2- piperazine

Piperazines, in contrast to pyrazines, abound in medicinal agents that moiety quite often occurs in side chains serving as a surrogate tertiary amine or as an ethylenedi-amine. A number of these have aheady been covered in passing in earlier chapters. The examples that follow have been chosen to illustrate the varied synthetic strategies 

In an analogous manner, reaction of 2,3-dichloroaniline (77-1) with nitrogen mustard gives the arylpiperazine (77-2). The remaining amine is then alkylated with 4-chlorobromobutane (77-3). Alkylation of the alkoxide from the hydroxycar-bostyril (77-4) affords the antipsychotic agent aripiprazole (77-5) [78]. 

The large majority of antipsychotic drugs act mainly as dopamine receptor antagonists reducing the excess responsiveness to that neurotransmitter present in psychoses. It was found a decade ago that antagonists of serotonin H2 showed promising antipsychotic activity in several model systems. These dmgs would be better tolerated than their predecessor since they should be devoid of side effects 

Compounds that inhibit HIV by binding to the specific receptor sites used by the virus to enter into the cells on the immune system cells, such as maraviroc (Chapter 8), 

In a three-component synthesis the amide (86-1) obtained from the ester (85-5) and benzyl isocyanide is reacted with the piperdone (86-2). The product from this transform consists of the addition product (86-3) where amide nitrogen in (86-1) as well as the carbon from the isocyanide have added to the carbonyl group on the piperidine. Treatment of the adduct (86-3) with a strong acid hydrolyzes the urethane function on the fert-butyloxycarbonic protecting group, leaving behind the primary 

The dehydrogenation of piperazines to pyrazine was first achieved by Stoehr (32), who heated piperazine (87) or its hydrochloride with zinc dust or, better, zinc dust and lime to give a yield of approximately 10% pyrazine (88). Since that time a number of publications and patents has described the conversion of piperazines to pyrazines by heating at elevated temperatures with various catalysts usually containing copper chromite (464) but also with palladium-charcoal (465) and platinum on alkali-washed firebrick (466), and also with other reagents. Some of these preparations are summarized in Table II.11 (464-475). 

Catalytic deamination of diethylenetriamine (86) over kaolin and alumina with some acidic admixtures at 280-400° to give pyrazine, piperazine, and other products has been examined (476). The conversion of a-amino acids, through piperazine-2,5-diones, with phosphoryl chloride to pyrazines has been discussed in Section IN. 

Sammes and co-workers (314) have also shown that some piperazine-2,5-diones (89) react with an excess of triethyloxonium iluoroborate to give a mixture of cis-and rra/is-2,5-diethoxy-3,6-dihydropyrazines (90) which can be oxidized with dichlorodicyanobenzoquinone (DDQ) to 2,5-diethoxypyrazines (91) in high yield. Many similar oxidations of dihydropyrazines have recently been described (314a). 

Some unusual zwitterionic pyrazines have been prepared by dehydrogenation of 1,4-disubstituted piperazine-2,6-diones. Honzl et al. (476a) prepared theanhydro-2,6-dihydroxy-l, 4-diphenyl-3,5-bis(phenylthio)pyrazinium dihydroxide [s/c] (92) (which yields adducts by dipolar cycloaddition of maleic anhydride or formaldehyde) by the reaction of 1,4-diphenylpiperazine-2,6-dione with benzenesulfonyl chloride in pyridine. Tanaka et al. (476b), from I,4-diphenylpiperazine-2,6-dione with benzoyl chloride, and tosyl chloride in pyridine at reflux, obtained the anhydro - 3 - benzoyl - 2,6 -dihydroxy -1,4 -diphenyl - 5 - (p - toly lthio)pyrazinium dihydroxide [src] (93), together with some of the S-p-tolyl analogue of (92). 

