June 5, 19.52
COMMUNICATIONS TO THE EDITOR
2947
anhydrous chloroform has an additional band a t 4500 A. ( E m 36) which is characteristic of a-diIV. M. MCLAMORE carbonyl compounds. Chemically the hydrates WALTERD. CELMER behave as typical aldehydes. Positive Schiff and RESEARCH LABORATORIES VIRGILV.BOGERT silver mirror tests are observed and three derivaCHAS. PFIZER AND C O . , INC. FRANK C. PENNINGTON tives involving the aldehyde group have been preBROOKLYN 6, NEWYORK I. A . SOLOMONS pared from cortisone aldehyde, the dimethyl and RECEIVBD MAY9, 1952 diethyl acetals (VII, VIII) and the diacetate (IX). The aldehyde hydrates have approximately the same activity as cortisone and hydrocortisone in ALDEHYDES DERIVED FROM CORTISONE AND rat liver glycogen deposition tests.' The nitrone HYDROCORTISONE and diacetate in the cortisone series are also active, Sir: while the acetals appear to be inert. I t has, furCortisone (I) and hydrocortisone (X), Kendall's compounds E and F, have been converted to the thermore, been noted that cortisone and hydrocorcorresponding 21-aldehydesI A4-3,11,20-triketo-l7a- tisone aldehyde hydrates cause adrenal atrophy hydroxypregnene-21-a1 (V) and A4-3,20-diketo- and thymus involution similar to that resulting 11p, 17a-dihydroxyprenene-21-a1(XIII), which are upon administration of the parent hormones.2 The approximate equivalence in biological activity biologically active. On treatment of cortisone (I) with p-toluenesul- of cortisone and hydrocortisone with the correfonyl chloride a mixture of the pyridinium @-tolu- sponding 21-dehydro compounds is in contrast to enesulfonate and chloride (11, 111) was obtained. results with desoxycorticosterone and the related The latter salt was treated with p-nitrosodimethyl- 21-aldehyde. This aldehyde is only one twentyaniline to give the nitrone (IV), isolated in two fifth as effective as desoxycorticosterone in the forms, red plates and yellow needles, having identi- Everse-deFremery work test. (1) Several modifications of the procedure of Pabst, Sheppard and cal decomposition points. The nitrone was hydro-
140°, [ a ] " ~-51.4, was identical with the antibiotic obtained from the Streptomyces fermentation.
Kuizenga (Endoc~inology,41, 51 (1947)) have been employed by Drs. C. C. Porter and R. H. Silber of the Merck Institute for Therapeutic Research, to whom we are indebted for the reported results. (2) We are obliged to Dr. C. A. Winter, Merck Institute for Therapeutic Research, for these tests. (3) H. Reich and T. Reichstein, Helo. C k i m . Acta, 22, 1124 (1939).
COR
E. F. ROGERS RESEARCH LABORATORIES W. J. LEANZA MERCK& Co., INC. J. P. CONBERE K. PFISTER 3 R D RAHWAY, AT. J. RECEIVED MAY19, 1952 X I I1 111 IV V
c=o c=o c=o c=o c=o c=o c=o c=o
R CHIOH CHzPy+OTsCHtPy +C1CH=N(O) CeH4N(CHa)z CHO CH(0H)z CH(0CHa)z CH(OCzH6)z CH(0COCHs)z CHzOH CHzPy "C1CH=N(O)CsH4N(CHs)z CHO CH(0H)z
M . p., OC.
285-290 dec. 290-291 dec. 189-190 dec. 210-215 dec. C Q . 225 dec. 142
c=2)
$231°
A NEW STREPTOMYCES ANTIBIOTIC'
Sir : A new antibiotic, exhibiting highly specific in vi+18Z0 VI tro activity against Mycobacteria, has been isolated VI1 $176' from a species of Streptomyces. The antibiotic VI11 77 $165' IX c-0 + 990 may be recovered by successive n-butanol extrac169 X CHOH tions of the culture broth after filtration from the X I CHOH 295-296 dec. $232O mycelium a t pH 2.0. The butanol extracts are XI1 CHOH 186-188 dec. combined and the acidic antibiotic extracted with XI11 CHOH sodium carbonate solution. The alkaline solution XIV CHOH 155-160 dec. +155O is adjusted to p H 4.5, and then repeatedly exlyzed by dilute acid to cortisone-21-aldehyde (V), tracted with butyl acetate. Evaporation of the which crystallized from aqueous acetone as the butyl acetate leaves a dark brown sirup which is colorless hydrate (VI). (Anal. (after drying a t 25' dissolved in hot ethylene dichloride, treated with (1 mm.) 4 hr.) Calcd. for C21Hz80a: C, 67.00; activated carbon, and filtered. On cooling, the anH, 7.50. Found: C, 67.01; HI 7.75). Theyellow tibiotic crystallizes in long white needles. Recrysfree aldehyde was regenerated from the hydrate tallization can be effected from hot water, warm by several hours drying a t 110' (1 mm.). (Anal. acetone, or methanol. Calcd. for C21H2605: C: 70.36; HI 7.31. Found: This new antibiotic is a monobasic acid, pK 5.1. C, 70.09; H, 7.52). Titration molecular weight data are in agreeBy an analogous procedure, hydrocortisone (X) ment withand the formula C9H1603NS, m.p. 139-140", was converted Via the pyridinium chloride (XI) [ a ] " ~-54 (c 1, methanol). (Anal. Calcd. for and nitrone (XII) to hydrocortisone-21-aldehyde CgHx03NS: C, 49.77; HI 6.91; N, 6.45; S, 14.75. hydrate (XIV). (Anal. Calcd. for C21H3006: C, Found: C, 49.96; H I 7.09; N, 6.51; S, 14.83). 66.64; H, 7.99. Found: C, 66.94; H, 7.69). Solutions of the pure material exhibit a blue fluoThe ultraviolet absorption spectra of cortisone rescence on exposure to ultraviolet light. There aldehyde hydrate (max. 2380 A., Em 15,700) aFd is no characteristic ultraviolet spectrum. The hydrocortisone aldehyde hydrate (max. 2420 A,, (1) Since the completion of this work, we have learned t h a t this E , 16,000) in methanol resemble those of cortisone antibiotic (actithiazic acid) has been independently isolated and s y n and hydrocortisone. Cortisone free aldehyde in thesized by a group a t Abbott Laboratories.
