the most potent and least toxic in this series, by assessing physostigmine lethality. Compound 12 was also subjected to X-ray analysis

Penem dithiocarbamates, 10 were synthesized from the alcohol 6 , in high yields and favourable ratio between the penem and the undesired penam isomers. In vitro antibacterial activity showed a dependence on polarity and steric hindrance of the side chain at C-2. Best results were obtained with the piperazino derivatives 10 l–n , while catechol 10 p did not show the expected improvements in anti-pseudomonal activity.

The synthesis and the spectroscopic characterization of a new potential drug for urinary incontinence, adosupine, is described. Adosupine and its potential synthesis impurities were analyzed by a new HPLC method that was developed with a C18 reversed-phase column. The analysis was made under isocratic conditions, with a mobile phase of acetonitrile:water (15:85, v/v). Resolution of all synthesis impurities was allowed. The method was also applied to stability studies of adosupine in solid state and in solution under different conditions. With the conditions used, only one degradation product was shown by HPLC analysis; it was isolated, characterized, and identified as the hydrolysis product of the lactam ring present in the adosupine structure.

New pyridobenzo-and dipyridothiadiazepindioxides 3–5 and two isomers 13–14 were synthetized and their anti HIV-1 activity and the cytotoxicity were evaluated in vitro . A good antiviral activity was shown by pyridobenzothiadiazepindioxides 4 , compound 4a being the best.

The synthesis of different anthracyclines of the daunorubicin family, fluorinated at position 8 or 10 is described. The 8-fluoroderivatives ( 2a-c ) were obtained by glycosylation of the corresponding fluorinated aglycones. The 10-fluoroderivatives ( 2d-g ) were synthesized directly from daunorubicin ( 1a ) and idarubicin ( 1c ) following a non deglycosidative approach. 8-( S )-Fluorodoxorubicin was obtained from 8-( S )-fluorodaunorubicin, although in very low yield.

(+,−)4-Demethoxy-8-fluro-(7,8-trans)-daunomycinone is obtained by total synthesis and coupled with daunosamine to give 8-(S)-fluoroidarubicin-N-trifluoroacetate, the first anthracycline substituted with a fluorine atom on ring A.

Three new tetracyclic structures, containing the azepine ring, were synthesized: 11,12-dihydro-6H-benzofuro[3,2-c][2]benzoazepine-6,11-dione, 5,6,11,12-tetrahydroindolo[3,2-c][2]benzoazepine-6,11-dione and 11,12-dihydro-6H-benzofuro[3,2-c][2]benzoazepin-6-one.

Two new tetracyclic structures, containing the diazepine ring, were synthesized: 5,6-dihydro-12H-benzofuro[3,2-b][1,5]benzodiazepin-6-one and 5,6-dihydro-12H-benzofuro[3,2-b]pyrido[3,2-f][1,5]diazepin-6-one. Thus N-(2-haloaryl)-2-[(2-cyanophenyl)oxy]acetamides were cyclized to the corresponding N-(2-haloaryl)-3-amino-2-benzofurancarboxamides and then, through the formation of the central diazepine ring, to the title compounds. Formation of the diazepine ring took place only when an electron-withdrawing group was present in the molecule to facilitate the nucleophilic attack of an amine in the benzofuran intermediate.

A new series of 6-(hydroxyethyl)penems 2-substituted with amino acid-related side chains was synthesized. The nature of the amino acyl derivative proved to be crucial both from a synthetic point of view, as beta-lactam ring opening can compete with C-2 nucleophilic substitution, and for antibacterial activity. Primary amino acid amides emerged as the most suitable side chains for enhancing permeability through a Gram-negative outer membrane. In vitro activity of the new 2-[(aminoamido)methyl]penems 3a-u was influenced by the nature and position of the amide moiety, the ring size for cyclic amides, and the configuration of the amino acid. Compounds bearing amides derived from small N-methyl amino acids (such as 3a) or from cyclic amino acids (such as prolinamide 3p and 4-hydroxyprolinamide 3r) showed broad spectrum in vitro activity against both Gram-positive and Gram-negative microorganisms.

