Piperazine Prazosin

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. 

Giardina, D., Gulini, U., Massi, M., Piloni, M.G., Pompei, P., Rafaiani, G. and Melchiorre, C. (1993) Structure-activity relationships in prazosin-related compounds. 2. Role of the piperazine ring on alpha-blocking activity. Journal of Medicinal Chemistry, 36, 690-698. 

Introducing this into a reaction with l-(2-furoyl)piperazine gives prazosin... 

Terazosin Terazosin, l-(4-amino-6,7-dimethoxy-2-quinazohnyl)-4-(2-tetrahydrofuroyl)-piperazine (12.2.13), only differs from prazosin in that the furyl radical is replaced with a tetrahydrofuryl radical. It is synthesized in exactly the same manner except using l-(2-tetrahydrofuroyl)piperazine instead of l-(2-furoyl)piperazine [48-51]. 

Prazosin (hydrochloride), 2-[4-(fur-2-oyl)piperazin-l-yl]-6,7-dimethoxy-4-quinazolinamine, a-adrenoreceptor antagonist antihypertensive [19216-56-9],... 

Prazosin] (furane piperazine Synthetic a2A-R blocker [0.2] (alA-R) [antihypertensive]... 

The most practical route used in the synthesis of numerous 6,7-dimethoxy-2-(l-piperidyl)- or 6.7-diniethoxy-2- piperazin-l-yl)quinazolin-4-amines substituted with various chemical groups in the piperidino or piperazino moiety, which are analogs of the hypotensive agent prazosin, is the cyclization of 5-methylisothioureas 1 with an excess of ammonium chloride. The highly pure hydrochlorides 2 are obtained in yields of more than... 

The main difference between prazosin, terazosin, and doxazosin lies in their pharmacokinetic properties. As men-lloncd above, these differences are dictated by the nature of the acyl moiety attached to the piperazine ring. A comparison of these three agents with respect to their oral bioavailability, half-life, and duration of action is shown in Table 16-2. These drugs are metabolized extensively, with the me-taNiies excreted in the bile. 

Prazosin hydrochloride (2[4- (2-furoyl)piperazin-l-yl 4-amino-6,7-dimethoxyquinazoline hydrochloride) [19237-84-4] M 419.9, m 278-280°, 280-282°, pK s 6.5. The salt is recrystallised by dissolving it in hot MeOH, adding a small volume of MeOH/HCl (dry MeOH saturated with dry HCl gas) followed by dry Et20 until crystallisation is complete. Dry it in vacuo over solid KOH till the... 

The role of piperazine ring of prazosin was investigated through its replacement by an a, (u-alkanediamine chain (Giardina et al., 1989). It turned out that the piperazine ring may not be essential for activity at a,-adrenoreceptors and that activity and selectivity depend on the length of alkane chain and A -methylation of both the amide and the 2-amino functions. 

The finding that the affinity profile of prazosin-related quinazolines can depend on the type of moiety linking the two nitrogen atoms of the piperazine ring of prazosin, prompted us to further modify the structure of analogue 2. In particular, two types of structural modifications were performed on the structure of 2, that is, replacement of the... 

Fig. 1. Design strategy for the synthesis of prazosin (l)-related compounds by replacing the piperazine ring of prazosin with an a,o>-al-kanediamine chain, a decahydroquinoxaline system and a cystamine moiety, affording 2, cyclazosin and cystazosin (3), respectively.

Bolognesi, M.L., Budriesi. R., Chiarini, A., Poggesi, E., Leonard , A., Melchiorre, C., 1998. Design, synthesis, and biological activity of prazosin-related antagonists. Role of the piperazine and furan units of prazosin on the selectivity for a,-adrenoreceptor subtypes. J. Med. Chem. 41, 4844-4853. 

Giardina, D., Brasili, L., Gregori, M.. Massi, M., Picchio, M.T., Quaglia, W., Melchiorre, C., 1989. Structure-activity relationships among prazosin-related compounds. Effect of piperazine ring replacement by an alkanediamine moiety on a,-adrenoreceptor blocking activity. J. Med. Chem. 32, 50-55. 

Giardina, D., Crucianelli, M., Marucci, G., Melchiorre, C., Polidori, C., Pompei, P., Massi, M., 1996a. Pharmacological evaluation of prazosin- and doxazosin-related compounds with modified piperazine ring. Arzneim.-Forsch./Drug Res. 46 (II), 1054-1059. 

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