Piperazines Subject

The monotosylation of 2,5-dihydroxybenzenesulfonicacid iscarried out in a pyridine medium by treating it with tosyl chloride, thus preferably isolating the 2-hydroxy-5-tosyloxybenzene-sulfonic acid, pyridine salt. This product subjected to reflux with an alcoholic solution of piperazine yields 2-hydroxy-5-tosyloxybenzenesulfonic acid, piperazine salt. 

In some cases we may benefit from using an external agent to carry out the desired separation through crystallization. Thus, in the case of isomeric and non-isomeric mixtures of close-boiling acidic or basic materials we may use a suitable base or acid to carry out dissociative extractive crystallization, akin to dissociative extraction referred to in Section 4.2.1. For instance, for a mixture of p- and m-cresol or p-cresol and 2,6-xylenol we may use a base like anhydrous piperazine to obtain a precipitate of relatively pure p-cresol salt of piperazine, which can then be filtered and subjected to recovery of piperazine for recycle. Similarly, we may add a substance which forms an adduct with the desired substance. 

Finally, while on the subject of possible clinical effects of (%2 antagonism, it should be noted that many of the 5-HT, agonists (e.g., buspirone, gepirone, and ipsapirone] that were developed or tested for antianxiety and antidepressant effects are extensively metabolized to l-(2-pyrimidyl]-piperazine, itself an active 0(2-adrenoceptor antagonist (G. Bianchi et al. 1988). Whether this is relevant in vivo in humans remains to be seen. 

The methylene groups at positions 3 and 6 of piperazine-2,5-diones are known to undergo facile condensation with aldehydes to form the corresponding a,/3-unsaturated amides. Two earlier reviews have dealt with this subject. (75FOR51 80FOR251). The review by Sammes covers the literature to 1972 on the synthesis, stereochemistry, and reactivity of... 

Piperazine-2,5-dione formation can occur not only in the case of dipeptides esters or amides containing a free amino group, but also during the activation of N-blocked or protected IV-alkyl amino acids containing dipeptides or even tripeptides. Thus, the activated dipeptide Z-Gly-Pro-ONp (76) afforded the Z-protected piperazine-2,5-dione 77 when subjected to buffered dioxane solution at pH 8 (Scheme 29)J159 ... 

Quinazolines are of great interest in the pharmaceutical industry as protein tyrosine kinase inhibitors. Dener et al 8 described a synthesis starting from 2-methoxybenzaldehyde, Wang, or Rink resins. With the aldehyde resin reductive aminations were undertaken to yield polymer-bound secondary amines (Fig. 7). The latter were subjected to 2,4-dichloro-6,7-dimethoxyquinazoline to give the 4-amino-substituted derivatives. These were then allowed to react with primary or secondary amines at 135-140° in the presence of DBU in DMA. As a result of a detailed scope and limitation study, Dener et al,28 note that some bifunctional amines, such as piperazine, give to some extent dimeric derivatives. 

Unapproved piperazine products become subject to FDA regulatory action. 

For a few years after the development of the first interfacial composite membranes, it was believed that the amine portion of the reaction chemistry had to be polymeric to obtain good membranes. This is not the case, and the monomeric amines, piperazine and phenylenediamine, have been used to form membranes with very good properties. Interfacial composite membranes based on urea or amide bonds are subject to degradation by chlorine attack, but the rate of degradation of the membrane is slowed significantly if tertiary aromatic amines are used and the membranes are highly crosslinked. Chemistries based on all-aromatic or piperazine structures are moderately chlorine tolerant and can withstand very low level exposure to chlorine for prolonged periods or exposure to ppm levels... 

Symmetrical piperazine-2,5-diones may be prepared in very good yields by subjecting a-halocarboxamides to PTC using the novel Duolite A-109 as catalyst (equation 176)931. 

Examples of photorearrangement in nitrones and heteroaromatic N-oxides have again been described, and the subject has been critically reviewed. The hydroxyoxaziridines (81) have been prepared by irradiation of the corresponding 1-pyrroline 1-oxides (82), ° whereas photorearrangement of the dinitrone (83) gave the oxaziridines (84) and (85) and the lactam (86) oxaziridines (84), (85), and (86) were converted into the piperazine-2,5-dione (87) by further irradiation. ... 

In most patients, piperazine is free of adverse reactions. Mild gastrointestinal disturbances may occur neurotoxicity is rare. Eczematous skin reactions, lacrimation, rhinorrhea, joint pains, productive cough, and bronchos-pasm can develop after sensitization, especially with occupational exposure. Urticaria has also been reported. When hypersensitivity reactions occur it should be withdrawn and not used again in the same patient. Mononitrosylation of piperazine can occur in the stomach, releasing the potential carcinogen A-mono-nitrosopiperazine, but there is no direct proof of risk in human subjects. 

Piperazine is taken orally by nonfasting subjects. For large roundworms, one dose a day on two consecutive days reportedly cures approximately 90% of cases treated (27). This drug can be used for pinworms with a 7-d course of treatment. 

Haloperidol is a butyrophenone derivative with antipsychotic action similar to that of piperazine phenothiazines such as fluphenazine. Haloperidol (0.5 to 2 mg t.i.d.) is indicated in the management of psychotic disorders in Tourette s disorder for the control of tics and vocal utterances in severe behavioral problems of children with combative and explosive nature in hyperactive impulse disorder in children associated with aggression, low fmstration tolerance, and impulsive behavior, and in elderly subjects with senile dementia (see also Table 9). 

Because of the relationship of the reduced ring system to piperazine, various derivatives have been studied and found to have activity on the central nervous system (CNS). Thus the compound 68 was found to be more active than the corresponding pyrido compound (69) in the mouse amphetamine-induced toxicity and hypermotility tests. Certain phenothiazine derivatives are the subject of recent patents. " Various other 2-substituted perhydropyrrolo[l,2-a]pyrazines have been patented as sympatholytics, antihistaminic, anticholinergic, and antitremorine compounds, CNS depressants,antiarrhythmics, ° coronary dilators, and anticonvulsants and analgesics. " ... 

The first three equations were developed to show the specific contribution of bulk (Eq. 1), lipophilicity (Eq. 2), and length of the substituents (Eq. 3). The 21 compounds used in equation 1 vary at positions 6, 7 and 8. The 22 compounds studied in equation 2 vary only at position 7 having a fluorine at position 6 and N-ethyl at position 1. Finally, equation 3 was developed from eight compounds in which the substituent at positions 1 were varied with a fluorine at position 6 and unsubstituted piperazine at position 7. Equations 4 through 6 show equivalent models based on a sample of 71 compounds. Using more recent biological data, a subset of the compounds from this earlier study was subjected to a QSAR analysis with the results reported later in this chapter. Further, as also will be reported in this paper, the problem of developing more than one statistically equivalent model is common to the quinolone antiinfectives. 

This subject has been investigated for the case of piperazine polymers and diacyl piperazines as model substances ... 

Chapter 15. The molecule of chlorpromazine was subjected to many changes, one of which was to provide a long-acting form for discharged patients. Thus an injection of 25 mg of fluphenazine enanthate, dissolved in oil, provides maintenance therapy for 2 to 3 weeks. Fluphenazine is 10- 3-[4-(2-hydroxyethyl)-piperazin-l-yl]propyl -2-trifluoromethylphenothiazine, obviously derived from chlorpromazine which is 10-(3-dimethylaminopropyl)-2-chlorophenothiazine 12,110). 

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