,March 20, 19.57
COMMUNICATIONS TO THE EDITOR
showed almost no activity as the amide donor. Under the conditions of the experiment shown in Table 11, glutamine supply limits DPN synthesis. Thus, in a separate experiment under similar conditions, with NA held constant a t 10 pmoles per vessel, DPN synthesis in the presence of 0, 4, 10 and 20 pmoles of glutamine was 0.052, 0.104, 0.172 and 0.274 pmole, respectively. Further investigations are in progress seeking t o elucidate the mechanism of pyridine nucleotide synthesis from nicotinic acid and its amide.
1515
/I
3
(7) Predoctoral Fellow of the National Institute9 of Health.
DEPARTMENT OF BIOCHEMISTRY DUKEUKIVERSITY SCHOOL OF MEDICINE J. PREISS’ DURHAM, NORTHCAROLINA PHILIPHANDLER 11, 1957 RECEIVED FEBRUARY pJ
THE ISOTROPIC LENGTH OF POLYMER NETWORKS
01.
Fig. 1.-Plot of ratio of isotropic length after cross-linking
Li t o initial length LOagainst the square root of the fraction Sir: A general theory of the elastic properties of of the units crosslinked p ’ l z . polymer networks was developed in a recent paper’ linking density decreases deviations from linearity and this theory was applied t o the cross-linking of occur and Li/Lo appears to approach unity. Achighly oriented chains. Whereas for a network cording to equation (38) of ref. 1, Li/Lo should formed in the usual way by cross-linking chain vary directly as p ’ l P for chains with perfect axial molecules in random arrangement the isotropic orientation, and for an infinitesimal amount of length Li of the network (;.e., its length under no cross-linking Li should shrink to zero. This bestress) must obviously be independent of the de- havior is indicated by the linear portion of the gree of cross-linking, it was shown t h a t for a net- curve and its extrapolation to the origin. Since work formed by the random cross-linking of highly the chains prior t o network formation are neither oriented chains Li should increase directly as the completely nor perfectly oriented, deviations from square root of the fraction p of the units cross- linearity would be expected a t low cross-linking linked. Although i t has been reported that the densities where L i should tend to remain constant cross linking of stretched rubber results in an in- as observed. The slope of the linear portion of the crease in its isotropic (zero stress) length,*v3 curve is fifteen while theoretically it is estimated to adequate data are not available to test the afore- be about ten. It appears that “racked rubber” mentioned deduction. We wish to report the re- can serve as a good model for the physical behavior sults of studies of the isotropic length of natural of the fibrous proteins. rubber networks formed from chains in a highly Further details of the experimental methods, a oriented state. These results give strong support more thorough discussion of these results as well to the theoretical conclusions. as a comparison of the isotropic melting temperaThe highly oriented state of the rubber, prior t o ture and swelling behavior of different type netcross-linking is obtained by modification of the works will appear in a forthcoming paper.6 “racking process” originally described by F e ~ c h t e r . ~ (6) D . E. Roberts and L. Mandelkern, in preparation. The wide angle X-ray pattern6 indicates that the DOKALD E. ROBERTS BUREAU OF STANDARDS specimen is in a highly oriented state and the ratio NATIONAL 25, D. C. LEOMANDELKERN of the extended length to retracted length is about WASHINGTON BAKERLABORATORY OF CHEMISTRY eleven. The samples were cross-linked by subject- CORNELL UNIVERSITY PAULJ. FLORY ing them to y-ray irradiation from a Co60 source. ITHACA, N. ‘17. The efficiency of cross-linking in the highly oriented RECEIVED JANUARY 28, 1957 racked’ rubber was found to be twice that for unoriented rubber. HORMONES AND RELATED COMPOUNDS. I n Fig. 1 the ratio of Ll to the initial length Lo ADRENAL V. FLUORINATED &METHYL STEROIDS is plotted against p a l z . A fiftyfold range in crosslinking is encompassed by these experiments and S i r : We recently have reported’ the preparation of a the isotropic length increases by a factor of two and a half. At the higher degrees of cross-linking the number of 6-methylated analogs of adrenal hordata are well represented by a straight line which mones which show unusual potentiation of glucoextrapolates to the origin. However, a s the cross- corticoid activity with no sodium-retaining properties. The group of Sa-fluoro- and 21-fluoro-6(1) P.J. Flory, THISJOURNAL, 78, 5222 (1956). methyl steroids reported herein represents a con(2) R. D. Andrews, E. E. Hanson and A. V. Tobolsky, J . A p p l . Phrs., 17, 352 (1946). tinuation of this work. Compound 111 described (3) J. P. Berry, J. Scanlan and W. F. Watson, Trans. Faraday SOC. below is by far the most potent glucocorticoid re62, 1137 (1956). ported to date. (4) H . Feuchter, Karrtschrrk, Dec.. p. 6 (1925); pp. 8, 28 (1928). ( 5 ) C. C. Davis and J. T. Blake, “The Chemistry and Technology of Rubber,” Reinhold Publishing Corporation, New York, N . Y.. 1937, p. 78.
