NOTES
January, 1963
77
Q
D(
- )Ephedrine
D(
- )Pseudoephedrine
Fig. 1.-Relationship of the functional groups in the D-diastereoisomers, ephedrine and pseudoephedrine (preferred conformations not implied).
At this dose level D( -)pseudoephedrine produced no pressor response whatever, and in fact, produced a small, transient drop in blood pressure. D ( -)Ephedrine produced a rise in blood pressure of approximately 70 mm. If the test animal was pretreated with D ( - ) pseudoephedrine and given D ( -)ephedrine one-half hour later, there was no pressor response, indicating that, a t these doses, D ( -)pseudoephedrine is capable of completely blocking the pressor effect of D( -)ephedrine. Since D ( -)pseudoephedrine itself did not produce any pressor response it was assumed that this was a true blockade and that cross-tachyphylaxis was not involved This was borne out by the finding that pseudoephedrine given a t the peak of the pressor response to D ( -)ephedrine caused an immediate return of the blood pressure to normal. These effects were not obtained when the other ephedrine isomers (L( +)ephedrine, L( +)pseudoephedrine) were tested under the same conditions. I n a further series of experiments, it was found that pretreatment with D ( -)pseudoephedrine blocked the pressor effect of tyramine and amphetamine, and augmented the pressor response of norepinephrine. In these respects the action of D ( -)pseudoephedrine appears very similar to that reported for methylphenidate.3f4 Methylphenidate (methyl-a-phenyl-2-piperidine acetate) contains two asymmetric carbon atoms. and therefore can exist in two diastereoisomeric forms, e7 ythro and threo. When methylphenidate is represented as in Fig. 2 , the resemblance to the isomers of ephedrine becomes apparent. This resemblance led us to make the assumption that the active racemate of methylphenidate is the threo racemate, and this has been stated by D r ~ e yrecently. ,~ Although the absolute configurations of the isomeric methylphenidates are not known, we have drawn the threo enantiomorph which is configurationally identical to D ( -)pseudoephedrine because the action of methylphenidate is essentially the same as the action of D ( -)pseudoephedrine. Burn and Rand6 hare demonstrated that ephedrine, tyramine, amphetamine, and certain other sympathomimetic amines act by releasing norepinephrine from (3) R. A. ~ I a x w e l l ,A. J. Plummer, S. D. Ross, J. J. Paytas. and A. D. Dennis, Arch. Intern. Pharmacodyn., 112, 26 (1957). (4) H. J. Povalski and E. D. Goldsmith, Proc. Soc. Esp. Piol. Med., 101, 717 (1959). (.5) J . Druey, “A La Recherche De M6dicaments De SynthBse,” presented a t 1’ Convenci6n Bienal De La Industria Farmaceutica Espafiola, 1961, p. 17. (6) J. H. Burn and M. J. Rand, J. Physiol. (London), 1 4 4 , 514 (1958).
er ythro-Methylphenidate threo-Methylphenidate Fig. 2.-Relationship of the functional groups in the Ddiastereoisomers of methylphenidate (preferred conformations not implied).
storage sites. Muskus, et uZ.,’ have suggested recently that ephedrine and norephedrine are compounds which have indirect activity (release of norepinephrine from storage sites) as well as direct activity (at effector site). The experiments described in this note indicate that D( -)pseudoephedrine blocks the pressor effects of ephedrine regardless of whether these effects are indirectly or directly produced. Investigations are being carried out to determine the exact nature of this blocking action. Experimental Preparation of the Isomers of Ephedrine.-Ephedrine alkaloid (Merck) was converted into a mixture of four isomers by boiling in p-cymene in the presence of sodium methoside.sl9 The two racemates were obtained by fractional crystallization. ( A)Ephedrine waa resolved through formation of the (+)-mandelate salts according to Manske and Johnson.10 ( &)-Pseudoephedrine WEB resolved through formation of the (+)-tartrate salts according to Spath and Gohring.1I These resolutions were carried out primarily to obtain L( +)ephedrine, and D( - )pseudoephedrine, neither of which is commercially available. D( - )Ephedrine was obt&ed from M a c k and Company, and L( +)pseudo ephedrine from L. Light and Company, Ltd., England.