Piperazine or piperazine-eHjO Benzene solution over copper chromite catalyst, 215-500° single pass 35-40% yield Pyrazine 464 

Dipole-moment measurements in benzene solution on 1,4-dimethylpiper-azine and on a series of 1 -alkyl-4-tm-butylpiperazines120 show clearly that the N-alkyl groups exist predominantly in the expected position and indicate a value of 1.8 kcal mol-1 for the N-methyl group. This must now be considered a minimum value, and kinetic protonation of 1,4-dimethylpiperazine with 13C-NMR analysis of the products326 gives 2.96 + 0.05 kcal mol . An attempt312 to apply the line-broadening method failed.313 

At — 45°C the, 3C-NMR spectrum of A/,/V-dichloropiperazine shows absorption for the ee and ea conformers, giving AG° 0.5 kcal mol-1 (—45°C) favoring the diequatorial conformer 407.332 This represents a much reduced 

Horikoshi, M. Morii, and N. Takeguchi, Chem. Pharm. Bull. 23, 754 (1975). 

Neglecting high energy conformations, cis-1,4,5,8-tetramethylperhy-dro[2,3-b]pyrazinopyrazine (416) exists as an enantiomeric pair of confor-mers 417 and 418 interconverting by ring inversion. For the trans isomer, only conformations 419 and 420 need to be considered. A 13C- and H-NMR 

Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. 

A number of diarylmethyl alkylpiperazines, such as, for example lidoflazine, have found use as coronary vasodilators for the treatment of angina. The most recent of these interestingly incorporates a 2,6-dichloroaniline moiety reminiscent of antiarrhythmic agents. Treatment of the piperazine carboxamide 124 with acetone leads to formation of the nitrogen analogue of an acetal, the aminal 125. Alkylation of the remaining secondary nitrogen with chloroamide 126 leads to the intermediate 127. Exposure to aqueous acid leads to hydrolysis of the aminal function 

The anxiolytic agent buspirone (131) is notable for the fact that it does not interact with the receptor for the benzodiazepines. This difference in biochemical pharmacology is reflected in the fact that buspirone (131) seems to be devoid of some of the characteristic benzodiazepine side effects. The spiran function is apparently not required for anxiolytic activity. Alkylation of 3,3-dimethylglutarimide with dichlorobutane in the presence of strong base yields the intermedi- 

A piridazine ring forms the nucleus for a rather unusual nontricyclic antidepre.ssant. Condensation of the keto ester 136 with hydrazine leads to the cyclic hydrazide 137. Oxidation, for example with bromine, gives the corresponding pyridazone 138. The oxygen is then replaced by chlorine by reaction with phosphorus oxychloride. Displacement of the halogen in 139 with N-ethylami-nomorpholine affords minaprine 140 [30]. 

Reaction of 2,3-dichlorobenzoyl chloride with cyanide ion leads to the corresponding benzoyl cyanide (141). Condensation of that reactive intermediate with aminoguanidine 142 leads to the hydrazone-like product 143. Treatment with base results in addition of one of the guanidine amino groups to the nitrile function and formation of the 1,2,4-triazine ring. The product, lamo-trigine (144), is described as an anticonvulsant agent [31]. 

Triforine is metabolized in plants to many products that are not toxic to fungi according to The Pesticide Manual (Tomlin, 2000). It is regarded as environmentally safe. 

In general, piperazine and a good munber of its salts e.g., adipate, calcium edetate, citrate, phosphate and tartrate— have been employed profusely in therapeutic treatment of roundworm and pinworm infections. Piperazine itself is a representative example of this class of compoimds  

It is used as an anthelmintic for the management and treatment oipinworm and roundworm infestations. 

Mechanism of Action. The drug blocks the response of the ascaris muscle to ACh, thereby affording flaecid paralysis in the worm, which is eventually dislodged from the intestinal mner lumen and ultimately get expelled in the faeces. 

N-Diethyl-1, 4-methyl-1-piperazineearboxamide citrate 1-Diethylcarbamyl-4-methyl-piperazine dihydrogen citrate USP  

It is effective against various forms offilariasis, including Bancmft s onchocerciasis, and laviasis. It is also foimd to be active against ascariasis. 

