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[figure: see text] Substituted 2,3,3a,4,5,7a-hexahydrobenzo[d]isothiazole 1,1-dioxides and 3,4,4a,5,6,8a-hexahydro-2H-benzo[e][1,2]thiazine 1,1-dioxides, novel cyclic sulfonamides, were synthesized by the thermal Diels-Alder reaction of triene derivatives of buta-1,3-diene-1-sulfonic acid amide. The stereochemical outcome of the reaction was determined by… (More)
A novel series of nonpeptide CCK(2) receptor antagonists has been prepared, in which 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1, 4]diazonine (5) was used as a chemical template. This uncommon ring system was obtained in a highly substituted form and in high yield by ozonolysis of the enamine bond of 1,2,3,4-tetrahydro-9H-pyrido[3, 4-b]indole derivatives… (More)
A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models. We now report the discovery of compounds in which the BCO skeleton has been replaced with bicyclic,… (More)
In the course of structural explorations around a series of potent CCK2 receptor antagonists, it was noted that simple N-methylation of the indolic N-H in the parent molecule gave rise to behavior in vivo that was consistent with the compound acting as an agonist. Exploration in vitro confirmed this property, and it was shown that the agonist action could… (More)
Histamine was converted to a selective histamine H3-receptor antagonist by capping the primary amine with 2-naphthalenesulfonyl chloride. Higher receptor affinity and lower variability in the data from the various bioassays were achieved with the 2-naphthalensulfonamides of histamine homologues.
omega-(1H-Imidazol-4-yl)alkane-1-sulfonamides were prepared and found to be potent histamine H(3) receptor antagonists. High receptor affinity and a low difference in the data between the bioassays were achieved with 5-(1H-imidazol-4-yl)pentane-1-sulfonic acid 4-chlorobenzylamide (16). Good in vitro profiles were also obtained for 2-hydroxysulfonamide and… (More)
The syntheses and structures of three cyclophanes containing two (Z)-dehydrophenylalanine residues are reported; the length of the tethers between the two amino acid residues is easily altered and changing this parameter has a significant effect on the solid state structures of the cyclophanes.
The conformationally constrained analogues of phenylalanine, tetrahydroisoquinoline-3-carboxylic acid (Tic), Sic, Hic and Nic, and the new amino acid Xic have been incorporated into a potent and highly selective cholecystokinin-2 (CCK(2)) receptor antagonist (2) in place of the phenylalanine residue, producing compounds 15a-e. High selectivities for CCK(2)… (More)
Two distinct routes to beta-cycloalkylalanine derivatives have been developed. The first route employs the reaction of the iodoalanine-derived zinc-copper reagent 2 with cycloalk-1-en-3-yl phosphates, and the second uses the palladium-catalysed coupling of the iodoalanine-derived zinc reagent 1 with cycloalkenyl triflates; in each case, catalytic… (More)
We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton. We wish now to report on compounds arising out of our earlier work which have substantially greater affinity as antagonists for the CCKB/gastrin receptor system and which maintain, or improve on, the… (More)