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Herein we describe the synthesis of a series of new potent tachykinin NK(2) receptor antagonists by the modulation of the C- and N-terminal moieties of ibodutant (MEN 15596, 1). The N-terminal benzo[b]thiophene ring was replaced by different substituted naphthalenes and benzofurans, while further modifications were evaluated at the C-terminal tetrahydropyran moiety. Most compounds demonstrated a high affinity for the human NK(2) receptor and high in vitro antagonist potency, indicating that a wide range of substituents at both termini can be incorporated in the molecule without detrimental effects on the interactions with the NK(2) receptor. Selected compounds were tested in vivo confirming their activity as NK(2) antagonists. In particular, after both iv and id administration to guinea pig, compound 61 b was able to antagonize NK(2)-induced colonic contractions with a potency and duration-of-action fully comparable to the reference compound 1 (MEN 15596, ibodutant).

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.

We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B(2) receptor (hB(2)R) antagonists. Here we report, in detail, how this family of compounds was designed, synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB(2)R and high in vivo potency after topical administration to the respiratory tract. The series was designed on the basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists and is characterized by the presence of an alpha,alpha-dialkyl amino acid. The first lead (17) of the series was submitted to extensive chemical work to elucidate the structural requirements to increase hB(2) receptor affinity and antagonist potency in bioassays expressing the human B(2) receptor (hB(2)R). The following structural features were selected: a 2,4-dimethylquinoline moiety and a piperazine linker acylated with a basic amino acid. The representative lead compound 68 inhibited the specific binding of [(3)H]BK to hB(2)R with a pKi of 9.4 and antagonized the BK-induced inositolphosphate (IP) accumulation in recombinant cell systems expressing the hB(2)R with a pA(2) of 9.1. Moreover, compound 68 when administered (300 nmol/kg) intratracheally in the anesthetized guinea pig, was able to significantly inhibit BK-induced bronchoconstriction for up to 120 min after its administration, while having a lower and shorter lasting effect on hypotension.

We have studied the solvent dependent radical bromination of toluene sulfonyl chlorides. The use ofacetonitrile allows to avoid chlorinated solvents and to improve the yield and the reproducibility of theprocess. Keywords : Radical bromination, N -bromosuccinimide, benzyl bromide, aromatic sulfonyl chloride.Recently, we developed a series of bradykinin B2receptor antagonists potentially useful for airwaysinflammatory pathologies.[1,2] The central part of thestructure of compounds belonging to this series ischaracterized by the building block 2,4-dichloro-3-methylbenzenesulfonyl, as shown for compound MEN16132 (Scheme 1 ). In the course of our research project, weneeded to assess the synthesis of the said building block andof few analogues differently substituted in the aromatic ring.Therefore we studied a method of radical bromination of 2,4-dichloro-3-methylbenzenesulfonyl chloride ( 1 ) [3] to yield 3-The accepted mechanism is a free-radical process, where N -bromosuccinimide (NBS) is used as a source of low-concentration bromine [5], which produces bromine radicals,initiates the reaction, and consumes the liberated HBr by aionic process. [6] A lot of variants to such process have alsobeen reported, i. e. the use of 2,2'-azobis(2-methylpro-pionitrile) (AIBN) or benzoyl peroxide (Bz

1,3-Dipolar cycloaddition of N-benzyl-C-(methoxycarbonyl)nitrone (3a), N-benzyl-C-phenylnitrone (3b), N-benzyl-C-cyanonitrone (3c), N-(p-methoxybenzyl)-C-cyanonitrone (3d), N-phenyl- (3e) and N-(2-pyridyl)-C-methylnitrones (3f) to bicyclopropylidene (2) gave the corresponding cycloadducts 5a−f in 100, 95, 94, 100, 93 and 71% yields, respectively. Treatment of these bisspirocyclopropanated isoxazolidines with trifluoroacetic acid in acetonitrile furnished the corresponding 3-spirocyclopropanated β-lactams 7a−f in 78, 75, 75, 94, 96 and 96% yields, respectively. The structures of the cycloadduct 5b and of the β-lactam 9a were proved by X-ray crystal structure analyses. Thus, this new method furnishes compounds with a 5-azaspiro[2.3]hexan-4-one skeleton in 68−94% overall yield in two simple steps. β-Lactams 7a, 7b, and 7d were converted into their N-acyl derivatives 9a, 9b, 9d and 11 in 44, 28, 39 and 78% yields, respectively. Heating of the β-lactams 9b and 11 with tert-butyl glycinate (12) or with tert-butyl (S)-phenylalaninate (14) in DMF led to ring-opening of the β-lactam moiety to give β-dipeptides 15, 16 and 17 in 61, 84 and 79% yields, respectively, while β-lactam 9a gave the amide 13 (51% yield). β-Lactams 7e and 7f turned out not to be transformable into such peptide products (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Starting from pyrrole- and indole-2-carboxylic acids 5 a and 5 b, the tri- and tetracyclic N,N-dibenzylcyclopropylamines 7 a and 7 b have been synthesized in 52 and 33 % overall yield, respectively. The synthesis of the enantiopure tetracyclic diamine 10 has been achieved applying the established set of reactions to N-tert-butoxycarbonylindoline-2-carboxylic acid (8) in 46 % overall yield. The amide 15 could not be prepared in the same way starting from the N-tert-butoxycarbonylproline 11. In fact, in the allylation step the stereogenic center was deprotonated and the doubly alkylated amide 13 was formed. However, the desired intermediate 15 could be obtained from L-proline in 49 % yield performing first the N-allylation step, then the introduction of the amide function. From 15, the cyclopropane-annelated pyrrolizidine 16 was obtained in 70 % yield as a mixture of (1aS,6aS,6bR)-16 and (1aR,6aS,6bS)-16 diastereoisomers in a ratio of 1:2.9.

