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COMMUNICATIONS TO THE EDITOR
Vol. 86
in 8-N-acetylglucosaminidase levels was reported for levels of I1 reported above. Whether these favorable the synovial fluid of patients suffering from severe results can be duplicated in man cannot be ascertained rheumatoid arthritis6 without prolonged clinical studies. We envisaged that 11~,17-dihydroxy-3,20-dione-1,4MERCKSHARP & DOHME RALPHHIRSCHMANN pregnadien-2 1-y1 2-acetamido-2-deoxy-~-~-glucopyran- RESEARCH LARORATORIES ROBERT G. STRACHAN OF MERCK & Co., INC. DIVISION P. BUCHSCHACHER oside (I) should show antiinflammatory activity only RAHWAY, KEWJERSEY L. H. SARETT after cleavage by /3-N-acetylglucosaminidase, because MERCKINSTITUTE FOR S. L. STEELMAN cortisol 2 1-methyl and hexadecyl ethers possess subTHERAPEUTIC RESEARCH K. SILBER stantially no systemic cortisone-like activity.6 Lack of RAHWAY, NEWJERSEY systemic activity of I, in conjunction with preferential RECEIVED JULY31, 1964 enzymatic cleavage at the inflamed site, should cause I t o be an effective but relatively nontoxic antiinflammatory agent. Radical Anions as Intermediates in Substitution Reactions. Carbon Alkylation of Nitroparaffin Salts The Koenigs-Knorr condensation of prednisolone (11) with 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-a-~Sir: glucopyranosyl chloride led to 118,17-dihydroxy-3,20Nitroparaffin salts normally undergo oxygen alkyladione- 1,4-pregnadien-21-yl 2-acetamido-3,4,6-tri-0- tion on treatment with alkyl halides.' However, inacety~-2-deoxy-~-~-g~ucopyranoside ( I I I ) , m.p. 246stances are known in which the result is carbon alkyla248'; [ a ] " D +36" (c I , CHCla);' ::A: 243 mp (log tion. Thus, when p-nitrobenzyl chloride is treated c 4.17). Anal. Found: C, 60.98; H, 7.02. Methwith a salt of 2-nitropropane an 83-95% yield of anolysis afforded I , m.p. 1S3-184'; [ ( Y ] ~ ~ Df66' the carbon alkylate is With o-nitro( c 1, MeOH); "A':: 243 mp (log c 4.19). Anal. benzyl chloride a 37-46y0 yield of the carbon alkylate Found: C, 62.13; H , 7.47; N, 2.28. Incubation of I is isolated. Significantly, m-nitrobenzyl chloride gives with ~-N-acetylglucosaminidase7gave the theoretical no carbon amount of 11. As expected, the addition of 2-acetK' R' 0 amido-2-deoxy-~-g~uconolactone inhibited the enzyK"CH2X I . I +/ R-C-NOZ ----+ R-C--NO2 or R-C=N matic hydrolysis.8 Unlike prednisolone phosphate, I \ I was not rapidly converted into prednisolone after CHzR" OCHsR', parenteral. injection into a rat or dog. When plasma I I1 levels of I I were determined after intravenous adminIn 1961 it was established that the uniqueness of the istration of I , the blood levels of 11 never reached more p-nitrobenzyl system depends not only on the pthan one-fifth those obtained after the subcutaneous nitro group but also on the leaving group; the more injection of an equimolar amount of prednisolone 21easily displaced the leaving group the less carbon phosphate. Incubation of tritiated I9 with sera and alkylate is produced.2 For example, p-nitrobenzyl joint fluids of two arthritic patients'O resulted in more chloride gives 92y0 carbon alkylation while p-nitroenzymatic hydrolysis per unit volume in the joint benzyl iodide gives an 86% yield of the oxygen alkylfluids than in the Sera and this difference was particuate. In contrast, the unsubstituted benzyl system larly striking (17-fold) in a severely ill patient." shows no leaving-group effect; the reactions of benzyl Compound I was tested in the rat in the granuloma chloride, bromide, iodide, or tosylate with the lithium inhibition assay after subcutaneous administration. salt of 2-nitropropane all give 82-84y0 yields of benzalI t showed eight-tenths of the antiinflammatory podehyde. It was proposed2 that oxygen alkylation, the tency of an equimolar dose of 11. Indices for undeusual mode of reaction of a nitroparaffin anion, derives sired effects were, however, considerably smaller simply from nucleophilic displacement by the oxygen (two-tenths that of I1 for body weight loss, threeof the anion on the benzylic carbon but that in the ptenths that of I1 for thymus involution, and fournitrobenzyl series, with a difficultly displaced leaving tenths that of I1 for ACTH inhibition). A very group, a second mode of attack by the nitroparaffin striking separation of an undesired effect was observed anion has a chance to compete and i t is this second in a standard ulcerogenic assayT2in the rat, where I process which is productive of carbon alkylation. had