One patient reported by Pepys et al. (1972) gave an immediate wheal and flare response to prick tests with piperazine, but that is the only reported evidence of an IgE-mediated response. 

Piperazine salts seem therefore to be capable of forming antigenic determinants and thus taking part in immunologically mediated adverse reactions, at least under certain circumstances such as occupational exposure. Under conditions of normal anthelmintic therapy such problems are minimal. 

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The hexahydrate fonns colourless crystals, m.p. 44 C (104 C when anhydrous), b.p. 126 C. Made by the action of alcoholic ammonia on 1,2-dichloroethane, piperazine is used in human and veterinary medicine in the treatment of threadworm and roundworm infestations. 

B) Secondary amines, (i) Aromatic amines. Monomethyl and monoethylaniline, diphenylamine. (ii) Aliphatic and other amines. Diethyhmine, di-n-propylamine, di-isopropylamine. Also piperidine piperazine diethylene-diamine). 

Tetrahydroquinoline Tetrahydro-iso-quinoline Indole Carbazole Piperazine... 

XXIII xxin, 1st 1936 3458-3554 Two Cyclic Nitrogens. Stem nuclei Piperazine, 4. Diazo-... 

A series of compounded flame retardants, based on finely divided insoluble ammonium polyphosphate together with char-forming nitrogenous resins, has been developed for thermoplastics (52—58). These compounds are particularly useful as iatumescent flame-retardant additives for polyolefins, ethylene—vinyl acetate, and urethane elastomers (qv). The char-forming resin can be, for example, an ethyleneurea—formaldehyde condensation polymer, a hydroxyethylisocyanurate, or a piperazine—triazine resin. 

Many patents have been issued on the use of pyrogaUol derivatives as pharmaceuticals. PyrogaUol has been used extemaUy in the form of an ointment or a solution in the treatment of skin diseases, eg, psoriasis, ringworm, and lupus erythematosus. GaUamine triethiodide (16) is an important muscle relaxant in surgery it also is used in convulsive-shock therapy. Trimethoprim (2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine) is an antimicrobial and is a component of Bactrin and Septra. Trimetazidine (l(2,3,4-trimethoxybenzyl)piperazine (Vastarel, Yosimilon) is used as a coronary vasodilator. l,2,3,4-Tetrahydro-6-methoxy-l-(3,4,5-trimethoxyphenyl)-9JT-pyrido[3,4- ]indole hydrochloride is useful as a tranquilizer (52) (see Hypnotics, sedatives, ANTICONVULSANTS, AND ANXIOLYTICS). Substituted indanones made from pyrogaUol trimethyl ether depress the central nervous system (CNS) (53). Tyrosine-and glycine(2,3,4-trihydroxybenzyl)hydrazides are characterized by antidepressant and anti-Parkinson activity (54). 

Significant quantities of amine and amide esters are formed by side reactions (9). In addition, with dialkanolamines, amide diesters, morpholines, and piperazines can be obtained, depending on the starting material. Reaction of dialkanolamines with fatty acids in a 2 1 ratio, at 140—160°C, produces a second major type of alkanolamide. These products, in contrast to the 1 1 alkanolamides, are water soluble they are complex mixtures of AJ-alkanolamides, amine esters, and diesters, and still contain a considerable amount of unreacted dialkanolamine, accounting for the water solubiUty of the product. Both the 1 1 and the 2 1 alkanolamides are of commercial importance in detergents. 

Classic A/-heterocychc ligands, eg, bipyridyl (bipy), terpyridyl, imidazole, pyrazine, phenanthroline, piperazine (including alkyl- and aryl-substituted derivatives), and polypyrazol-l-yl-borates (bis, tris, and tetra), have all been found to coordinate Th(IV) chlorides, perchlorates, and nitrates. The tripodal hydrotris(pyrazolyl)borates, HBPz, have been used to stabilize organometaHic complexes (31). Bis-porphyrin Th(IV) "sandwich" complexes have been... 

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