Synthesis of N-Substituted Piperazinyl Carbamoyl and Acetyl Derivatives of Tetrahydropapaverine: Potent Antispasmodic Agents.

Abstract

The synthesis and structure-activity-relationship (SAR) for a series of N-substituted piperazinyl carbamoyl 7-15 and piperazinyl acetyl 18-26 derivatives of tetrahydropapaverine have been carried out. The general synthetic methods of carbamoyl tetrahydropapaverine analogues involve N-substituted piperazines and carbamoyl imidazole tetrahydropapaverine as starting materials. Another route for synthesizing these compounds, involving the formation of carbamoyl imidazole piperazine has also been explored. Acylation of tetrahydropapaverine followed by substitution with various piperazinyl moities afforded the acetyl tetrahydropapaverine derivatives. Variously substituted piperazines have been used to monitor the effect of electron releasing and electron withdrawing substituents upon the antispasmodic activity of the molecules. Effect of varying electron densities on the antispasmodic activity, by altering the position of these groups on the benzene ring has also been monitored. Pharmacological methods involve the in vitro antispasmodic activity studies on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, a promising compound 7, a potent muscle relaxant as compared to papaverine has been obtained.

Synthesis and Antispasmodic Activity Evaluation of Bis-(Papaverine) Analogues

“…Compound 22 was found to be the most potent compound among the series. However, contrary to our predictions, none of the bis analogues were able to beat the best compound of our previously reported 26) piperazinyl based tetra substituted urea derivative of papaverine.…”

“…Tetrahydropapaverine efficiently displaced one of the imidazole rings of carbonyldiimidazole 26) to give tetrahydropapaverine carbamoyl imidazole 19 on refluxing it with carbonyldiimidazole (CDI) in tetrahyrofuran (THF) for 24 h. The reaction of methyl iodide with carbamoyl imidazole 19 (4 molar equivalents) in acetonitrile for one day at room temperature produced the imidazolium salt quantitatively. This imidazolium salt required no additional purification for final conversion to ureas.…”

“…Papaverine, a benzylisoquinoline alkaloid, is a well known smooth muscle relaxant and a vasodilator. 23,24) Considering these factors and in continuation to our earlier efforts 25,26) of finding a potent antispasmodic agent, we envisaged that dimers of papaverine with suitable linkers at nitrogen can turn out to be more potent antispasmodic agents in comparison to papaverine.…”

Papaverine, an opium alkaloid influences hepatic and pulmonary glutathione s-transferase activity and glutathione content in rats

“…In an earlier communication from our laboratory (11,12), we documented the vasodilative effects of papaverine analogsand reported that analogsof this opium alkaloid possesses potent antispasmodic activity. The present study was a step ahead to evaluate the effect of oral administration of papaverine (an opium alkaloid known for its vasodilative effect (13,14), on the GST activity and GSH content in the rat liver and lung for its presumptive role in chemoprevention of chemical carcinogenesis.…”

Stimulation of lipid peroxidation and impairment of glutathione-dependent defense system in wistar rats treated with cryptopine, a rare non-narcotic opium alkaloid

“…noscapine (15,16) and papaverine (17).Cryptopine, (Figure 1) a non narcotic alkaloid remains in the tarry waste mother liquors that are left behind after the removal of morphine and codeine from opium. In 1918, Watt (18) commented on the relatively high content of cyptopine in Indian opium (about 0.3 %) which is high for this alkaloid, only seventh in average amount in opium.…”