(1) G. B. Spero, J. L. Thompson, R. J. Magerlein, A. R. Hanze, H. C. Murray, 0. K. Sebek and J. A. Hogg, TEIS JOURNAL,78, 6213 (195G).
1516
COMMUNICATIONS TO THE EDITOR
Vol. 79
Ga-methyl-1I/?, 17a-dihydroxy-21-acetoxy- diene-3,20-dione (XIII), m.p. 216-222'. Anal. Found: F, 3.63. thionyl chloride in pyridine to 6a-methyl-17aCompounds 111, IV, V, IX, X, XI, XI1 and XI11 hydroxy - 21 - acetoxy - 1,4,9(11)-pregnatriene-3,20- all show considerably greater glucocorticoid and dione (I), m.p. 192-194'; [.(ID 18' (acetone); anti-inflammatory activity4 than does hydrocorXgz 'Ic 239 nip, ab1 = 15,450. Anal. Found: tisone in animal assays. Compound 111, 6aC, 72.03; H, 7.57. This was converted by known methyl - 9 a - fluoro - l l p , l 7 a - dihydroxy - 21 - acemethods3 to a crude 9,ll-bromohydrin and then toxy- 1,4-pregnadiene-3,2O-dione, was more active to the 6a-methyl-9/3,ll~-oxido-l7a-hydroxy-21in the anti-inflammatory assay than any of the acetoxy-1,4-pregnadiene-3,2O-dione (II), m.p. 260- previously reported analogs of hydrocortisone of 265'; [a]D 60' (pyridine); XEz a'c 249 mp, which we are aware. Its enhancement of the glucoU M = 16,150. Anal. Found: C, 69.48; H, 7.21. corticoid activity was particularly noteworthy, beReaction of I1 with hydrofluoric acid gave 6,ing 120 times as active as hydrocortisone when admethyl - 9 a - fluoro - 1lp,17a - dihydroxy - 21 - ace- ministered parenterally, and 190 times hydrotoxy-1,4-pregnadiene-3,20-dione(111), m.p. 237- cortisone by oral administration. None of the 239'; [ a ] D 87' (acetone); hgg 239 mp, above compounds exhibited appreciable sodium rea M = 15,250. Anal. Found: C, 65.94; H, 6.95; taining proper tie^.^ F, 4.72. Hydrolysis of I11 with potassium bicar(4) Assays were performed by members of t h e Department of Endobonate in methanol produced 6a-methyl-9a-fluoro- crinology of T h e Upjohn Company a n d will be reported in detail else11/3,17a,21-trihydroxy - 1,4- pregnadiene - 3,20-dione where. T h e glucocorticoid assays were by t h e method of R. 0. Staf . (IV), m.p. 243-250 (dec.); [ a ] = 93' (dioxane); ford, L. E. Barnes, B. J. Bowman and M. M. Meinzinger, Pvoc. SOL. E x + . Biol. &fed., 89, 371 (1955): t h e anti-inflammatory assays by a XE2 a". 238 mp, a~ = 15,150. modified granuloma pouch technique ( A . Robert and J. E. h'ezamis, Anal. Found: C, 67.48; H, 7.61; F, 5.02. Con- Acta Endocrinologisa, in press). (5) This may be contrasted with t h e activity of 2-metbyl-9uversion of IV to the corresponding 21-fluor0 analog3 gave Ga-rnethyl-9a,21-difluoro-ll~, 17a-dihydroxy- fluorohydrocortisone reported by W. W. Bymes, L. E. Barnes, B. J. Bowman, W. E . Dulin, E. H. Morley a n d R. 0. Stafford, Proc. Soc. 1,4 -pregnadiene -3,20-dione (V), rn.p. 262-274 E x p . Biol. M e d . , 91, 67 (1956). where t h e mineralocorticoid properties (dec.); [ a ] D 71' (acetone); LE2 239 mp, ab1 were shown t o be enhanced t o B much greater extent t h a n t h e glucocorticoid. = 15,000. Anal. Found: C, 66.87; H, 7.69; F, 9.80. G , B. SPERO LABORATORIES j. L. THOMPSON In a like manner 6a-methyl-l1P, 17a-dihydroxy- RESEARCH F. €1. LINCOLN UPJOHNCOMPANY 21-acetoxy-4-pregnene-3,20-dione'was converted THE AALAMAZOO, h I I C H I G A N W. P. SCHNEIDER to a similar series of compounds: 