Piperazine derivatives

Piperazine Derivatives. Treatment of piperazine-2,5-diones with an excess of triethyloxonium fluoroborate gives 2,5-diethoxy-3,6-dihydropyrazines (390), which can be oxidized to the parent pyrazines (391) by dichloro-cyanobenzoquinone. c/s-Diben lpiperazin ione gives a mixture of cis- and /ra j-dihydropyrazines (390). Pyrolysis of the /ro s-isomer gives 3-benzyl-2,5-diethoxypyrazine (392) in high yield with the elimination of 

A report of the electrochemical reduction of pyrazine to 1,4-dihydro-pyrazine, and subsequent reductive decomposition of dihydropyrazine, has appeared.  

The major fragmentation pathways have been elucidated in the mass spectra of some JVN -diarylpiperazines.  

The synthesis and e.s.r. spectra of some hindered piperazine nitroxide radicals, e.g. (393), have been reported.  

Included in this group are the anthelminthics piperazine and diethylcarbamazine (Fig. 4.8). They are both safe drugs available in the form of simple salts, mainly citrates. 

Piperazine is a diethylenediamine used extensively in swine and chickens, but seldom in cattle and sheep. Piperazine preparations can be administered via either the feed or drinking water at a dosage of 275-440 mg/kg bw to pigs and 250 mg/kg bw to chickens. 

Piperazine and its salts are readily absorbed from the gastrointestinal tract, but nitrosation may occur in the stomach (32). The major portion of the absorbed drug is metabolized in tissues and the remainder, which is about 30-40%, is excreted in the urine. Piperazine is detectable in the urine as early as 0.5 h after drug administration. Although there is a wide variation in the rates at which piperazine is excreted by different animal species, urinary excretion is practically complete within 24 h. 

Diethylcarbamazine has long been used in sheep and especially in cattle for treatment of lungworm infections. Intramuscular injection is the routine 

Diethylcarbamazine is rapidly absorbed from the gastrointestinal tract. Peak concentration in the blood occurs at about 3 h after oral administration and falls to zero within 48 h. The drug is distributed almost equally throughout all body compartments, with the exception of the fat, and there is little tendency for accumulation with repeated doses. Excretion occurs almost entirely through the urine, with most of the drug appearing in form of metabolites. 

Cliffe, US Patent 5,541,326 (July 30, 1996) Assignee John Wyeth Brother, Limited Utility Treatment of Anxiety 

The product from Step 1 (3.2mmol) was dissolved in 50ml CH2CI2 and treated with 1,T-carbonyldiimidazole (3.6 mmol) and aniline (4.4 mmol), stirred 18 hours, concentrated, and purified by chromatography on silica gel using diisopropyl ether/diethyl ether. Thereafter, the product was dissolved in 10 ml hot propan-2-ol and the solution acidified with ethereal HCl. The material crystallized upon trituration with ether and 0.897 g product isolated as dihydrochloride quarter hydrate, mp = 250-255 °C (dec.). Elemental analysis data supplied. 

Amide derivatives of l-(2-methoxyphenyl)piperazine acids were also prepared by the author in the current invention. Other amide derivatives have been prepared using N-[4-[4-(2-methoxyphenyl)-l-piperazinyl]butyl]-2,2-dimethylpropanoic acid and are described (1). 

In a subsequent investigation by the author (2) the radiolabeled piperazine derivative, N-(2-(l-(4-(2-[ H-methoxy]phenyl)-piperazinyl))-ethyl)-N-(2-pyridinyl)cyclohexane carboxamide, was prepared. 

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Syntheses of piperazine derivatives by combining microbial and chemical reactions 99YGK466. 

Though dental afflictions constitute a very significant disease entity, these have received relatively little attention from medicinal chemists. (The fluoride toothpastes may form an important exception.) This therapeutic target Is, however, sufficiently Important to be the focus of at least some research. A highly functionalized piperazine derivative that has come out of such work shows prophylactic activity against dental caries. Condensation of the enol ether 1 of thiourea with ji-pentylisocyanate gives the addition product 1J. Reaction of this with diamine 78, derived from piperazine, leads to substitution of the methylthio moiety by the primary amine, in all likelihood by an addition-elimination sequence. There is thus obtained ipexidine (79). ... 

Synthesis of the CNS depressant/tranquil izer tioperidone (59) begins by alkylation of piperazine derivative with 4-chlorobutyronitrile to give Lithium aluminum hydride... 

A somewhat more complex theophylline derivative includes both the purinone nucleus and a piperazine side chain more commonly associated with HI antihistaminic compounds. The starting epoxide, 66, is available from treatment of the anion of purinone 65 with epichlorohydrin. Alkylation of the epoxide with monosubstituted piperazine derivative 67, leads to tazifylline (68) [11]. 

Piperazine derivatives Alkylene glycols Various diacids 31... 

Reaction Conditions Temperaturc=603 W/F=200 g h mol, NHa/EAsSO EDA ethylenediamine, El ethyleneimine, PA piperazine derivatives CHA chabazite, FAU faujasite 00, LTL Linde type L, MOR mordenite, EDTA-MOR Na-mordenite was treated with EDTA and then ion-exchanged to H-form, MFl ZSM5. 

