Piperazines special

Alfuzosin (91) is a prazosin-like hypotensive adrenergic a-1 receptor blocker with the special structural feature that two carbons have been excised conceptually from the piperazine ring normally present in this series. Following the usual sequence for this series, reaction of 4-amino-2-chloro-7-dimethoxyquinazoline (89) with the tetrahydro-2-furyl amide of 3-methylaminopropyla-mine (90) gives alfuzosin (91) [25], Alfuzosin is claimed to cause less orthostatic hypotention (dizziness or fainting upon sudden rising) than prazosin. 

The piperazines influence brain function through their effects on brain chemistry at different receptors, or specialized locations within nerves allowing them to communicate with each other through chemical messengers called neurotransmitters. By stimulating different groups and locations of nerve cells that contain a specific neurotransmitter called serotonin, piperazine derivatives can have varied, profound effects on mood, learning, perceptions, and movement. 

Nearly symmetrical molecules deserve special mention. Benzene and piperazine are uncharged and have no dipole moment, so the Born-Kirkwood-Onsager model predicts AGs — 0- However, AM1-SM2 predicts —0.5 and —7.8 kcal/mol, respectively, in good agreement with the experimental -0.9 and -7.4 kcal/mol. In benzene the result comes as the sum of a hydrophobic AGcds = 1.4 kcal/mol and a hydrophilic AGe p = —2.0 kcal/mol whereas in piperazine both terms are hydrophilic (AG ds 4.1 kcal/mol, AGg p = —3.7 kcal/ mol), and they reinforce each other. Similar reinforcement occurs in many other compounds [e.g., p-bromophenol (AGs -4.4 kcal/mol, AGg p = —2.7 kcal/mol)], in which case AM1-SM2 predicts AGs 7.0 kcal/mol versus an experimental value of —7.1 kcal/mol. 

Protection of the amino group by protonation is of importance only in very special cases. Some activated amino acids and peptides can be obtained only as their salts, since the free compounds form diketo-piperazines or polymers . One amino group in diamino mono-carboxylic acids can be protected in certain cases by protonation (salt formation). In neutral solution the amino acids are present as a Zwitterionic inner salt, therefore reaction of benzyl phenyl carbonate or ethyl trifluorothiolacetate with lysine in neutral solution 23+o.a.o. 

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