Tranquillizer

A -dialkylchloroalkylamines, R2N(CH2)nCI. Formed by treating the alkanolamine with thionyl chloride. Of importance in the synthesis of pharmaceuticals, particularly tranquillizers, e.g. amidons. 

CifiHijClNj. White plates m.p. 125 C. Diazepam is one of several benzodiazepines which are very widely used as minor tranquillizers for allaying anxiety, as hypnotics or, in sufficiently high dosage given intravenously, as pre-anaesthetic sedatives. 

Substituted phcnothiazines form an important group of tranquillizers, e.g. chlor-promazine. Some, e g. promethazine, have powerful antihistamic activity. 

Tranquilizers. Fluphena2ine hydrochloride [146-56-5] triduopera2ine hydrochloride [440-17-5], and triduproma2ine [146-54-3] are all triduoromethyl substituted phenothia2ine chemicals useful in the management of psychotic disorders. 

Drugs. Ring-fluotinated aromatics have found broad pharmaceutical appHcations, eg, in tranquilizers, hypnotics, sedatives, antibacterial agents (qv), etc. Representative monofluorinated dmgs are Hsted in Table 4. Arprinocid [5579-18-15] is a fluoroaromatic-based veterinary dmg that has found wide acceptance as a coccidiostat for chicken feed. 

Drugs. Ttifluoromethyl-based pharmaceuticals had been limited to phenothiatine tranquilizers and benzothiadiazine 1,1-dioxide diuretics (qv). However, new dmgs have been developed (Table 11). One of the key properties of the CF group is its high lipophilicity it increases the Hpid solubiUty of the pharmaceutical and thus accelerates absorption and transport within the host organism. 

Biological Activities and Analogues. Somatostatin exerts some neurotropic actions, eg, as a tranquilizer and as a spontaneous motor activity depressor. It also lengthens barbiturate anesthesia time and induces sedation and hypothermia. These actions are consistent with the strong association between somatostatin and GABA in the primate cerebral cortex, 90—95% of somatostatin-positive ceHs also contain GABA (100). 

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). 

The alkaloid reserpiae [50-55-5] which is isolated from the roots of Kauwoljia serpentina T., contains a gaUate trimethyl ether moiety. Reserpiae is used as an antihypertensive and a tranquilizer. A vinylogue of reserpiae, rescinnamine [24815-24-5] is also an antihypersensitive (75). Methoxsalen [298-81-7] (8-methoxypsoralen 7JT-9-methoxy-furo [3,2- ] [l]benzopyran-7-one) (21), a furocoumatia that occurs ia plants, eg, l eguminosae and Umbelliferae is used ia the treatment of vitiligo, as a suntanning promoter, and as a sunburn protectant. It is also available by synthesis (76). 

Phiorog1iicino1-3,5-dimethyl-1-(2-amino-3-hydroxyhutyryl)ether is characterized by antiarrhythmic activity (176). 2,4-Diacylphloroglucinols were patented as compounds with pronounced anthelmintic activity (177). Phloroglucinol mono- and di-(2-chloroethyl) ethers have antispasmodic or tranquilizing activities (178). 2-(3,5-DiaLkoxyphenoxy)ethylamines have antispasmodic, choloretic, sedative, and vasodilating effects (179). 

Neuroleptic analgesia is so called because the combination of a major tranquilizer, a neuroleptic dmg, and a potent opiate produces an anesthetic state characterized by sedation, apathy, and mental detachment (see Psychopharmacological agents) (152). Iimovar [8067-59-2] a combination of droperidol [648-72-2], C22H22FN2O2, (19) and fentanyl (9) citrate, is used for procedures that do not require muscle relaxation. However, the onset of action is slow. 

Combinations of barbiturates and benzodiazepine tranquilizers or even antihistaminergics having sedative properties are sometimes used. Furthermore, infusion of anesthetics can be used to provide long-term anesthesia for intensive care medicine. The antagonist flumazenil (18) is available to reverse the effects of anesthetics of the benzodiazepine class. 

Another injectable anesthetic widely used in feline and primate practice is ketamine hydrochloride [1867-66-9]. Ketamine, a derivative of phencychdine, can be chemically classified as a cyclohexamine and pharmacologically as a dissociative agent. Analgesia is produced along with a state that resembles anesthesia but in humans has been associated with hallucinations and confusion. For these reasons, ketamine is often combined with a tranquilizer. The product is safe when used in accordance with label directions, but the recovery period may be as long as 12—24 h. 

It must be remembered that all anesthetics and tranquilizers are used by the practitioner following a risk—benefit evaluation. General anesthesia, even being adininistered by an experienced practitioner, can result in death through cardiac or respiratory depression. The veterinarian is acutely aware of these risks and chooses the dmg and method of adininistration considering the patient s health status, the nature of and need for the procedure, and the likelihood of success. 

Immediate treatment of an exposed individual is essential. The U.S. regimen includes the pretreatment, and after exposure atropine and 2-PAM are self-adininistered. Eurther treatment includes up to two additional doses, followed by the tranquilizer VaHum. As required, artificial respiration is instituted, clearing the airway if necessary. The current standard U.S. Army atropine item is the automatic injector, Atropen, designed for self-adininistration by the individual in the field. 

In addition, various pyridopyridazines have been claimed to have activity as antibacterials and antiseptics, antitubercular agents, analgesics, anti-inflammatories, antiallergics, tranquillizers, CNS depressants and muscle relaxants. 

Fused isoxazoles (631) were prepared as GABA analogs (75MI41604) and some exhibited CNS depression effects (74JAP(K)7480062) or were effective as minor tranquilizers, muscle relaxants and/or sleep inducers (76USP3966748, 79USP4163057). 

Preparation of spirooxaziridines from cyclic ketones poses no problems nor does oxaziridine synthesis from cyclic Schiff bases, which was preferably carried out with pyrro-lines to give, for example (245) (59JCS2102) and, in connection with tranquilizer synthesis, with heterocyclic seven-membered rings to give, for example, (246) (63JOC2459). 

The benzodiazepine fused azetes (353 R = Et, Pr) have been claimed as useful tranquilizers and sedatives (76BRP1448895). However, their stability and formation from benzodiazepines (352) by reaction with an aldehyde and base is hard to reconcile with the proposed structure. 

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