The Analgesics

Analgesics represent an important class of drugs that is used primarily for the relief of severe pain. They are classified as narcotic and nonnarcotic. 

The opiates are perhaps the oldest drugs known to man. Opium contains a complex mixture of almost 25 alkaloids. The principal alkaloid in the mixture, and the one responsible for analgesic activity, is morphine, 11. Pure morphine is especially good for treating dull, constant pain, and periodic pain. Unfortunately, it has a large number of side effects, which include the depression of the respiratory center, excitation, nausea, euphoria, dependence, and others [6]. 

A newer compound (14, bremazocine) has a longer duration, has 200 times the activity of morphine, appears to have no addictive properties, and does not depress breathing. 

The nonnarcotic analgesics are widely used as nonprescription drugs. They are also efficient for the relief of mild pain and symptoms of rheumatoid arthritis [9], For example, acetaminophen, 15, sold under the trade name Tylenol, is a widely used nonprescriptive drug. Acetaminophen is usually prepared by reacting p-aminophenol with a mixtime of glacial acetic acid and acetic anhydride [8]. 

Phenacetin, 16, is also a nonprescription drug that represents the ethyl ether of acetaminophen and is prepared from p-ethoxaniline [8]. 

---

A synthesis of the analgesic substance phenacetm is outlined in the following equation What IS the structure of phenacetm ... 

The amount of aspirin in the analgesic tablets from a particular manufacturer is known to follow a normal distribution, with p, = 250 mg and = 25. In a random sampling of tablets from the production line, what percentage are expected to contain between 243 and 262 mg of aspirin ... 

What is the 95% confidence interval for the analgesic tablets described in Example 4.13, if an analysis of five tablets yields a mean of 245 mg of aspirin ... 

After heating to 50 °C in a water bath, the sample was cooled to below room temperature and filtered. The residue was washed with two 5-mL portions of CCI4, and the combined filtrates were collected in a 25-mL volumetric flask. After adding 2.00 mL of the internal standard solution, the contents of the flask were diluted to volume with CCI4. Analysis of an approximately 2- tL sample gave LfD signals of f3.5 for the terpene hydrate and 24.9 for the camphor. Report the %w/w camphor in the analgesic ointment. 

The first syathesis of morphine, and therefore also codeiae, was completed ia 1956 (58). Although an additional twelve or so syntheses have been reported siace then, isolation of morphine remains more important than any synthetic process. However, synthetic endeavors continue to demonstrate new synthetic tools and capabiUties and to conduct the search for modified analogues that retain the analgesic properties of morphine but are nonaddicting. 

FLUOROBIPHENYLS Fluorobiphenyls are incorporated into the analgesic and antiinflammatory dmgs diflunisal [22494-42-4] and flurbiprofen [5104-49-4]. The first is a difluoro compound and the other monofluoro. 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

The quest for compounds that combined the analgesic properties of morphine, were nonaddictive, and lacked the side effects of nalorphine, led to the development of the dmgs shown in Table 3. These compounds have both agonist and antagonist activities. Nalbuphine (14) (23) and buprenorphine... 

Health Hazards Information - Recommended Persoruil Protective Equipment Fresh air mask for confined areas rubber gloves protective clothing full face shield Symptoms Following Exposure Will bum eyes and skin. The analgesic action may cause loss of pain sensation. Readily absorbed through skin, causing increased heart rate, convulsions, and death General Treatment for Exposure ... 

According to Eddy, as quoted by Small, the analgesic action of neopine, n omorphine, 6-acetylneomorphine or 3 6-diacetylneomorphine (p. 218) is definitely less than that of morphine and its corresponding analogues. The first two are about half as toxic as codeine and morphine respectively, and the second pair are more toxic than their morphine analogues. None of the four shows the Straub reaction and the convulsant action is less marked. 

Hydrolysis of the nitrile in 130 (obtained by an alkylation analogous to that used to prepare 126) affords the acid, 131. esterification with ethanol affords the analgesic agent, norpipa-none (132). ... 

Thus, acetylation of aniline affords acetanilide (20), an analgesic widely used in proprietary headache remedies. A similar transformation on p-aminophenol gives the analgesic, acetaminophen (21). It is of interest that the latter is also formed in vivo on administration of 21. An interesting preparation of this drug involves Schmidt rearrangement of the hydrazone (24) from p-liydroxyacetophenone. ... 

Catalytic reduction of codeine (2) affords the analgesic dihydrocodeine (7) Oxidation of the alcohol at 6 by means of the Oppenauer reaction gives hydrocodone (9)an agent once used extensively as an antitussive. It is of note that treatment of codeine under strongly acidic conditions similarly affords hydrocodone by a very unusual rearrangement of an allyl alcohol to the corresponding enol, followed by ketonization. 

The ring-contracted analog of alphaprodine is prepared by a variation of the scheme above. Alkylation of 109 with ethyl bromoacetate affords the lower homolog diester (115). Dieckmann cyclization followed by saponification-decarboxylation yields the pyrrolidine (116). Reaction with phenylmagnesium bromide leads to the condensation product (117) acylation with propionic anhydride gives the analgesic agent prolidine (118)... 

Reductive amination of vanillin with ammonia leads to benzylamine 94. Acylation of that compound with (Z)-9-octadecenoyl chloride affords the analgesic olvanil (95) [23]. 

---