Cardiotonic agents

Phthalazines commonly possess adrenergic activity. One such, carbazeran (77), is a cardiotonic agent. Its patented synthesis involves nucleophilicaromatic displacement of chiorophthal-azine derivative 7 with piperidinyl carbamate 76 to give carbazeran (77)... 

The narrow therapeutic range of digitalis related cardiotonic agents has resulted in an extensive effort to identify compounds in other structural classes which will improve cardiac function. The discovery of the heterocyclic cardiotonic drug, amrinone, led to research on other heterocyclic compounds for that indication. The imidazopyridine, isomazole (57), is representa-... 

K.-M. Chu, S.-M. Sliieh, S.-H. Wu and O. Y.-P. Hu, Enantiomeric separation of a cardiotonic agent pimobendan and its major active metabolite, UD-CG 212 BS, by coupled achiral-cliiral normal-phase high-performance liquid chromatography , 7. Chromatogr. Sci 30 171-176(1992). 

Canthine skeleton 52 Cardiotonic agent, heart failiu-e 3 Caspase-3 inhibitors, non-peptide 269 Catch and release , 2,4,5-trisubstituted pyrimidines 98 Chloro dehydroxylation 17 Click chemistry, 1,4-disubstituted triazoles 45... 

Fig. 1 Heterocycles bearing a 2-pyridone moiety with wide range of medicinal applications. Amrinone WIN 40680 1 is a cardiotonic agent for the treatment of heart failure. ZAR-NESTRA 2 is a selective farnesyl protein inhibitor and NP048 3 is a pilicide with novel antibacterial properties. The 2-pyridones 4, 5 and 6 are schematic representations of the three categories of 2-pyridones that wiU be covered in this chapter i.e., substituted 2-pyridones 4, 2-quinolones 5 and other ring-fused 2-pyridones 6...

Kiuchi F, Iwakami S, Shibuya M, Hanaoka F, Sankawa U. (1992). Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem Pharm Bull (Tol o). 40(2) 387-91. Kobayashi M, Shqji N, Ohizumi Y. (1987). Gingerol, a novel cardiotonic agent, activates the Ca2+-pumping ATPase in skeletal and cardiac sarcoplasmic reticulum. Biochim Biophys Acta. 903(1) 96-102. 

Dihydropyridazines of type (56) have been claimed as antiarrhythmic and cardiotonic agents [170], while compounds of type (57) and (58) show antiarrhythmic activity [174,175]. 

For a wide variety of 6-aryl-3(2//)-pyridazinones (including those discussed in the chapter on cardiotonic agents and antithrombotics [1]), bronchodila-tor activity has been claimed in patents [104,114-116,129,423,424]. Thus, for instance, the bronchospasmolytic effects (guinea-pig tracheal-chain preparations) of compounds of type (99) have been found to exceed those of xanthines [425]. The therapeutic index of these compounds (which inhibit phosphodiesterase at lower concentrations than xanthines and do not interact with adenosine receptors) is larger than that of xanthines. 

Carbuterol, 41 Cardiotonic agent, 53 Carisoprodol, 21 Carmantadine, 20 Camiustine, 12 Carnidazole, 245 Cartazolate, 469... 

Preparation of the cardiotonic agent butopamine (23) starts with reductive ami nation of ketone Acylation of... 

Cardiotonic agents are sometimes called positive inotropic drags, i.e. substances that enhance the strength of muscle contractions, and in this case those that enhance the strength of myocardium contraction. Cardiotonic drugs are intended for treating cardiac insufficiency. 

Ohizumi. Gingerol, a novel cardiotonic agent, activates the Ca -pump-ing ATPase in skeletal and cardiac ZO062 sarcoplasmic reticulum. Biochim Biophys Acta 1987 903(1) 96-102. 

Bipyridine resembles nicotine in its pharmacological properties but is not as active. The 3,4 -bipyridine derivative 113 known as amrinone and its relatives are of interest as cardiotonic agents. 4,4 -Bipyridine has been tested as an insecticide, but it is not of practical value.It is used in the study of the electrochemistry of cytochrome c and acts as a polymerization catalyst or hardening agent for various resins. l-Hexyl-4,4 -bipyridinium salts are especially effective as electron carriers in photochemical hydrogen producing systems. l,l -Dimethyl-4,4 -bipyridinium (92 R = R = CHj) and l,l -dibenzyl-4,4 -bipyridinium... 

An analogous scheme is used for the synthesis of the cardiotonic agent milrinone [28]. The key aminoformyl derivative (26-2) is obtained in this case by condensation of 4-pyridylacetone (26-1) with DMF acetal. Reaction with cyanoacetamide in the presence of a strong base proceeds exactly as above to give the pyridone (26-3) by a parallel set of transformations. Note that the nitrile is left as such in this drug. 

The role of the pyridone ring as a pharmacophore in cardiotonic agents such as amrinone (25-6) has been noted earlier very analogous activity is obtained with compounds in which the heterocylic ring is replaced by a pyridazinone. The synthesis of the first of these agents, pimobendan (35-6), starts with the acylation of the amino group in nitro-aniline (35-2) with anisoyl chloride (35-1) to give amide (35-3). 

The quinazolinone moiety (36-3) for the cardiotonic agent prindoxan (36-5) is formed by reaction of diamine (36-1) with carbonyl diimidazole (36-2). Friedel-Crafts acylation of the product with the half-acid chloride from methyl succinate gives the corresponding keto-ester (36-4). The pyridazinone (36-5) is then obtained by condensation of that product with hydrazine [38]. 

Replacement of the hydrazine function by a substituted 4-piperidinol leads to a compound that has been investigated as a cardiotonic agent that acts by increasing the contractile force of cardiac smooth muscle. The preparation is quite analogous to those above. The key step involves the displacement of chlorine from the substituted chlorophthalazine (68-1) with the ethyl carbamate from 4-piperidinol (68-2) to afford the alkylation product carbazeran (68-3) [77]. 

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