Acknowledgment.-This research was supported in part by a grant from the Development Fund of the Ohio State University. (7) A. Muskus, V. Trendelenburg, and W. W. Fleming, The Pharmacologist, 4, No. 2, 162 (1962). ( 8 ) D. Scheving a n d W. Krauss, German Patent 673,486 (1939)LChem. A b s t ~ . ,33, 4274 (193911. (9) D. L. Tabern, U. 9. Patent 2,214,034 (1941)[Chem. Abstr., 36, 754 (1941)l. (10) R. H. F. Manske and T. B. Johnson, J . Am. Chem. SOC., 5 1 , 1906 (1929). (11) E. Spath and R. Gohring, Monatsh., 41, 319 (1920).
A Hydroxamic Acid Analog of Cortisone R. W. KIERSTEAD, A. FARAONE ASD M. W. GOLDBERG Research Laboratoriea, Hoffmann-La Roche, Inc., Nutley, N. J . August 8, 196.9
Iiumerous modifications have been carried out on the 21-hydroxymethylene grouping in the corticoid series’ (1) For leading references, see R. E. Schaub and hl. J. Weiss, J . Org. Chem., 26, 1223 (1961): also H. D. Brown, A. R. Matauk, D. R. Hoff and L. H. Sarett, J . Org. Chem., 27, 961 (1962); M. Marx and L. L. Smith, U. S. Patent 3,020,275 (Feb. 6, 1962); W. S. Allen and hl. J. Weiss, J . Org. Chem., 26, 4153 (1961); H. D. Brown, A. R. RIatsuk, D. R. Hoff T6th, Z. Tuba and a n d L. H. Sarett, J . Org. Chem.. 26, 5052 (1061); L. Ssporny, Nature, 191, 607 (1961); E. J. Agnello and G. D. Laubaoh, U. S. Patent 2,920,999 (Jan. 12, 1960); E. J. Agnello, R. Pinson, S. K. Figdor, G. M. K. Hughes, H. W. Ordway, B. 31. Bloom an0 C . D. Laubach Ezperientia, 16, 367 (1960).
:.
and this approach has led to a numhrr of biologically interesting steroids. I t ocmrrrd to us that it might of interest to prepare the rorresponding hydroxamiv acids in which the 21 -hydroxxmethylene is replacwi 1)y a, hydroxylamine grouping Recent reports? on ~nthesisof caertain steroidal cyclic hydroxamic acid derivatives (1-hydroxylactams) prompt? 11s to ('ommunicatc the results of our investigation. Itcaction of I ioc-hydrosy-:3,11-dioxo-4-etiocholenic wid methyl ester3 with 2-methyl-%-ethyl-l,3-dioxolanc gave the ketal I. The latter mmpound readily i \ a s hydrolyzd with alcoholic potassium hydroxide, and acidification with a solution of dihydrogen sodium phosphate gave the acid 11. Trcatment of 11 with n c h c anhydride in pyridine gave the corresponding acetat(> 111. Both I11 and its corresponding sodium salt rcmtcd with oxalyl (ahloride in t h c usual manner, n ith subsequent treatment TI ith hydroxylamine undcr a varictv of caonditions. I n every ( a i ~ sintractable ~ mis-
111, R = A c
a
CON H OCH3 OH
IV
#-OH
1
VI
NHOH
J
NHOCH3
I
m
C=O
-
Oc=o H
d
Biological Activity.'-111 nitact rats. compoui1dy \ and TI1 showed no activity when assayed at 20 the dose (hy w i g h t ) of hydrocortisone, nhich ~ V P S:I 50% thymus iiirolutio~iin this test. Both 1-ant1 1 - 1 I \\ere inactix E 111 thc clotton pellet graiiuloma pi ocwhic. In adrennlec*tomized rats. both 1-a n d 171 \I crc I I I W ~1 1 111 the thymus ill\ olution assay :uid 41o1\ ~1 no antic*ortiw i d acti\rity 11hen administcrcd cwiic*iii.iciitlv \I i t h liydroc~oi-t i\oii(> timc3-
