Phenothiazine nucleus

Alkylated sulfonamide groups have proven useful additions to the phenothiazine nucleus. The same seems to hold true in the thioxanthene series. Chlorosulfonation of the benzoic acid, 38, followed by displacement with dimethylamine affords the sulfonamide, 39. This is then taken on to the substituted thioxanthone (41) by the sequence of steps shown above Grignard condensation followed by dehydration gives thiothixine (42). 

Attachment of the basic side chain to the phenothiazine nucleus by means of a carbonyl function apparently abolishes the usual CNS or antihistamine effects shown by most compounds in this class. The product azaclorzine instead is... 

Tranquillizing drugs based on the phenothiazine nucleus potentiate the action of narcotic analgesics [157] although there are some reports to the contrary [158] and certain derivatives, notably methotrimeprazine (levomepromazine, Levo-prome, Veractil) (—)-(LV), are claimed to have intrinsic analgesic activity. In mice, (-)-(LV) is more potent than morphine in a variety of tests [159, 160] for example hot-plate EDso value of 1.02 mg/kg, that of morphine 2.1 mg/kg. 

Attachment of the basic side chain to the phenothiazine nucleus by means of a carbonyl function apparently abolishes the usual CNS or antihistamine effects shown by most compounds in this class. The product azaclorzine instead is described as an anti anginal agent. Reduction of proline derivative 106 with lithium aluminum hydride gives the corresponding fused piperazine 107. Use of that base to alkylate the chloroamide 109, obtained from acylation of phenothiazine with 3-chloropropionyl chloride, leads to azaclorzine (110). ... 

Chlorpromazine is 92 to 97% bound to plasma proteins, principally albumin [5,20], It crosses the blood-brain barrier, and concentrations of the drug in the brain are higher than those in plasma [17], The relationship of plasma concentration to clinical response and toxicity has not been clearly established. Chlorpromazine and its metabolites cross the placenta and are distributed into milk [21]. About 10-12 metabolites of chlorpromazine in humans have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is metabolized to an N-oxide or sulfoxide derivative. These metabolites may be excreted as their 0-glucouronides, with small amounts of ethereal sulfates of the mono- and dihydroxy derivatives. The major metabolites found in urine are the monoglucouronide of N-demethylchlorpromazine and 7-hydroxychlorpromazine [2]. Although the plasma half life of chlorpromazine itself has been reported to be few hours, the elimination of metabolites may be very prolonged [8, 22-24]. 

Phenothiazine nucleus may be prepared by the sulphuration of diphenyl amine in the presence of sulphur and iodine which is then treated with the corresponding Grignard complex of 2-(diethylamino) propyl bromide to yield the ethopropazine (base). The resulting base is dissolved in an appropriate solvent and treated with an equimolar quantity of HCl to form the official compound. 

Synthetic pathways to fluphenazine (I) are shown in figure 6. The synthesis usually involves the addition of the propylpiperazine ethanol side chain to the 3-trifluoromethyl-phenothiazine nucleus (II). The following routes to (l) have been reported ... 

Propiomazine hydrochloride exhibits an anodic wave at +0.8v in acidic aqueous solution at a concentration range of 10 - to 10 5k using a stationary platinum electrode vs. a calomel reference electrode, suitable for a quantitative assay O. The wave corresponds to the oxidation of the stilfur in the phenothiazine nucleus to the sulfoxide l. 

Triflupromazine is prepared by addition of the dimethylaminopropyl sidechain to the phenothiazine nucleus (II)or its N-acetyl derivative (III) and conversion of the base to the hydrochloride (I). Diazotization of the 7-aminoanalogue (IV) also yields I. 

The simultaneous a-b disconnection of a phenothiazine nucleus provides fragments 72 and 73 (Scheme 36). The following synthetic schemes corresponding to this fragment analysis have been described in the chemical literature ... 

The side chain can also affect electronic events of the tricyclic ring system. Electron spin resonance experiments allowed Fenner S to suggest that the influence of the side chain of phenothiazine on the formation of free radicals showed a correlation between the redox activity of the phenothiazine nucleus and dynamic aspects of stereochemistry. For example, there was a difference in the formation of cationic free radicals between promazine and alimemazine. The latter has a branched side chain, and forms cationic free radicals only under irradiation. It differs from promazine in pharmacodynamic properties, reported s to result in considerably shifted ion exchange equilibria. A kinetic study of the oxidation of dopamine by dialkylaminoalkyl phenothiazine cationic free radicals showed that a strong correlation existed between side-chain structures and oxidation rates phenothiazine free radicals with two carbon side chains had faster rates than those with three carbon side diains, albeit both were very rapid at physiological pH. 

The above reasoning rules out the formation of any truly ionic or covalent bonds between the phenothiazine nucleus and I2. Thus no new infrared absorption band associated with such bands may be produced. 

One of the most significant differences between the spectra of CPZ and CPZ l2 is the appearance of a new, weak, but distinct band at about 1700 cm (see Figure 7a). This new band also appears in the spectrum of the CPZ HCl l2 complex (Figure 7a). This new band also appears in the spectrum of the CPZ HCl l2 complex (Figure 6a) and must therefore be due to some vibration concerning the phenothiazine nucleus. The new band increases in intensity and shifts to higher frequency, i.e., from 1680 to... 

Another interesting example is provided by derivatives of the phenothiazine nucleus. It gives rise to a stable radical after oxidation. For example, chlorpromazine reversibly loses an electron through the action of light and dioxygen ... 

Vilallonga et al. [27] suggested from a study of the surface tension of several phenothiazines in 0.1 m HCl that the most probable arrangement of the molecules at the air-water interface is with the phenothiazine nucleus lying flat and the side chains directed into the aqueous solution. 

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