Piperazine rings

Incorporation of a second nitrogen atom in the side chain, particularly when that atom is part of a piperazine ring, was found to give a series of major tranquilizers similar in biologic activity to chlorpromazine, but of much increased potency. Alky-... 

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. 

A new ionic polymeric polycarbamate was synthesized after steps of polyurethane chemistry using 3-iso-cyanatemethyl-3,5,5-trimethylcyclohexyl isocyanate, 2,5-dimethyl-2,5-dihydroperoxyhexane, 1,6-butanediol, 2,4-tolylenediisocyanate, and N,N -bis(j3-Hydroxy-ethyOpiperazine [27]. Modification of the nitrogen of the piperazine ring into quaternary ammonium salt by treatment with methyliodide gave the MPI high electroconductivity. 

The transformation of several fluoroquinolone antibacterials was examined and a number of products from ciprafloxacin were tentatively identified (Zhang and Huang 2005). The qninolone ring was nnchanged, and the major prodnct was produced by fission of the piperazine ring to an aniline. 

To round out this group of drugs in which the piperazine ring appears to serve primarily as a basic spacer unit, or a conformationally restricted ethylene-diamine unit, reaction of N-phenylpiperazine (135) with acrylonitrile produces nitrile 136. Conversion... 

It has been found subsequent to this that attachment of the basic center in the guise of a piperazine ring... 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Alkylation of the 3-lactim ether, (4A)-3-ethoxy-4-isopropyl-l,4-dihydropyrazino[2,l-3]quinazolin-6-one with BnBr gave pure l,4-/ra r-diastereomer. The higher diastereoselectivity - as compared to the lactams - was explained by the fully boat conformation of the piperazine ring in the lactim ethers <2005TA3160>. 

An analogous approach has been utilized to generate the central piperazine ring of 337 via dimerization of 5-amino-4-bromo-2-phenyl-2,4-dihydro-pyrazol-3-one 336 under basic conditions in good yield (Equation 91) <2003HAC211>. 

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

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. 

DPP-8/9 selectivity, it exhibited poor oral bioavailability in the rat due to metabolic instability of the piperazine ring. 

FIGURE 8. MM2-85 calculated lp—N—C—H rotational potential curve (C in the tricyclic ring system) for 68, with a pseudoequatorial piperazine ring. The conformations A (dashed line) and B (solid line) are defined in Scheme 6. Reproduced with permission from Reference 108... 

Delavirdine (4.91), a selective inhibitor of HIV-1 reverse transcriptase, also contains an amido N-atom as part of a piperazine ring. In rats and monkeys, cleavage of the amide bond constituted only a minor pathway [56]. 

This definition for aliphatic amines can be used to direct protonation of these species although it should be noted that our ionization model uses more complex definitions to prevent simultaneous protonation of both nitrogen atoms in a piperazine ring. 

Graindorge and co-workers" reported the synthesis of 2,5,7,9-tetranitro-2,5,7,9-tetraaza-bicyclo[4.3.0]nonane-8-one (113) (K-56, TNABN) from the nitration of 2,5,7,9-tetraazabi-cyclo[4.3.0]nonane-8-one dihydrochloride (112) with dinitrogen pentoxide in absolute nitric acid, the latter obtained from the condensation of urea with l,4-diformyl-2,3-dihydroxy-piperazine (111) in hydrochloric acid. Treatment of (112) with nitronium tetrafluoroborate in nitromethane results in the nitration of the piperazine ring nitrogens only and the isolation of (114) in 86 % yield (Table 5.2). 

Moore and Willer reported the synthesis of some nitramine explosives containing a furazan ring fused to a piperazine ring. The tetranitramine (46) is synthesized from the condensation of 3,4-diaminofurazan (DAF) (24) with glyoxal under acidic conditions followed by A-nitration of the resulting heterocycle (45). The calculated performance for the tetranitramine (46) is very high but the compound proves to be unstable at room temperature. Instability is a common feature of heterocyclic nitramines derived from the nitration of aminal nitrogens. 

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