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Methyl 3-(4'-Methyl-3'-oxo-1 '-cyclohexenyl)butanoate (II).11 -The preceding acid (29.2 g, 0.14 mol) in purified tetrahydrofuran (600 ml) and dry ieri-butyl alcohol (600 ml) was added gradually to distilled, stirred liquid ammonia (1500 ml). With continued stirring, lithium metal (16.7 g, 2.4 mol) was added in small pieces during 45 min. The deep blue solution was stirred for 5 hr, then quenched with methanol (150 ml) and stirred overnight during evaporation of the ammonia. Water was added and the organic solvents were removed in vacuo. The residue was diluted with water to 2 1., then cooled in ice, acidified with cold 4 N hydrochloric acid, and quickly extracted thrice with ether. The combined extracts were dried, cooled in ice, and mixed with an excess of ethereal diazomethane. The ether solution was washed with aqueous sodium bicarbonate and water, dried, and concentrated. The residue was stirred with 2.5 A7 hydrochloric acid (500 ml) for 3 hr, and organic material was isolated with ether. The extract was dried and concentrated, and the residual keto ester 11 distilled: bp 110°( 0.25 mm) 22.4 g, 76%); Xmax-(EtOH) 234 nm (« 11,000); ir (film) 1735, 1720 (weak), 1665,

A series of N-[(heteroaryl)alkyl]pyrido[2,1-b]quinazolines were evaluated for their ability to inhibit the binding of radiolabeled platelet activating factor (PAF) to its receptor on dog platelets. The most potent compounds in this series were found to be pyrido[2,1-b]quinazoline-8-carboxamides possessing a four- or six-carbon chain between the carboxamide nitrogen atom and a 3-pyridinyl or 5-pyrimidinyl moiety. Since earlier metabolism studies with pyridoquinazolinecarboxamides suggest that the carboxamide moiety is labile to hydrolysis in vivo, attempts were made to find isosteric replacements for this group. The substitutions examined led to a loss of activity; however, insertion of a methyl group on the carbon atom alpha to the carboxamide nitrogen led to an enantioselective enhancement of potency. (R)-2-(1-Methylethyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-11-oxo-11H- pyrido[2,1-b]quinazoline-8-carboxamide (34) was more potent than the corresponding S enantiomer in the PAF binding assay and was also shown to be more resistant to degradation by amidases present in whole liver homogenates obtained from guinea pig, dog, and squirrel monkey. The corresponding rac-2-(1-methylethyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-11-oxo-11H- pyrido[2,1-b]quinazoline-8-carboxamide (33) was found to inhibit transient PAF-induced thrombocytopenia and decreases in blood pressure in guinea pigs after intravenous or oral administration and to have a duration of action of greater than 5 h after an oral dose of 200 mg/kg. Compound 33 thus represents the prototype of a new class of orally active PAF antagonists.

A number of indoles containing the 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl side chain have been prepared by standard methods. Alternate, novel syntheses of indole-2-carboxamides and indole-2-carbonitriles have been developed. The title compound, 7e, was found to be a potent inhibitor of bovine prostaglandin synthetase in vitro and to lower serum prostaglandin levels after oral or intraperitoneal administration to rats. Consistent with prostaglandin synthetase inhibition, 7e prevented arachidonic acid induced diarrhea in mice and also collagen, ADP, or epinephrine induced platelet aggregation in human platelet-rich plasma. In contrast to many prostaglandin synthetase and platelet-aggregation inhibitors, 7e had neither ulcerogenicity nor systemic antiinflammatory activity in rats.