The synthesis and the spectroscopic characterization of a new potential drug for urinary incontinence, adosupine, is described. Adosupine and its potential synthesis impurities were analyzed by a new HPLC method that was developed with a C18 reversed-phase column. The analysis was made under isocratic conditions, with a mobile phase of acetonitrile:water (15:85, v/v). Resolution of all synthesis impurities was allowed. The method was also applied to stability studies of adosupine in solid state and in solution under different conditions. With the conditions used, only one degradation product was shown by HPLC analysis; it was isolated, characterized, and identified as the hydrolysis product of the lactam ring present in the adosupine structure.

A new series of 11-[(aminoalkyl) carbonyl] derivatives of 6,11-dihydrobibenzo [c,f] [1,2,5] thiadiazepine 5,5-dioxide (10-39) were synthesized and evaluated for potential antidepressant activity in the apomorphine-induced hypothermia (Apo 16) tests. Effects on reserpine-induced hypothermia and toxicity for the most potent antagonists of Apo 16 hypothermia were also studied. Structure-activity relationships are reported. Anticholinergic effects were evaluated for compound 12, identified as the most potent and least toxic in this series, by assessing physostigmine lethality. Compound 12 was also subjected to X-ray analysis

This paper shows the advantages of using chemometric strategies in QSAR of NKA analogues containing D-Tryptophan and behaving as highly selective NK-2 receptor antagonists: a) detecting the sequence with optimal antagonist activity, and b) having a strategy for selecting a few most informative sequences. The data set is included on disk as RVD .DAT.

The relative conformation of the aromatic rings and the amide bridge of diethylmethyl-2-[p-(o-propoxybenzamido)benzoyloxy]ethylammonium bromide has been established by a combined analysis of non-selective, single-selective and double-selective pulse experiments using, as a basis of comparison, the Dreiding molecular model of the compound.

A structure-activity study on neurokinin A and its C-terminal fragment NKA (4–10) has been performed in order to find selective agonists for the NK-2 receptor and identify chemical modifications suitable for protecting the peptides from degradation, while maintaining activity. Five series of compounds have been prepared and tested: 1. the complete series of the L-Ala monosubstituted analogues of NKA; 2. a series of NKA fragments from the C- or N-terminal; 3. the complete series of NKA (4–10) analogues monosubstituted with β-Ala; 4. a series of NKA (4–10) analogues with monosubstitutions in pos. 4, 8, 10 or multisubstitutions in two or more of the same position; and 5. a series of 6 NKA (4–10) analogues monosubstituted with 1-amino,1-cyclohexane carboxylic acid residue. It has been found that the most selective agonists for the NK-2 receptor system are [βAla8]NKA (4–10) and [Nle10]NKA (4–10). Protection from aminopeptidase may be obtained by acetylation of the N-terminal amide of NKA (4–10), while partial protection from endopeptidases should be expected from the presence of β-Ala in position 8. Conformational constraints induced with 1,amino,1-cyclohexane carboxylic acid residue gave weakly active compounds. Multiple substitutions reduce rather than potentiating the favorable effects of the corresponding monosubstituted compounds.

The relative conformation of the aromatic rings and the amide bridge as well as important details of the two side chains of the title compound in a DMSO-d6 solution have been established by use of non-selective and selective proton spin-lattice relaxation times coupled with nOe experiments. The complete analysis of 13C spin-lattice relaxation times has shown the main features of the dynamic behavior of the title compound.

Data relative to the synthesis and anti-convulsant properties of new 5,6-dihydro-dibenzo[b,e]azepin-6-ones are presented. Structure-activity relationships of various derivatives substituted in positions 5 and 11, as well as the importance of the steric hindrance of the substituents on biological activity are shown.

Replacement of the glycine in position 8 of the C-terminal heptapeptide NKA(4–10) with β-alanine gives rise to a potent and selective agonist for the NK-2 tachykinin receptor. The affinity of [β-Ala8]-NKA(4–10) to the NK-2 receptor is enhanced by almost one order of magnitude as compared to NKA(4–10), while affinity decreases at about the same extent at NK-1 and NK-3 receptors, respectively. Synthesis and biological activities of a series of NKA(4–10) analogues systematically replaced in each position with β-alanine are also reported.

Limited conformational constraints have been introduced in the sequence of the C-terminal fragment of the peptide neurotransmitter neurokinin A by N-methylation of individual peptide bonds, and the biological activities of the peptides thus obtained were evaluated in order to assess the effect of such conformational constraint on receptor selectivity. The analogue methylated in position 7 shows enhanced selectivity toward NK-1 receptor.