94192-78-6Relevant articles and documents
Inhibitors of Cyclic AMP Phosphodiesterase. 2. Structural Variations of N-Cyclohexyl-N-methyl-4-quinazolin-7-yl)oxy>butyramide (RS-82856)
Venuti, Michael C.,Jones, Gordon H.,Alvarez, Robert,Bruno, John J.
, p. 303 - 318 (2007/10/02)
A series of analogues of the cyclic AMP phosphodiesterase (PDE) inhibitor N-cyclohexyl-N-methyl-4-quinazolin-7-yl)oxy>butyramide (RS-82856, 1) was prepared by systematic variation of the side-chain substituent, length, position, connecting atom, and the parent heterocycle itself.The compounds were evaluated as inhibitors of cyclic AMP phosphodiesterase from both human platelets and rat or dog heart tissue and as inhibitors of ADP-induced platelet aggregation.Structure-activity correlations for the analogue series revealed significant limitations on the steric bulk of substituents on the 1,2,3,5-tetrahydroimidazoquinaazolin-2-one heterocycle and the position and length of the side-chain.As inhibitors of cyclic AMP phosphodiesterase (PDE), potency steadily increased with increasingly lipophilic side chains.In platelet aggregation inhibition studies, however, a maximum in activity was reached with 1, while more lipophilic compounds were significantly less active.Major changes in the heterocycle itself, represented by isomeric and other carbonyl variations, also decreased activity.The molecular features defined by this series of analogues of 1 correlate to a high degree with current understanding of thr chemical and topographical requirements of the active site of the FIII (type IV) form of cyclic AMP PDE.Selective inhibition of this enzyme has been proposed as the principal component of the positive inotropic action of a number of cardiotonic agents.
Method of treating heart failure using (2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolinyl)oxyalkylamides
-
, (2008/06/13)
Compounds according to the formula STR1 and the pharmaceutically acceptable acid addition salts thereof wherein: n is an integer of 1 to 6; R1 is hydrogen or alkyl of 1 to 4 carbon; R2 is hydrogen or R1 and R2 combined are oxo; R3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl and its acylates, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or amino acid side chains; R4 is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl; Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy; A is an amide forming group wherein the nitrogen substituents are: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms and its aliphatic acylates of 1 to 6 carbon atoms or aryl acylates of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR5, halo, --NH2, --N(R5)2, --NHCOR5, --COOH, or --COO(R5) group wherein R5 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an --NH2, --N(R5)2, --NHCOR5, --COOH, or --COOR5 group wherein R5 is lower alkyl; morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; pyrrolidinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (±)-decahydroquinolinyl or indolinyl. These compounds have inotropic activity.
