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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
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( 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).
March 20, 1957
COMMUNICATIONS TO THE EDITOR
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nature of pure ozone and the extreme facility with which i t explodes or detonates, has so far prevented combustion studies with pure ozone. C& I Before studies of the behavior of pure ozone with various fuel gases could be started profitably i t was first necessary to achieve the combustion or decomposition flame of pure ozone to oxygen. It could be expected, since the exothermic heat (at constant When a-chlorocyclopentanone is allowed to react pressure of 1 atm. and 291’K.) of the reaction O3+ with ethyl xanthamidate in boiling 1-propanol, 1.5 O? equals - 33,923 f 180 cal./mole, that apthere was obtained the crystalline compound, preciable flame temperatures should be attained 2,3,5,6 - tetrahydro - 4(H) - cyclopentathiazolo - 2- and that a stable ozone-oxygen flame should exist. one. Purification by recrystallization from water Flame temperature calculations can be made with or water-ethyl alcohol (9 :1) mixture gave product great accuracy since the enthalpy and the dissociaof m.p. 144-145’; Anal. Calcd. for C6H7NOS: C, tion constants for the 0 2 e 2 0 reaction are well 51.06; H, 5.02; N, 9.93; S, 22.60. Found: C, known ; these temperatures are, a t initial condi51.02; H, 4.96; N, 9.96; S, 22.90. Ultraviolet tions of 298’K. and 1.0 atm. pressure, for 100, ’ 0s in 0 2 , respectively, 66.7, 40.0 and 18.2 mole % absorption measurements a t PH 7 gave 252 mp, E 4430; ”’?A: 229 mp, E 2500. Meth- 2677O, 2277”, 1687” and 1027°K. By using pure ozone, containing less than a few ylation of this thiazolone with methyl iodide in a parts per million of organic impurities, as debasic medium gave rise to I which, after purification by crystallization from water, melted a t scribed originally by C. E. Thorp,2 we have been 70-71”. Anal. Calcd. for C7HsNOS: N, 9.04; able to burn ozone-oxygen mixtures to oxygen in S, 20.68. Found: N, 8.90; S, 21.00. Absorp- the entire range from 17-100 mole yo 03. The alltion data in the ultraviolet are 253 mp, Pyrex glass apparatus was extremely simple; i t consisted of a narrow glass gasholder, from which 231 mp, E 2720. E 4170; The pharmacodynamic evaluation of this com- any desired mixture of 0 8 - 0 2 or pure 0 3 could be pound revealed a rather surprising activity in re- delivered a t any predetermined rate, by simple disFrom the gasholder the ducing experimental pain. The Wolf-Hardy prin- placement with water. ciple for testing analgesia was employed in experi- gas mixture went to a Pyrex glass, quartz, or alumental animals according to a method described minum tip. Stopcocks greased with C,F?,+ 9 or by Gross.’ A beam of heat was directed against Kel-F, were used. The burning velocities were the tips of the tails of white mice and the reaction determined by the standard schlieren method. time measured from the onset of pain stimulus to In the range of 17 to about 50 mole % 0 3 , the flame the tail flick. Analgetic effects were expressed in cannot be observed visually, but can be seen very terms of prolonged reaction time to the pain stimu- easily on the screen of the schlieren apparatus. lus. With this method the above-mentioned com- The flame is visible above this range. Pure 100% pound produced a marked prolongation of the re- ozone burns with a faint, non-luminous flame, blue action time in the range of one-tenth to one-fifth in color, with a typical pink cast. The experiof the LD50. It was characterized by a rapid on- mental burning velocities, a t 298°K. and 1.0 atm. set of action and a maintenance of the analgetic pressure, are shown in Fig. 1. The ozone flame is of particular theoretical ineffect for several hours following parenteral administration. Compared to aminopyrine the mate- terest since i t is the simplest flame imaginable. rial was more potent, somewhat less toxic and de- Outside of the “fuel” O3 and the “product of combustion” 0 2 , the only possible intermediates are void of antipyretic activity. oxygen atoms. (6) According to Chemical Abstracts, an alternate name for I is NIn recent years Drs. J. 0. Hir~chfelder,~ Theomethylcyclopentano- [d]4-thiazolin-Z-one. dore von K8rm&n4and R. Sandri,5 and their as(7) F . Gross, Helu. Phrsiol. A d a , C31 (1947), w5. RESEARCH DEPARTMENT GEORGE DESTEVENS sociates, have developed the theory of laminar CIBAPHARMACEUTICAL PRODUCTS, INC. HEINOA. LUTS flame propagation. Dr. von K & r m h presented SUMMIT, YEWJERSEY J U R GA. SCHNEIDER his results recently6 and they are in essential agreeRECEIVED JANUARY 30, 1957 ment with Fig. 1. The more extensive data of Dr. Sand$ are given in Table I and are compared with THE PURE OZONE TO OXYGEN FLAME1 our experimental results in Fig. 1. As can be seen,
getics. This new substance is 2,3,5,6-tetrahydro3-methyl-4(H)-cyclopentathiazolo-2-one (I).6
AzzroH
Sir :
We live in a world of molecular oxygen and an overwhelming number of studies on combustion are devoted to oxidation with molecular oxygen. On the other hand, the active modification of the element, or ozone, has not been studied in the pure form. Ozone has been known since 1785, when van Marum observed its formation in the electric spark discharge in oxygen. The highly sensitive (1) This research was supported by the United States Air Force through the Air Force O 5 c e of Scientific Research of the Air Research and Development Command under Contract No. 18(600)-1475.
(2) C. E. Thorp, U. S. Patent 2,700,648, Jan. 25, 1965; see also “Bibliography of Ozone Technology,” Vol. 11’ “Physical and Pharmacological Properties,” 1955, Armour Research Foundation of Illinois Institute of Technology, Chicago, Ill. (3) J. 0.Hirschfelder, C. F. Curtiss and D. E. Campbell, J . P k y s . Chem., 67, 403 (1953); Proc. IVth International Symposium on Combustion, 1953, p. 197. (4) T . von Kdrmdn and S. S. Penner, “Selected Combustion Problems,’’ (AGARD) : Combustion Colloquium, Cambridge University, England, pp. 5-41 (1953), and C. A . , 48, 10409e (1954). (5) R . Sandri, Canadian J . Chcm., 3 4 , 313, 324, 331 (1956). (6) T.von Kbrm&n, Proc. VIth International Symposium on Combustion, held at Yale University, Aug. 19-24, 1956. (7) An extension of Sandri’s theory to ozone-rich mixtures will be published soon in Canadian J . Chcm. (1957).
