Heterocyclic compounds piperazine

Several other heterocyclic compounds are used as veterinary anthelmintics although they lack the spectrum of activity of the above classes. For example, the antischistosomal drug, praziquantel (14), is highly effective in the treatment of cestodes in animals and man. The piperazine-derived drug diethylcarbamazine (15a) is used as a filaricide and for treatment of lungworm infections in sheep and cattle. The mode of action of diethylcarbamazine (13a) is uncertain but recent studies suggest that an effect on the helminth cuticle may be important. 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

The method ofTsuruta was also extended to the synthesis of macromonomers containing piperazine cycles, and even diaza crown ethers81 84185). Here again the first step involves preparation of 1 1 adducts of p-divinylbenzene and the corresponding heterocyclic compound ... 

Schiff bases have been used in electroreductive cyclizations, leading to heterocyclic compounds. The bisimine (24), when reduced in glyme, affords the piperazine (25) in 42% yield after quenching with methyl iodide (equation 10). When the solvent is changed to dimethylformamide, saturation of the imino bonds takes place without ring closure. Transannular ring closure of diazocine (26) led to indolo-... 

Electrochemical alkylation and acylation are well-established reactions and have been employed for the formation of heterocyclic compounds. The reduction of azobenzene [127] or azomethine compounds [128] in the presence of Q ,ft>-dibromoalkanes leads to cyclic hydrazines, piperazines, or pyrrolidines. Similarly, reduction of nitrobenzene in the presence of 1,5-dibromopentane yields iV-phenylperhydro-l,2-oxazepine [129]. 

Over the past decades, Murai s and Chatani s groups developed a series of methodologies for the rhodium-catalyzed carbonylations initiated by C-H activation [73-76], A range of heterocyclic compounds, such as A-acylpiperazines, N-(2-pyridinyl)piperazines, 2-arylpyridines, and A-arylpyrazoles, were acylated with CO and ethylene (Scheme 6.24). 

In addition to the above, a number of other heterocyclic compounds, for example, 2-aroylbenzofurans, 1,3-benzoxathioles, dihydropyrans, 1,4-benzoxazines, hydantoin derivatives, piperazine-2,5-diones, thioethenes, 1-arylbenzimidazoles, benzofuran-1-oxides, piperazinones, thiazoles, 5-thiacyclohexanecarboxaldehyde, pyrroles, triazines, fused napthoquinone derivatives and P-lactams have been synthesised using PTC technique." ... 

C. Heterocyclic Compounds - The presence of analgesic activity in substituted piperazines is vouchsafed in several reports. The cinnamyl derivatives (32) and (33) are more active than aminopyrine, while the diaza-... 

Nitrone cycloaddition reactions with alkynes have been widely used for the synthesis of imidazolidine nitroxides (736) and (737), containing chelating enam-ino ketone groups (821). Different heterocyclic systems were obtained, such as 3-(2-oxygenated alkyl)piperazin-2-ones (738) (822), also compounds containing the isoxazolo[3,2-i]indole ring system (739) (823) and a new class of ene-hydroxylamino ketones- (l )-2-( 1-hydroxy-4,4,5,5-tetraalkylimidazolidin-2-ylidene)ethanones (740) (824) (Fig. 2.46). 

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. 

The enantioselective hydrogenation of prochirai heteroaromatics is of major relevance for the synthesis of biologically active compounds, some of which are difficult to access via stereoselective organic synthesis [4], This is the case for substituted N-heterocycles such as piperazines, pyridines, indoles, and quinoxa-lines. The hydrogenation of these substrates by supported metal particles generally leads to diastereoselective products [4], while molecular catalysts turn out to be more efficient in enantioselective processes. Rhodium and chiral chelating diphosphines constitute the ingredients of the vast majority of the known molecular catalysts. 

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. 

Incorporation of a piperazine function on the heterocyclic ring leads to a compound in which bronchodilator activity predominates. Treatment of the amino-amide (73-1) with trimethyl orthoformate provides the additional carbon atom for the formation of the quinazolone ring in (73-2). Reaction with phosphoms oxychloride in effect converts the ring to its aromatic form (73-3) by locking in the former amide as an enol chloride. Displacement of the halogen with the isobutyryl urethane (73-4) from piperazine affords piquizil (73-5) [82]. 

Yet another approach to these compounds consists of substituting the piperazine ring onto the preformed heterocyclic moiety. Ullman condensation of the substituted thiosalyciclic acid (40-1) with ort/zo-chloronitrobenzene results in the displacement of chlorine by thiophenoxide and the formation of the thioether (40-2). The nitro group in this last intermediate is then reduced to an aniline (40-3) the resulting amino acid is then cyclized thermally to the lactam (40-4). Treatment of that with phosphorus oxychloride gives the imino chloride (40-5). Reaction with N-methylpiperazine leads to the replacement of chlorine by nitrogen and the formation of clothiapine (40-6) [39]. 

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