Novel 5-HT3 antagonists. Isoquinolinones and 3-aryl-2-pyridones

Abstract

Synthesis and pharmacological evaluation of a series of 1,2-dihydro-1-[(5-methyl-1-imidazol-4-yl)methyl]-2-oxopyridine 5-HT3 antagonists are described. The key pharmacophoric elements were defined as a basic nitrogen, a linking group capable of hydrogen bonding interactions, and an aromatic moiety. 1,2-Dihydro-2-oxopyridine moiety could be a good linking group because of its nicely planar structure. The steric limitations of the aromatic moiety were investigated by X-ray analysis and computer analysis and shown to be optimal when the aromatic moiety was constrained within an arched planar system, which could be successfully replaced by 3-(2-thienyl)-2-oxopyridine function or 6-amino-7-chloro-1-isoquinolinone function without any loss of the activity. Among the synthesized compounds, 42 showed the most potent activity in the inhibition of Bezold-Jarisch reflex in rats. Compounds 44a and 64 were orally active in the protection against cisplatin-induced emesis in dogs or ferrets. Structure-activity relationships are discussed.

Sulfonylacetonitriles as Building Blocks in Copper‐Catalyzed Domino Reactions: An Efficient Apporach to Sulfonated Isoquinolin‐1(2H)‐ones

“…We tested various copper catalysts (compare entries 3, 5-8), and CuCl was found to be the most effective catalyst (entry 1). Next, we attempted to use different ligands, and N, N-dimethylethane-1,2-diamine (D) showed the highest activity (compare entries 6,[9][10][11][12][13][14][15][16][17][18]. Interest-ingly, the target product (3 e) was obtained in 57% yield in the absence of a ligand (entry 19), which implied the existence of an ortho-substituent effect (see Scheme 3), formation mechanism, the nitrogen atom of CONHR group may coordinate to Cu, which can stabilize the intermediate I and II).…”

“…Isoquinolin-1(2H)-one derivatives are important heterocycle unites that occur in numerous biological active natural products such as ruprechstyril, [11] dorianine, [12] thalifoline [13] and pancratistain [14 ] (Figure 1c). Besides this, isoquinolin-1(2H)-one derivatives are well-known to possess various important biological and medicinal properties, such as antifungal activities, [15] tachykinin recepters, [16] 5-HT3 antagonists, [17] and CPARPs inhibitors. [18] The broad range of medicinal and biological activities of isoquinolin-1(2H)-ones make them an attractive and challenging target for synthesis.…”

Palladium-Catalyzed Regio- and Stereoselective Synthesis of Aryl and 3-Indolyl Substituted-4-Methylene- isoquinolin-1(2H)-ones.

“…[2] Substituted isoquinolinones have been found in biologically active small molecules which exhibit antihypertensive activity. [3] Moreover, these heterocycles can be used as 5-HT3 antagonists, [4] rhokinase inhibitors, [5] thymidylate synthetase inhibitors, [6] PARP-1-inhibitors, [7] melatonin MT1 and MT2 receptor agonist, [8] and fascin-targeted anti metastatic agents. [9] Fittingly, the development of efficient strategies for their construction and peripheral functionalization represents still an active research area aimed to achieve structural diversity.…”

An efficient total synthesis of ruprechstyril fromRuprechtia tangarana

“…Substituted isoquinolones are orally effective antagonists of receptors 5-HT 3 (Matsui et al, 1992), thymidylate synthase inhibitors (Li et al, 1991), human tumour necrosis factor inhibitors and tachykinin receptors (Chao et al, 1999).…”