Antiemetics

Dimenhydrinate is an antiemetic especially usehil as an antinauseant in motion sickness, and for syndromes associated with vertigo such as Meniere s syndrome, radiation sickness, and vestibular dysfunction. It may produce mild drowsiness. It is FDA Category B for Pregnancy, and is available as an OTC preparation as well as by prescription. 

Pharmaceuticals. -Hydroxybenzaldehyde is often a convenient intermediate in the manufacture of pharmaceuticals (qv). For example, 2-(p-hydroxyphenyl)glycine can be prepared in a two-step synthesis starting with -hydroxybenzaldehyde (86). This amino acid is an important commercial intermediate in the preparation of the semisynthetic penicillin, amoxicillin (see ANTIBIOTICS, P-LACTAMs). Many cephalosporin-type antibiotics can be made by this route as well (87). The antiemetic trimethobenzamide [138-56-7] is convenientiy prepared from -hydroxybenzaldehyde (88) (see Gastrointestinal agents). 

Fig. 2. Pyrazole-derived pharmaceuticals (a) butaglyon [2603-23-8] an antidiabetic (b) dazopride [70181 -03-2] an antiemetic (c) feclobuzo [23111-34 ] an antiinflammatory (d) kebuzone [833-34-9], an antirheumatic (e) muzolimin [55294-15-0], a diuretic (f) phenazobz [20610-63-3], an antiasthmatic (g) selenofob [39102-63-1], an antibiotic (h) sulfamazo [65761-24-2], an antiseptic and (i) sulfinpyrazone [57-96-5], an antigout preparation (50).

Since there was some evidence that these compounds owe their action to interference with the action of histamine, this class has earned the soubriquet "antihistamines." This class of drugs is further characterized by a spectrum of side effects which occur to a greater or lesser degree in various members. These include antispasmodic action, sedative action, analgesia, and antiemetic effects. The side effects of some of these agents are sufficiently pronounced so that the compounds are prescribed for that effect proper. Antihistamines, for example, are used as the sedative-hypnotic component in some over-the-counter sleeping pills. 

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxy-benzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimetho-benzamide (11). ... 

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58). Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 [prepared by a route... 

Alkylation of the intermediate, 41, with l-bromo-3-chloro-ethane affords 49, the use of this to alkylate iv-(2-hydroxyethyl) piperazine affords oxypendyl (50), a neuroleptic with good antiemetic and antivertigo properties. 

Antiemetic. A compound that blocks the vomition reflex. 

Nabilone (37) is a synthetic 9-ketocannabinoid with antiemetic properties. One of the best of the various published routes to nabilone starts with the enolacetate of nopinone (33), which on short heating with lead tetraacetate undergoes allylic substitution to give Treatment with p-toluene-... 

Trans-2-chloro-9-(aj-dimethylamino-propylidene)-thioxanthene [MP 98°C, MP of the hydrochloride 225°C (corr.)], is a valuable medicinal agent, being used as a tranquilizer and antiemetic agent, whereas the corresponding cis isomer (MP 44°C, MP of the hydrochloride 209°C) is not useful for these indications, as described in U.S. Patent 3,115,502, which describes procedures for conversion of the cis to the trans form. 

---