Nonsteroid antiinflammatory agents

Synthetic Derivatives of Indoles as Pharmaceuticals. Thousands of indole derivatives have been prepared and evaluated as potential pharmaceuticals (32). Of those which have been put into use perhaps the most important are the nonsteroidal antiinflammatory agent indomethacin [53-86-1] (10) (33) and the p-adrenergic blocker pindolol [13823-86-9] (11) (34). 

In a similar scheme, acylation of 2-methoxynaphthalene gives ketone, 15. This is then converted to the acetic acid by the Wilgerodt reaction. Esterification, alkylation of the carbanion (sodium hydride methyl iodide), and finally saponification affords naproxen (17). The intense current effort on nonsteroid antiinflammatory agents and acrylacetic acids in particular make... 

Indazoles can be considered as either azaindoles or azaisoindoles depending on the reader s prejudice. Benzydamine (54) represents a drug with this heterocyclic nucleus. Alkylation of the amine of anthranilic acid methyl ester with benzyl chloride in the presence of sodium acetate gives 52. Treatment with nitrous acid leads to the nitrosoamine, which cyclizes spontaneously to the 3-ketoindazole system, 53. This intermediate forms an ether of its enol form on heating the sodium salt with 3-dimethylaminopropyl chloride. There is thus obtained benzydamine (54), a fairly potent nonsteroidal antiinflammatory agent with significant antipyretic and analgesic properties. 

A nonsteroidal antiinflammatory agent in which the benzent ring carrying the acetic acid moiety has been replaced by a pyrrole grouping is zomepirac (10). It is synthesized from... 

Derivatives of anthranilic acid have a venerable history as nonsteroid antiinflammatory agents. It is thus not surprising that the corresponding derivatives in which phenyl is replaced by pyridinyl show much the same activity. 

Though the great majority of antiinflammatory agents contain some form of acidic proton, occasional compounds devoid of such a function do show that activity. Thus the nonacidic pyrazolylpyrimidine epi razole (47) is described as a nonsteroid antiinflammatory agent. Reaction of pyrimidinone 42 with phosphorus oxychloride leads to the chloro derivative Replacement of halogen with hydrazine gives... 

A fully unsaturated tricyclic indole derivative serves as the aromatic moiety for a nonsteroid antiinflammatory agent. Preparation of this compound starts with the Michael addition of the anion from methyl diethylmalonate to cyclohexanone. The product (32) is then hydrolyzed and decarboxylated to give ketoester 33. Fischer condensation with p-chlorophenylhydrazine leads to the indole This is then esterified (35) and dehydrogenated to the carbazole 36. Saponification leads... 

It is by now apparent that the nature of the aryl group in the aryl acetic and aryl propionic acid antiinflammatory agents can be varied quite widely without loss of activity. The corresponding derivatives of homologous xanthones and thioxanthones thus both show activity as nonsteroid antiinflammatory agents. 

An imidazoquinazoline constitutes still another compound that does not fall in the classification of a nonsteroid antiinflammatory agent yet shows good platelet anti aggregating activity. Condensation of benzyl chloride 128 with the ethyl ester of glycine gives alkylated product... 

Fentiazac (134) is a member of the biarylacetic acid class of nonsteroidal antiinflammatory agents. Its. synthesis also involves the Hjtntzsch reaction. Tliiobcn/ainide (133) is reacted wiih 3-(4-chlorobenzoyl)-3-broinoprftpionic acid (132) to give feutiazoc (134) 46[. 

Botting JH (1999) Nonsteroidal antiinflammatory agents. Drugs of Today 35 225-235... 

In the pathogenesis of many chronic inflammatory diseases (e.g., rheumatoid arthritis, glomerulonephritis, colitis ulcerosa, Morbus Crohn, atopic dermatitis, psoriasis) autoimmune processes play an important role, too. Although first of all nonsteroidal antiinflammatory agents or glucocorticoids should be applied, immunosuppressive agents may also be indicated. 

An interesting example of this class of nonsteroidal antiinflammatory agents is ketoprofen (5). 

Salicylic acid analogues are often active as nonsteroidal antiinflammatory agents because they interfere with biosynthesis of prostaglandins. Diflunisal (3) appears to be such an agent. It is synthesized from the nitrobiphenyl 1 by catalytic reduction to... 

Chlorination enhances activity and is accomplished by treatment of 201 with chlorine in methylene chloride catalyzed by aluminum chloride. The nonsteroidal antiinflammatory agent bucloxic acid (202) results. 

DERIVATIVES OF PYRAZOLE Pyrazolones rank among some of the more venerable nonsteroidal antiinflammatory agents. The activity of antipyrine (154) was discovered not too long after that of aspirin. The preparation of a plethora of analogues of that compound, all bearing additional substitution at the 4-position, was described in some detail in the earlier volume. 

Substantial interest in the pharmacological properties of the nonsteroidal antiinflammatory agents related to mefenamic and flufenamic acid led to examination of a series of aminopyridines instead... 

The classic and most convenient synthesis of the indole moiety is that of Emil Fischer. Recent examples of its use for drug synthesis includes one preparation of the nonsteroidal antiinflammatory agent, indoxole (2). Reaction of ketone 1 with phenylhydrazine in acetic acid leads directly to indoxole (2). Alternately, anisoin (3) can be reacted... 

Because of the resonance stabilization possible in its deprotonated form, the 5-tetrazolyl moiety is actually nearly as acidic (pKa ca. 6) as many carboxylic acids. This has led to its inclusion in many drug series as a carboxyl surrogate. Apparently related in concept to indomethacin (26a), intrazole (26) is a nonsteroidal antiinflammatory agent which also inhibits platelet aggregation, and therefore is of potential value in keeping the contents of the... 

The compounds of medicinal interest in this group so far have all been nonsteroidal antiinflammatory agents or analgesics. The prototype is benzydamine (55).15 An interesting alternate synthesis of this substance starts by sequential reaction of... 

Probably inspired by ibuprofen and its analogues, the nonsteroidal antiinflammatory agent benoxaprofen... 

The majority of nonsteroidal antiinflammatory agents contain an acidic carboxyl group. A series of experimental agents in this class have been prepared in which the acidic proton is supplied by a highly enolizable proton from a function such as a p-dicarbonyl incorporated into a heterocyclic system. As an example, an acylated, highly oxidized isoquinoline moiety can fulfill this function (see also the benzo-thiazines below). Toward this end, reaction of... 

Among the heterocyclic systems that have been used to provide a backbone for acidic, nonsteroidal antiinflammatory agents are benzo-1,2-thiazine dioxides, such as 193-195. Entry to the ring system is gained by an interesting ringenlarging rearrangement. 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

Although most nonsteroidal antiinflammatory agents depend on the presence of an acidic proton for activity, examples of nonacidic drugs are scattered among the various structural classes. A furanopyrrole. 

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