A series of 138 nonchiral 3-amidinobenzyl-1H-indole-2-carboxamides and analogues as inhibitors of the blood coagulation enzyme factor Xa (fXa) were designed, synthesized, and investigated by X-ray structure analysis and 3D quantitative structure-activity relationship (QSAR) studies (CoMFA, CoMSIA) in order to identify important protein-ligand interactions responsible for biological affinity and selectivity. Several compounds from this series are highly potent and selective inhibitors of this important enzyme linking extrinsic and intrinsic coagulation pathways. To rationalize biological affinity and to provide guidelines for further design, all compounds were docked into the factor Xa binding site. Those docking studies were based on X-ray structures of factor Xa in complex with literature-known inhibitors. It was possible to validate those binding modes by four X-ray crystal structures of representative ligands in factor Xa, while one ligand was additionally crystallized in trypsin to rationalize requirements for selective factor Xa inhibition. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r(2) values using the leave-one-out method and repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined factor Xa binding site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. The final quantitative SAR information agrees with all experimental data for the binding topology and thus provides reasonable activity predictions for novel factor Xa inhibitors.

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Severe upper airway stenosis was diagnosed in a 23 year old woman who presented with hoarseness, cough and dyspnoea 8 yrs after initial diagnosis of ulcerative colitis. The respiratory symptoms worsened over the next few months, the patient eventually developing dysphagia and ultimately severe upper airway obstruction. The narrowest site was the glottis, which was severely stenosed by inflammatory swellings. Systemic corticosteroids led to rapid clinical improvement and restoration of normal airway patency within a few months.Ulcerative colitis is frequently associated with extraintestinal inflammatory manifestations. In the respiratory tract these usually take the form of chronic bronchitis, which occasionally develops into bronchiectasis. This case confirms that the inflammation can also involve the larynx and large airways.

The syntheses of two novel pentacyclic ring systems, the thieno[3,2‐f][1,2,4]triazolo[4,3‐a][1,4]diazepino‐[4,5‐a]benzimidazole and the indazolo[2,3‐d][1,2,4]triazolo[4,3‐a][1,4]benzodiazepine are described. Attachment of a propargyl linked quinolinone resulted in compounds 6 and 16 which showed PAF‐antagonist activity by the intravenous route of administration in guinea pigs. The more potent compound 16 also exhibited good oral activity with an ID50 of 0.2 mg/kg in the bronchoconstriction assay.

A series of [1,2,4]triazolo[4,3-alpha][1,4]benzodiazepines bearing an ethynyl functionality at the 8-position and the isosteric thieno[3,2-f][1,2,4]triazolo[4,3-alpha][1,4]diazepines were prepared and evaluated as antagonists of platelet activating factor. The effects of substitution were explored in in vitro and in vivo test systems designed to measured PAF-antagonistic activity. Results are discussed and compared with previously published data. Many of the compounds had activity superior to WEB 2086, compound 1. In general, the thieno analogues exhibited better oral activity than the corresponding benzodiazepines. The duration of activity upon oral administration was modulated by the substitution on the acetylenic side chain. Compounds 71 and 81 were selected for further pharmacological evaluation as a result of their good oral potency and exceptionally long duration of action.

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Substituted indole-2-carboxylic acid esters and amides are readily converted to the corresponding 3-chloroindolenines by reaction with ieri-butyl hypochlorite. These compounds rearrange in protic solvents to oxindoles with migration of the ester or amide function into the 3 position. 3-Substituted 2-acetylindoles and indole-2carboxylic acids are converted to the oxindoles with loss of the carbonyl function. The intermediate 2-alkoxyindoles may be isolated. Nitration of 3-substituted indole-2-carboxylates yields the corresponding 3-nitroindolenines. The structure of ethyl o-chloro-3-nitro-3-phenyl-3iT-mdole-2-carboxylate was determined by X-ray analysis. Ethyl 3-nitroindolenine-2-carboxylates also undergo acid-catalyzed rearrangement to ethyl oxindolecarboxylates. Treatment of 2-acetyl-3-nitroindolenmes with trifluoroacetic acid results in the formation of 2nitroindoles.The oxidative rearrangement of indoles to oxindoles during halogenation is by now a common reaction.1'2 It has been demonstrated in the alkaloid field3•4 that 3-haloindolenines are the key intermediates in this overall transformation. With few exceptions, •6 however, 3-chloroindolenines have seldom been properly characterized, and until recently7 no simple analog was disclosed in the literature.We have obtained crystalline 3-chloroindolenines of formula 2 (Scheme I) by treating indole derivatives of structure 1 with ieri-butyl hypochlorite in aprotic solvents. These 3-chloroindolenines were found to be of limited stability and to convert exothermally and in high yields to oxindoles 3 in protic solvents such as alcohol. The structure of these compounds was derived from their spectroscopic data and confirmed by conversion of ethyl 3-phenyloxindole-3carboxylate (3a) to the known 3-phenyloxindole 4.We have successfully extended this reaction to the indole-2-carboxamides 6, which were prepared by standard methods via the indole-2-carboxylic acids 5. Reaction of the indole-2-carboxamides with ieributyl hypochlorite again produced the crystalline 3chloroindolenines 7. These compounds underwent the same transformation to the oxindoles 8 when subjected to protic solvents. The fact that even the primary amide 6d rearranged in the same manner as(1)

Variously substituted indolo[2,3‐c]quinolines, benzofurano[2,3‐c]quinolines and their positional isomers indolo[3,2‐c]quinolines and benzofurano[3,2‐c]quinolines respectively, were prepared from both indole and quinoline derivatives by intramolecular nucleophilic displacement of aromatic fluorine. The formation of an indolo[2,3‐d]benzazepine was also observed.