6a-methyl-17aJ. A . HOGG hydroxy - 21 - acetoxy - 4,9 - (11)- pregnadiene - 3,20RECEIVED FEBRUARY 18, 1957 91' (Chf.); dione (VI), m.p. 175-176'; [ a ] D Xgzslc.239.5 mp, a M = 16,400. Anal. Found: C, 71.75; H, 7.71; Ga-methyl-9a-bromo-ll~,l7aA NEW ANALGETIC dihydroxy - 21 - acetoxy - 4 - pregnene - 3,20 - dione Sir: (VII), m.p. 153-155' (dec.); [a]D 148' (Chf.); To date the preparation of effective synthetic 239.5 mp, ab1 = 14.225. Anal. Found: analgetics has been confined to a great extent to Br, 16.0; Ba-methyl-9/3,11~-oxido-l7a-hydroxy-21acetoxy-4-pregnene-3,20-dione(VIII), m.p. 180- pyrazolone derivatives, e.g., aminopyrin (l-phenyl182'; [ a ]f~ 65' (Chf.); h ~ ~ a l242 e ' mp, U M = 2,3 - dimethyl - 4 - dimethylamino - 5 - pyrazolone)' 14, 625. Anal. Found: C, 69.41; H, 7.93; 6a- and phenylbutazone (1,2-diphenyl-4-buty1-3,5-pymethyl - 9 a - fluoro - 11/3,17a - dihydroxy - 21- razolidinedione) , 2 and to morphine-like analogs, acetoxy-4-pregnene-3,20-dione (IX), m.p. 219- such as meperidine (ethyl 1-methyl-4-phenylisoni220'; [ a ] D 113' (acetone); AFZaic.239 m p , UR.Z pecotate)3 and levorphan (3-hydroxy-N-methyl= 15,775. Anal. Found: C, 65.69; H, 7.49; morphinan).4 Each of these and related type F, 4.29; 6a-methyl-Sa-fluoro- 11/3,17a,21-trihy- compounds have suffered from certain disadvandroxy-4-pregnene-3,2O-dione(X), m.p. 228-230' ; tages, such as addiction and dependence (morphine and analogs), as well as toxic effects on the hemato[a]D 112' (acetone); A ~ ~ & ' " 2 3 9 m p=, 16,400. a~ Anal. Found: C, 67.20; H, 8.01; F, 5.47; and 6a- poetic system (pyrazolone derivatives), More methyl - 9a,21 - difluoro - 11/3,17a - dihydroxy - 4- recently i t has been reported5 that replacement of pregnene-3,20-dione (XI), m.p. 210-212" ; [ a ] D the 1-methyl group of meperidine with the phenyl 89' (acetone); X ~ ~ a a l 239 c . mp, aM = 14,225. ethyl or para-amino phenyl ethyl moiety leads t o a less toxic morphine-like compound. Anal. Found: C, 66.35; H, 8.07; F, 9.24. At this time we wish t o present a preliminary reI n addition, using the method of reference 3, 6amethyl- ll/3,17a,21-trihydroxy- 4 - pregnene - 3,20- port on the preparation of a compound which we dionel was converted t o 6a-methyl-llB,17a-di- have found to possess good analgetic activity in hydroxy-21 - fluoro -4-pregnene-3,20-dione (XII), experimental animals. The constitutional aspects m.p. 220-223'. AnaZ. Found: C, 70.14; H, of this new preparation are far removed from the 7.95; F, 6.76. Likewise, 6a-methyl-llp,17a,21- usual features attending previously outlined analtrihydroxy-1,4-pregnadiene-3,20-dione1gave 6a(1) A. Stolz, U. S. P a t e n t 579,412 (1897). ( 2 ) J. R. Geigy, A,-G., Swiss Patent 269,980 (1950). niethyl-llp,l7a- dihydroxy -21- fluoro -1,4- pregna(3) 0. Eisleb, U. S. Patent 2,167,351 (1939). The
1,4-pregnadiene-3,20-dione'was dehydrated by
+
+
+
+
+
+
+
Xzzdc
+
+
+
( 2 ) J. Fried a n d E F. Sabo, THISJOURNAL, 75, 2273 (1953). (3) By a modification of t h e method of P Tannhauser, R. J P r a t t a n d E V. Jensen, r b r d , 7 8 , 2658 (1956).
(4) 0. Schnider and A. Grussner, Hclv. Chim. Acta, 82, 821 (1949). ( 6 ) T. D. Perrine a n d N. B. Eddy, J . Org. Chcm., 21, 125 (1956): J. Weijlard, cf aE., THISJ O U R N A L . 7 8 , 2342 (1956).
