Substituted Alkanediols and Analogues
B. Substituted Alkanediols and Analogues
A good number of 1, 3-alkanediols and their structural analogues have been reported to be rea- sonably potent muscle relaxant drugs. A few examples of this group of compounds are discussed below.
Examples : Meprobamate ; Carisoprodol ; Tybamate ; Metaxalone. B1. Meprobamate INN, BAN, USAN,
MUSCLE RELAXANTS
2-Methyl-2-propyl-1, 3-propanediol dicarbamate ; 1, 3-Propanediol, 2-methyl-2-propyl-, dicarbamate ; 2-Methyl-2-propyl-trimethylene dicarbamate; B.P., U.S.P., Eur. P., Int. P., Ind. P. Equanil (R) (Wyeth) ; SK-Bamate (R) (SK & F) ; Miltown (R) (Wallace)
Synthesis
2-Methyl-2-n-propyl-1, 3-propane diol dissolved in toluene is condensed at 0°C with phosgene in the presence of dimethylaniline gives the chloroformate diester, which when subjected to ammonolysis yields meprobamate.
It possesses anticonvulsant and muscle relaxant properties. It has also been used as mild tranquilizer in the treatment of anxiety and tension but has now been more or less replaced by the benzodiazepines, e.g., diazepam.
children, 25 mg per kg body weight per day in divided doses.
C HAPTER
B2. Carisoprodol INN, BAN, USAN,
2-Methyl-2-propyl-1, 3-propanediol carbamate isopropylcarbamate ; N-Iso-propylmeprobamate. Carisoma (R) (Pharmax, U.K.) ; Rella (R) (Schering-Plough)
MEDICINAL CHEMISTRY
Synthesis
Reduction of diethyl-methyl-n-propyl malonic ester with lithium aluminium hydride yields the corresponding glycol, which on treatment with dimethyl carbonate undergoes cyclization and affords the cyclic carbonate. Ring cessation of the resulting product by the aid of isopropyl amine proceeds regiospecifically to afford the corresponding monocarbamate. Finally, the remaining hydroxyl group undergoes an exchange reaction in the presence of ethanol carbamate to yield carisoprodol.
Its actions are similar to those of mephenesin. The duration of action ranges between 4 to 6 hours. It is usually employed for the symptomatic relief of muscular spasm.
Dose : Usual, adult, 350 mg 4 times a day.
B3. Tybamate INN, BAN, USAN,
2-(Hydroxymethyl)-2-methylpentyl butylcarbamate ; Carbamic acid, butyl-, 2-[[(aminocarbonyl) oxy] methyl]-2-methylpentyl ester ; N.F. XIII
MUSCLE RELAXANTS
241 Tybatran (R) (Robins)
Synthesis
2-Methyl-2-propyl-1, 3-propanediol is prepared by reacting diethyl methylpropyl malonate in ether in the presence of lithium aluminium hydride and then treated with dilute sulphuric acid. This on treatment with phosgene in toluene by means of dimethylaniline yields 2-methyl-2-propyl-3-hydroxypropyl chlorocarbonate, which on reaction with n-butylamine forms 2-methyl-2-propyl-3-hydroxypropyl butylcarbamate. The resulting product on treatment with ethyl urethane in the presence of aluminium isopropoxide in boiling xylene yields ethanol during transesterification which is removed from the reaction mixture simultaneously and tybamate is obtained.
HAPTER anxiety and tension states in patients having psychoneurotic disorders.
Its actions and uses are similar to its congener meprobamate. It has been used in the treatment of
Dose : 250 to 500 mg 3 or 4 times per day.
B4. Metaxalone INN, BAN, USAN,
MEDICINAL CHEMISTRY
5-[3, 5-Xylyloxy) methyl]-2-oxazolidinone ; 2-Oxazolidinone, 5-[(3, 5-dimethyl-phenoxy) me- thyl]- Skelaxin (R) (Robins)
Synthesis
3, 5-Dichlorophenol on alkylation with 1-chloropropan-2, 3-diol affords a glyceryl ether which on treatment with urea and subsequent alkylation yields metaxalone.
Metaxalone is used for the relief of acute muscle spasm resulting from various injuries or strains. Because of its potential toxicity, it has been superseded by other drugs belonging to this class.