Phenylbutazone derivatives

These reactions can be opened up to all substances that can yield aniline derivatives in acid or basic medium. Carbamic acid derivatives, numerous variations of which are used as plant treatment agents, provide a striking application. As do urea herbicides and a variety of drug substances e. g. benzodiazepines or phenylbutazone derivatives. 

FIGURE 16.20 Successive ring openings and closures in phenylbutazone-derived antiinflammatory drugs. 

The NSAID and phenylbutazone derivative, feprazone, was found to be associated with HLA-B22 in a Scandinavian study—93 % of patients with a fixed drug eruption caused by the drug were HLA-B22 positive but no patients with fixed drug eruptions to other drugs were positive to HLA-B22 and this allele was found in 4 % of healthy controls. However, a number of factors, including the absence of HLA-B22 in 7 % of the Scandinavian patients with feprazone-induced fixed drug eruption, need further scrutiny before feprazone-HLA-B22 can be taken as a diagnostic marker. At the least, more extensive population studies are needed. 

A Hammett relationship of the form ApK = 5.8am has been proposed for 4-substituted pyrazoles (74TL1609) in order to explain the effect of 4-nitro ApK = 4.5, am = 0.71) and 4-diazo groups (Apiifa = 10.0, am = 1.76). The acidity constants of a series of pyrazolidine-3,5-diones have been determined (75AJC1583) and the 4- -butyl-1,2-diphenyl derivative phenylbutazone has a pK of 4.33. 

Iodine addition to the ter- [13] tiary nitrogen of the opium alkaloids and to the OCH3 group of the brucine with formation of an o-quinone derivative, probably ring opening in the case of phenylbutazone, ketazone and trimethazone detection by IR... 

Pyrazolone derivatives are analgesic substances that have been known for a long time. The use of antipyrine (phenazone) and aminopyrine was sharply curtailed after their bone marrow toxicity was reported. Other derivatives, however, like phenylbutazone. 

Table VI lists several drugs Inducing hepatic microsomal enzymes (5). These enzymes can metabolize the drug as well as other substrates. Barbiturates, grlseofulvln, and glutethlmlde Induce enzymes which metabolize coumarln and phenlndlone derivatives and thus reduce their anticoagulant activity. Dlphenylhydantoln and phenylbutazone stimulate cortisol hydroxylase activity and Increase the urinary excretion of B-hydroxy cortisol and decrease the concentration of cortisol In the plasma.

A fused heterocyclic compound (146) distantly related to the antiinflammatory agent cintazone (Chapter 12), which itself can be viewed as a cyclized derivative of phenylbutazone, retains the activity of the prototype, in the synthesis of 146, reaction of the nitroaniline 139 with phosgene gives intermediate 140, which is then reacted with ammonia to afford the substituted urea (141). Cyclization of the ortho nitrourea function by means of sodium hydroxide leads to the N-oxide (142) this last reaction represents... 

ATP inhibits only 6-PGDH and not G-6-PDH (G10). As previously reported for other enzymes, phenothiazine derivatives inhibit both G-6-PDH and 6-PGDH competitive with NADP since NADP protects G-6-PDH depending on its concentration (C4). Neither inhibiting nor activating action has been observed in phenylbutazone treatment (F2). 

From a series of 5,6-diphenylpyridazines prepared in Italy [91], chloro derivatives of type (20, R = 4-Me2NC6H4, 4-MeOC6H4) have been found to be anti-inflammatory, analgesic and antipyretic agents superior to phenylbutazone when tested in mice or rats. 

S2S. Street, H. V., Gas-liquid chromatography of submicrogram amounts of drugs. IV. Identification of barbiturates, hydantoins, amides, imides, carbamates, phenylbutazone, carboxylic acids and hydrazine derivatives by direct derivative fonnation within the gas chromatograph. J. Chromaiogr. 41, 358-366 (1969). 

Apart from the salicylates NSAIDs include several classes of weak acids like propionic acid derivatives such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen. Phenylbutazone is the most important representative of the pyrazolon derivatives which have a bad reputation for their risk of potentially fatal bone-marrow toxicity. To the acetic acid derivatives belong in-domethacin, diclofenac and sulindac. Sulindac is a pro-drug with less toxicity than indomethacin. The enolic acids include piroxicam, droxicam and tenoxicam. Meloxicam is an analog of piroxicam and has a high selectivity for COX-2. 

Pyrazolone derivative related to phenylbutazone. It has uricosuric action. It also inhibits platelet aggregation. 

Little information is available regarding tissue distribution or metabolic products of nonsteroidal anti-inflammatory drugs in cattle. The early synthetic compounds were simple derivatives either of salicylic acid such as acetylsalicylic acid and methylsalicylic acid, or of pyrazolone such as metamizole, oxyphenbuta-zone, phenylbutazone, propylphenazone, and suxibuzone. Modern nonsteroidal anti-inflammatory drugs are derivatives either of anthranilic acid such as dido-... 

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