Certain basic polyamides can be further prepared by reacting piperazine derivatives with amines [814]. 

This or the reverse order will give the observed product (135). Alkylation of piperazine 136 with 1-bromo-3-chloropropane gives the piperazine derivative 137 use of that intermediate to alkylate heterocycle... 

Pyrazino[l,2-tf]pyrazines 245 (Y = NH) were prepared from [6+0] fragments by bond formation a to the ring junction nitrogen atom in the reductive cyclization of the N-protected piperazine derivative 244 (Scheme 44) <2002W0055518>. 

Khazanov, E. Barenholz, Y., Gibson, D., Najraeh, Y. Novel apoptosis-including trans-platinum piperidine and piperazine derivatives Synthesis and biological characterization. J. Med. Chem. 2002, 45, 5189-5195. ... 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

Fluoroalkanesulfonyl azides 281 add readily to vinyl ethers to provide triazolines 282 in good yield (67-84%). At room temperature, slow decomposition of the products is observed with evolution of nitrogen and formation of piperazine derivatives 284. No other products are observed. Formation of piperazines 284 must involve cleavage of the triazoline ring with formation of zwitterionic intermediates 283 (Scheme 42) <2004JFC(125)445>. 

Efforts to find potent and selective DPP-4 inhibitors in the a-amino acid amide series were made in parallel with those in the (3-amino acid amides series. The structural origin of the earliest P-amino acid amide DPP-4 inhibitors traces back to two Merck HTS hits proline derivative 25 and piperazine derivative 26. These two screening leads were further progressed to P-amino acid amide DPP-4 inhibitors incorporating thiazolidine, proline and piperazine amide moieties (Figure 17.5). 

Lehotay, J. et al.. Separation of enantiomers of some 1,4-piperazine derivatives of aryloxy-aminopropanols on a vancomycin chiral stationary phase, Pharmazie, 54, 743, 1999. 

Fisher, M. J., Backer, R. T., Collado, L, et al. (2005) Privileged structure based ligands for melanocortin receptors—substituted benzylic piperazine derivatives. Bioorg. Med. Chem. Lett. 15, 4973-4978. 

Piperazine derivatives have been intensively investigated in structural biology studies due to their unique scaffolds. According to a substracture search in Rehbase... 

A recent literature survey revealed >3,000 piperazine substructure containing compounds accessed by isocyanide-based MCRs. Many of these piperazines are of commercial interest and therefore are described in patents as a primary literature source. Moreover, 430,000 piperazine derivatives are commercially available (according to a substructure search in eMolecules) [1]. Inspecting the general scaffold types in the database of the commercially available piperazine derivatives, it can be speculated that a considerable fraction of them were made by MCR technology. Some examples of piperazine derivatives via isocyanide-based MCRs from patent literature are listed in Table 1. 

The N-4-chlorobutyl benzodiazepine dione 221 (Scheme 46, Section 3.1.1.2 (1993MI249)) gives the piperazine derivative after amination with N-methyl piperazine. 

This group of drugs is subdivided into three subgroups depending on the type of substitution on the nitrogen atom of the phenothiazine ring. The subgroups are phenothiazines with an aliphatic side chain (chlorpromazine, promazine, triflupromazine), piperazine derivatives (acetophenazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine), and piperidines (mesoridazine, thioridazine). 

Piperazine derivatives inherent presence of stimulatory components.Phenothiazines with an aliphatic side chain and piperidine substituents have more of a sedative effect than piperazine derivatives. 

Like other piperazine derivatives of phenothiazine, prochlorpherazine reduces psychotic symptomatology and has a stimulatory effect. The most common synonym is meterazine. 

Thiothixene displays a specific chemical and pharmacological similarity to piperazine derivatives of the phenothiazine series, and is used for treating psychotic disorders. The indications for using thiothixene are the same as for chlorprothixene. Synonyms of this drag are orbinamon, navane, and others. 

Diethylcarbamazine is an anthelmintic drug that does not resemble other antiparasitic compounds although it has some relationship with piperazine derivatives and it has been useful in the management of filariasis due to Wuchereria bancrofti or Brugia malayi and Loa loa and of tropical eosinophilia. It is a lipoxygenase inhibitor and alters the surface structure of the parasite making it more susceptible to destruction by the host. It is well absorbed and widely distributed. It is eliminated with an half-life of 5-13 hours both by metabolism and excretion unchanged in the urine. 

Phenothiazines are classified on fhe basis of fheir chem-isfry, pharmacological acfions, and pofency. Chemical classifications include the aliphatic (e.g., chlorproma-ztne T/iorazme), piperidine (e.g., thioridazine Me//an7), and piperazine subfamilies. The piperazine derivatives are generally more potent and pharmacologically selective than the others. The thioxanthenes (e.g., thiothixene Navane) are chemically related to the phenothiazines and have nearly equivalent potency. The... 

Chemical Class Piperazine derivative I Ciinicai Pharmacology ... 

Mecfianism of Action A piperazine derivative that antagonizes alpha-adrenergic, dopamine, histamine, and serotonin receptors also inhibits reuptake of serotonin and norepinephrine. Therapeutic Effect Diminishes symptoms of schizophrenia and depression. 

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