(x
Experimental6 3-Cyclic Ethylene Acetal of 17cu-Hydroxy-3,11-dioxo-4-etiocholenic Acid Methyl Ester (1j.-A mixture of 19.28 g. of 1 7 ~ liytlroxy-3,l l-dioxo-4-etioc~holeiiic.arid methyl ester3 in 320 rill. of 2 - m e t h ~ ~ l - 2 - i ~ t h y l - l , : i - ~ ~ i o xand o l a 600 n ~ ~ m g . of p-t,oliicwrsul[oiiic acid n-as heatcd to boiling arid \vas distillrtl slo\vly for 2.5 hr., about 200 ml. of distillate being collected in this time. T l i ~ cooled reaction mixture \vas diluted with ether-nict,hyl(:lie chloride ( 2 . 5 :1 ) arid \vas \\-ashed successively n-ith 5 5 :quroris sodium bicarbonate and \v:+t,er. 'The organic lsyer \vas drirtl (S:t?SO,) and concentrated to dryness urider reduced pressurcn. Thrrr crystallizations of the rrsidur frorri methylene chlorid., t,Iw :tijove Iirocedurc \vas rept:,zt,chtl txvicr 011 t,he rc,sidues, to give total of 16.3!1 g . ( 7 5 . 5 ( ! ;over-:dl yirld) of rrritlt~ I . ('rystallizatiori from nrr~thylriic~chloritlr cxthvr gave :tu arialytical s:tmplr. 1ii.p. 1!)5.~5-198'. 10' % - 1 .-I" (c, 1.04'). A'!:: 2.8X, 5.7:3 a11d 5.87 p . . I / m i . (':~lctl. For C2dHi..0i;: C'. 08.2!): H,7.!)7. Found: (', (i8.48: H , 8.11 , 3-Cyclic Ethylene Acetal of' 17~-Hydroxy-3,1l-dioxo-4-etiocholenic Acid iII).-A solution of 14.53 g. of the rrude ketal 1 (ni,p. 186-190") i r i 185 nil. ( J f 10'; inethaiirilic potassium hydroxide \vas heated under reflux for 15 niin. The reaction niistiire \v:is theii caooletl :tiid ev:ipor:ited to tlryiiess iiiicler retliircttl ~)ressure. Tlic pale yellotv residue \vas dissolveil in 900 1111. of u.:it,r:r and t h r cooled solution \\-:ts acidified to :tlmut pH 4 ..i ljy t h r a~lditiotioi 1200 inl. of :r saturated solutioii of tlihytlrogc~ii sodiuiii pliospliatt.. The rr:siiltiiig colorless 1irecipit:Ltc \v:i,s filt,ered, \v:tshcti u i t h \r:Ltcr a i i t i drietl. Crystallization froiii ehloroforrii--t.t,lior g:ivt: with the authrritic s:mple. 3-Cyclic Ethylene acetal of 17~-Acetoxy-3,11-dioxo-4-etiocholenic Acid (III'1.-To :L solutimi of 13.14 g. of I1 in 27 ml. of anhydrous pyridine was :itlded 9.5 inl. of freshly distilled :wctic. aiihgdritiP. the temperature of the mixture tieing lielit M o w 30" ljy eyteriid i*ooling. The renctioii mixture n-as then :illowed t o s t : d overnight, :it room tempemtiire tint1 \vas fiii:illy heated a t 50" for 90 inin. It \v:ts t,hen evaporated to dryness in :t v:icuuiii. 'rlir residuth \viis tnlct:n up in ethcr--mc.thylcnc chloride ( 2 . 5 :1 ) :t1icl \vas n.aslir:d :3 times ivith r\,:itcr. 'The combined organic layer \v:w dried ( S a 2 $ ;) ( itrid eorict:ntratid t o dryness undpr reduced prwIIP i v : ~ s crystdlizcrl froin met hylcnc cliloridib :ig , of 111. m.p. 217.3 -220.5'. --Ifurther 0.58 g. ) \vas rwovored froni the rnothrr liquors (tot:tl ryst:illization f r o l u methylene chloritle-(dirr gave thcs :tri:tl>~tir:tlenmpli., i i i . ] j . 918.3-230". [ C Y ] aeu -38" f r . O,(j72),A!:' 5.77, 5 . 8 5 ant1 7.05 p . . l j / d . C':ilc