A variety of spirocyclopropane-annelated tetrahydropyridinones of types 14/15 and 18/19 have been prepared in good yields (68−80%) by means of 1,3-dipolar cycloadditions between nitrones 25, 31, and 34 and cyclopropylidenespiropentane (7) and 7-cyclopropylidenedispiro[2.0.2.1]heptane (8), with subsequent thermal rearrangement. While the overall reactions of nitrones 25 and 31 with 7-cyclopropylidenedispiro[2.0.2.1]heptane (8) occurred with the commonly observed regioselectivity (i.e., the initially formed cycloadducts of type 12/13 rearranged to give compounds 29, 30, and 33 as major products), the reactions of 31 and 34 with cyclopropylidenespiropentane (7) and of 34 with 7-cyclopropylidenedispiro[2.0.2.1]heptane (8) showed an opposite trend. Thermal rearrangement of compound 27 gave a mixture of pyridinone 29 and ring-opened product 30 (19 and 58% yields, respectively). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Histone deacetylases are promising molecular targets for the development of antitumor agents. A novel series of histone deacetylase inhibitors of the hydroxamic acid type were synthesized for structure−activity studies. Thirteen tricyclic dibenzo-diazepine, -oxazepine, and -thiazepine analogues were studied and shown to induce variable degrees of histone H3/H4 and tubulin acetylation in a cellular model of myeloid leukemia sensitive to all-trans retinoic acid (ATRA). Multiparametric correlations between acetylation of the three substrates, tumor cell growth inhibition, and ATRA-dependent cytodifferentiation were performed, providing information on the chemical functionalities governing these activities. For two analogues, antitumor activity in the animal was demonstrated.

The (3S)-3-alkoxypyrroline N-oxides 7 and 27 were easily prepared from L-malic acid and used as starting materials for enantiospecific syntheses of stereodifferentiated polyhydroxyindolizidines. Selection of the appropriate modality (inter- or intramolecular) for 1,3-dipolar cycloaddition of the cyclic nitrone with 5-hydroxypentenoic acid derivatives gave access to either [1,8a]-trans- or -cis-hydroxyindolizidines 31 and 24, respectively, through elaboration of the primary cycloadducts. Moreover, the choice of the esterification conditions (Ph3P/DEAD or DIC/DMAP) used in linking the nitrone and the dipolarophile moieties in the intramolecular approach determined the absolute configuration of the final product, allowing the selective synthesis of both enantiomers, (−)-24 and (+)-24. This strategy required protection of the nitrone functionality to avoid racemization of the unprotected hydroxy nitrone during the introduction of the dipolarophile moiety. Protection/deprotection were achieved by cycloaddition/retro-cycloaddition reactions. The different propensity of some pyrrolo[1,2-b]isoxazolidines to undergo retro-cycloaddition with regeneration of the nitrone functionality was investigated both experimentally and by semiempirical and ab initio calculations on model compounds. The relative calculated activation energies were qualitatively in good agreement with the experimental observations. Fumaronitrile was found to be a convenient protecting reagent for the nitrone moiety and could be removed by retro-cycloaddition at lower temperatures than styrene and ethyl acrylate. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

A variety of tris- and monoprotected derivatives with the 1-amino-3-azabicyclo[3.1.0]hexane and 1-amino-3-azabicyclo[4.1.0]heptane skeleton 10 have been synthesized by intramolecular reductive cyclopropanation of α-(N-allylamino)-substituted N,N-dialkylcarboxamides 6, 8, and 9. Starting from derivatives of the naturally occurring amino acid serine (4a, 4b), the enantiomerically pure compounds 10a and 10b were obtained with endo/exo ratios of 2.5:1 (a) and 2:1 (b), in 26 and 30% overall yields, respectively. The unprotected bicyclic amines 11aa, 11ab, 11ba, and 11ad have been prepared by palladium-catalyzed hydrogenative deprotection of 10aa, 10ab, 10ba and 10ad, respectively, under acidic conditions, in 91, 95, 96, and 99% yields, respectively. X-ray crystal structure analyses of 10aa and 10ad in each case found an equatorial position of the N-benzyl group on the heterocycle and a common boat conformation for the 3-azabicyclo[3.1.0]hexane and 3-azabicyclo[4.1.0]heptane skeletons as a whole. One-step preparations of the bicyclic diamines 11ac (41% yield) and 14a (48% yield) have been performed by application of the Kulinkovich−de Meijere procedure to the nitriles 12a and 12b. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

The 1,3-dipolar cycloadditions of a series of chiral acrylates and acrylamides with 2-tert-butoxycarbonyl-1-pyrroline N-oxide were studied. The synthesis of enantiopure tert-butyl (2R,7aR)- and (2S,7aS)-2-hydroxy- 3-oxo-tetrahydro-1H-pyrrolizine-7a(5H)-carboxylates starting from the acryloyloxazolidinone derived from (S)-phenylalanine is reported.

The enantiomerically pure indolizidine (-)-21 has been synthesized starting from L-malic acid. The key intermediate 20 has been assembled through an intramolecular 1,3-dipolar cycloaddition of a nitrone generated in situ by retrocycloaddition from isoxazolidine 17 or 18. The configuration of the new three stereocenters was set up with complete control in the cycloaddition step. The presented synthetic route provides a general and highly selective methodology toward indolizidines having the [1,8a]-cis configuration.