- CARDIOTONIC PHOSPHODIESTERASE INHIBITORS COMPLEXED WITH WATER SOLUBLE VITAMINS
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This invention is directed to a formulation of cardiotonic phosohodiesterase inhibitors with a water-soluble vitamin, comprising a lyophilization step performed on a solution of the complex in an aqueous/organic solvent system. The formulation results in a complex that has been found to have enhanced solubility (over the compound alone) in a parenterally or orally acceptable solvent, and the lyophilization process yields a product with superior stability permitting an extended shelf life
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- Inhibitors of Cyclic AMP Phosphodiesterase. 4. Synthesis and Evaluation of Potential Prodrugs of Lixazinone (N-Cyclohexyl-N-methyl-4quinazolin-7-yl)oxy>butyramide, RS-82856)
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The cyclic AMP phosphodiesterase (cAMP PDE) inhibitor and cardiotonic agent lixazinone (N-cyclohexyl-N-methyl-4-quinazolin-7-yl)oxy>butyramide, RS-82856, 1) and its acid and base addition salts were found to be insufficiently soluble in formulations suitable for intravenous administration.These results prompted an investigation into potential prodrugs with enhanced aqueous solubility designed to deliver 1 by three distinct mechanisms: (1) decarboxylation of α-carboxamides; (2) hydrolytic loss of a solubilizing N-1-(acyloxy)methyl or (N,N-dialkylamino)methyl moiety; or (3) intramolecular closure of a guanidino ester or amide.The target compounds were evaluated as delivery systems for 1 by three criteria: (1) chemical conversion rate to 1 under physiological conditions; (2) inhibition of type IV cAMP PDE at a fixed time point; and (3) in vivo inotropic activity in anesthetized dogs by both intravenous and oral administration.Release of 1 from 4a (series 1) was found to be too slow to be of value as prodrug of 1, since decarboxylation could be induced only by strong acid, conditions under which hydrolytic ring opening was found to severely compete.Conversely, 1 was released too readily on exposure of (N,N-dialkylamino)methyl derivatives such as 8d (series 2) to physiological conditions, although no large increase in aqueous solubility was realized.Finally, both the physicochemical and in vitro studies indicated that ring closure of the guanidinium esters and amides 17a-k (series 3) to 1 was quantitative and pH- and time-dependent, suggesting the possibility of delivery of the open, water-soluble prodrug form, followed by closure to 1 in plasma.Detailed examination of these agents in vivo, however, demonstrated that only those compounds that rapidly cyclized to 1, as measured by plasma levels of 1, exhibited inotropic activity, indicating that the open prodrug form was not efficiently absorbed upon oral administration.
- Venuti, Michael C.,Alvarez, Robert,Bruno, John J.,Strosberg, Arthur M.,Gu, Leo,et al.
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p. 2145 - 2152
(2007/10/02)
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- Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide
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Evaluation of a series of lactam heterocyclic analogues of cilostamide as inhibitors of cyclic AMP phosphodiesterase derived from both human platelets and rat heart in comparison with their corresponding methoxy-substituted heterocycles has revealed that the N-cyclohexyl-N-methyl-4-oxybutyramide side chain of 2 is an important lipophilic and/or steric pharmacophore. Attachment of this side chain to the parent heterocycle of the potent cyclic AMP phosphodiesterase inhibitor anagrelide afforded the hybrid structure RS-82856, shown to be more potent than either of its progenitors as an inhibitor of cyclic AMP phosphodiesterase or of ADP-induced platelet aggregation. The available in vitro data suggest that 1 possesses potentially useful antithrombotic and cardiotonic properties.
- Jones,Venuti,Alvarez,Bruno,Berks,Prince
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p. 295 - 303
(2007/10/02)
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- (2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolinyl)oxyalkylamides, compositions and the use thereof
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Compounds according to the formula an optical isomers thereof, or a pharmaceutically acceptable acid addition salt thereof wherein: n is an integer of 1 to 6; R1 is hydrogen or alkyl of 1 to 4 carbons; R2 is hydrogen or R1 and R2 are combined to form an oxo group; R3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl of an alpha-amino acid side chain; 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 NR5R6 wherein R5 and R6 are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acrylate thereof 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, -OCOR7, halo, -NH2, -N(R7)2, -NHCOR7, -COOH, or -COO(R7) group wherein R 5 is lower alkyl; and phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with at least one lower alkyl, halo or lower alkoxy group or an -NH2, -N(R7)2, -NHCOR7, -COOH, or -COOR7 group wherein R7 is lower alkyl; or wherein R5 and R6 are combined to form a compound selected from the group consisting of: morpholinyl; piperidinyl; perhexylenyl; N-loweralkylpiperazinyl; pyrrolidinyl; tetrahydroquinolinyl; tetrahydroisoquinolinyl; (+/-)-decahydroquinolinyl and indolinyl. These compounds are cyclic AMP phosphodiesterase inhibitors useful as antithrombotic agents and the like in mammals. The compounds also have inotropic and anti-metastatic activities.
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- Method of treating heart failure using (2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolinyl)oxyalkylamides
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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.
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- N,N-Disubstituted-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-B]quinazolinyl)oxyalkylamides
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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 carbons; R2 is hydrogen or R1 and R2
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