Theme: Aromatic compounds as drugs (p-Aminophenol derivatives, quinones, phenols). Acids of aromatic series, their salts, esters and amides as drug substances.
Aromatic compounds
Phenols
Thymol (Isopropyl m-cresol) is obtained from oil of thyme by alkaline extraction followed by acidification.
Thymol occurs as large colorless crystals, with an aromatic thymelike odor. It is sparingly soluble in water, but soluble in alcohol and organic solvents. Thymol has fungicidal properties and is used in alcoholic solutions and in dusting powders for the treatment of tinea infections.
Resorcinol (m-dihydroxybenzene, resorcin) is synthetically prepared.
It occurs as white needle-shaped crystals or powder that is soluble in water and alcohol. Resorcinol is light-sensitive and readily oxidized. It should be stored in light-resistant containers. It is much less stable in solution, especially at alkaline pH.
Despite its weak antiseptic propeties (phenol coefficient, 0.4), resorcinol is used in 1% to 3% solutions and in ointments and pastes, in concentrations of 10% to 20% for the treatment of skin conditions such as ringworm, eczema, psoriasis, and seborrheic dermatitis; resorcinol possesses keratolytic properties to augment its antiseptic action.
Identification of phenols derivatives. A. All phenols react with iron(III) chloride solution to form a color compounds. Phenols with one hydroxy group form a violet compounds, phenols with two OH- groups – blue compounds, thymol does not react with iron chloride.
B. Diazo coupling.
Primary arylamines react with an acidic solution of sodium nitrite to form arenediazonium ions, which are stable in aqueous solution at 0* to 5*C. The process of converting an arylamine into an arenediazonium ion is called diazotization and occurs with a wide variety of derivatives.
Arenediazonium salts are not usually isolated. Solutions of arenediazonium salts react with a number of reagents. Arenediazonium ions are very weak electrophiles that react with highly activated aromatic rings to form azo compounds in the reaction called diazo coupling.
C. Phenols can be oxidixed to carbonyl-containing compounds. The oxidation of phenol by chromic acid, for example, forms a quinone.
Quinones are not aromatic compounds. They are α, β-unsaturated ketones.
D. By alloying of resorcinol with phthalic anhydride we obtain the yellow-red alloy, which is soluble in sodium hydroxide solution to form a green solution.
E. Phenols undergo a number of other electrophilic substitution reactions that are possible only because of their high reactivity. They react with the weakly electrophilic diazonium ion to form azo compounds.
Another weak electrophile the nitrozyl cation (NO+), formed by the reaction of sodium nitrite and sulfuric acid, react with phenols to form nitrozophenols.
F. Reaction with bromine. Bromation of phenols occurs at the orto- and para-positions.
Assay. Carry out a back titration using a 0.1N potassium bromate (KBrO3) as a titrant. The surplus of potassium bromate forms equivalent (equal) amount of bromine (Br2) that determine by iodometry.
For assay of Thymole carry out simple bromatometry titration using a methyr-red as an indicator.
Another phenol derivatives:
Riodoxole and Thebrophene are antiantiviral agents.
Naphthamone and Diphezil – antihelminthic drugs.
Dibunole is a cytostatic agent.
p-Aminophenol derivatives
The hydroxilated (o, m, p), better known as the aminophenols, are quite interesting from the standpoint of being considerably less toxic than aniline. The para-compounds (C-3) is of particular interast from two standpoint: namely it is the metabolic product of aniline, and it is the least toxic of the three possible aminophenols. It also possesses a strong antipyretic and analgesic action. However, it is too toxic to serve as a drug, and for this reason, there were numerous modifications attempted.
One of the first was acetylation of the amine group to provide N-acetyl-p-aminophenol (acetaminophenol), a producr that retained a good measure of the desired activities. Another approach to the detoxication of p-aminophenol was the atherification of the phenolic group. The best known of these are anisidine(C-9) and phenetidine (C-10), which are the methyl and ethyl ethers, respectively. However, it becomes apparent that a free amino group in these compounds, although promoting a strong antipyretic action, was also conducive to methemoglobin formation. The only exception to the preceding was for compounds in which a carboxyl group or sulfonic acid group had been substituted on the benzene nucleus. In these compounds, however, the antipyretic activity also had disappeared. The foregoing consideration led to the preparation of the alkyl ethers of N-acetyl-p-aminophenol of which the ethyl ether was the best and is known as phenacetin (C-11). The methyl and propyl homologues were undesirable from the standpoint of causing emesis, salivation, diuresis and other reactions. Alkylation of the nitrogen with a methyl group has a potentiating effect on the analgesic action, but, unfortunately, has a highly irritant action on mucous membranes.
Phenacetin (Acetophenetidin; p-acetophenetidin)
Phenacetin may be synthesized in several steps from p-nitrophenol. It occurs as stable, white, glistening crystals, usually in scales, or a fine, white crystalline powder. It is odorless and slightly bitter. It is very slightly soluble in water (1:1300), soluble in alcohol (1:15) and chloroform (1:15), but only slightly soluble in ether (1:130). It is sparingly soluble in boiling water (1:85).
Phenacetin forms eutectic mictures with chloral hydrate, phenol, aminopyrine, pyrogallol.
It was once used widely as an analgetic and antipyretic, having essentially the same actions as acetanilide. It should be used with the same cautions because the toxic effects are the same as those of acetaminophen, the active form to which it is converted in the body.
Acetaminophen (N-Acethyl-p-aminophenol; 4’-hydroxyacetanilide; Datril; Tempra; Tylenol)
This may be prepared by reduction of p-nitrophenol in glacial acetic acid, acetylation of p-aminophenol with acetic anhydride or ketene, or form p-hydroxyacetophenone hydrazone. It occurs as a white, odorless, slightly bitter crystalline powder. It is slightly soluble in water and ether, soluble in boiling water (1:20), alcohol (1:10), and sodium hydroxide.
Acetaminophen has analgetic and antipyretic activities comparable with those of acetanilide and is used in the same conditions. Although it possesses the same toxic effects as acetanilide, they occur less frequently and with less severity; therefore, it is considered somewhat safer to use. However, the same cautions should be applied. The required FDA warning label reads: “Warning: do not give to children under three years of age or use for more than ten days unless directed by a physician”.
It is available in several nonprescription forms and, also, is marketed in combination with aspirin and caffeine (Trigesic).
Identification. A. Phenacetin and acetaminophen give color reactions with solution of K2Cr2O7 and diluted HCl.
An intense stable violet is obtained with acetaminophen, and unstable violet than comes to red with phenacetine. These reactions are based on the hydrolysis of amides to p-aminophenols that react with K2Cr2O7 to form indophenol.
B. Both preparations form acetic aced by boiling with diluted hydrochloric acid.
C. As all phenols acetaminophen reacts with iron (III) chloride solution to form a blue-violet compound. Phenacetin does not react with iron (III) chloride.
Assay. Make hydrolysis of substance and carry out nitirtometric titration use a starch as an indicator.
Quinone derivatives
Vitamin K
The term vitamin K was applied to the vitamin isolated from alfalfa, and a similar principle from fishmeal was named vitamin K2. Vitamin K2 refers to a series of compounds called the menaquinones. These have a longer side chain with more unsaturation. Many other closely related compounds possess vitamin K activity. The synthetic compounds menadione and menadiol are referred to as vitamin K3 and K4.
Vitamin K is a naphthoquinone derivative containing diterpenoid units biosynthesized by the intermediate, geraylpyrophosphate.
Numerous compounds have been tested for their antihemorrhagic activity, and significant biologic activity is manifested in compounds with the following structure when:
1. ring A is aromatic or hydroaromatic
2. ring A is not substituted
3. ring B is aromatic or hydroaromatic
4. R equals OH, CO, OR, OAc (the R in OR equals methyl or ethyl)
5. R’ equals methyl
6. R” equals H, sulfonic acid or an alkyl group containing ten or more carbon atoms. A double bond in the β, γ-position of this alkyl group enhances potency, whereas, if the double bound is further removed, it exerts no effect. Isoprenoid groups are more effective than straight chains.
7. R”’ equals H, OH, NH2, CO, OR, Ac (the R in OR equals methyl or ethyl).
It is interesting that, if ring A is benzenoid, the introduction of sulfur in place of –CH=CH- in this ring in 2-methylnaphthoquinone permits the retention of some antihemorrhagic activity.
Products:
Menadione (2-methyl-1,4-naphthoquinone; menaphthone; thyloquinone).
On a mole-for-mole basis, menadione is equal to vitamin K1 in activity and can be used as a complete substitute for this vitamin. It is effective orally, intravenously and intramuscularly.
Menadione Sodium Bisulfite (2-methyl-1,4-naphthoquinone sodium bisulfite; Hykinone, Vikasol) is prepared by adding a solution of sodium bisulfite to menadione.
Menadione sodium bisulfite occurs as a white, crystalline, odorless powder. One gram of it dissolves in about 2 ml of water, and it is slightly soluble in alcohol. It decomposes in the presence of alkali to liberate the free quinone.
Menadione Sodium Diphosphate (tetrasodium 2-methyl-1,4-naphthalenediol bis(dihydrogen phosphate); Synkayvite; Kappadione) is a white hygroscopic powder, very soluble in water, giving solutions that have a pH of 7 to 9.
It is available in ampules for use subcutaneusly, intramuscularly, intravenously and in tablets for oral administration.
Identification. A. Menadione Sodium Bisulfite and Menadione Sodium Diphosphate yield the reaction characteristic of sodium salts and durn with yellow flame.
B. Menadione Sodium Bisulfite reacts with concentrated sulphuric acid to form sulphur(IV) oxide.
C. Destruction of Menadione Sodium Bisulfite in base medium to sodium sulphite and 2-methyl-1,4- naphthoquinone. 2-Methyl-1,4- naphthoquinone may be identified by its melting point (104-107*C).
This reaction may be used for assay of vitamin K. For this reason reduce obtained 2-methyl-1,4- naphthoquinone to 1,4-dioxi-2-methylnaphtaline and titrate with 0.2N Ce(SO4)3 using a o-phenantroline as an indicator.
