fore Ia, have the same configuration. The coiifiguration of (+)-a-lipoic acid, which is prepared' from Ia, is hence correctly represented by V, arid t h a t of ( - )-a-lipoic acid by VI. It is interesting to note t h a t aleprestic acid (( )-3-(2-cyclopenten-l-y1) -pentanoic acid), a chaulnioogra oil acid which differs from a-lipoic acid in having an ethylene function in place of the disulfide linkage, has the same configuration as T'.i
+
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JVM. H. XICTTOLS CHEMICAL LABORATORY SEI\, YORKCSIVERSITY K G R T XfISI,O\l' ATE\!' Y O K K ,;:j, 1 ' .Y. \I-ILLIAM C. ~ZELCCH RECEIVED APRIL 3, 1936
(.IV) A NEW SYNTHETIC ANALGESIC
!~
Sir: COOCHi COOH COOH Efforts begun here some years ago had as their glutarate (III)a yielded benzyl 6-methyl-7-carbo- most stiiiiulating result the recognition of phenmethoxyheptanoate, b.p. 136-157" (0.23 mm.), ethyl as a potentiating group when substituted for v Z 5 D 1.4886,d2j41.046, [ c v ] ' ~ D f4.6" (c 6.7, pyridine); methyl on the nitrogen atom of certain analgesic calcd. for CliH,,OI: C, GO.(;; H,8.2; MD, SO.:'; compounds. Thus X-phenethylnormorphine' is fouiid: C , Kl.0; H, i . 9 ; M D S0.3. Catalytic hydro- eight times as putent as morphine though also genolysis over jr;. Pd,iC gal-e 6-methyl-/-carbo- inuch inore toxic.? This is a somewhat surprising niethoxyheptanoic acid, b .p. 141-1 43' (0.3mm.) ,n 2 5 ~ finding since heretofore all the evidence has sup1.4444, d"4 1.045,[ a I z 7f5.5" ~ (c 6.4,pyridine); ported the belief that the methyl radical is optimal calcd. for ClaHls04: C, 39.4; H, 9.0; XD 51.6; for the production of significant analgesic a c t i ~ n . ~ found: C, 39.9; H, S.0; MD 31.5. Saponification In fact diminished activity or even antagonism to yielded X-methyloctariedioic acid (II'), r1i.p. 07-9So, analgesia have been by far the iiiore frequent re[ o ] ? * D i- (5.9' (c 3.1, pyridine) ; calcd. for C~H1604: sults of modification of the methyl group on the C, 3 7 . 3 ; H, 8.6; found: C, 37.9; H , 8.3.The con- tertiary nitrogen of analgesic s ~ b s t a n c e s . ~How,~ figuration of I11 has been elucidated5; consequently ever, while S-substituents which on normorphine that of IT' is now established. produce antagonism frequently fail t o produce I t was found (Fig. I) that IT' and IIa form a. con- similar results when substituted for the K-methyl of tinuous series of solid solutions, while 11: and IIb vther types of analgesic agent, our studies arid those are immiscible in the solid state. These results of Perrine and Eddyi suggest t h a t the beneficial permit the conclusion6 t h a t 11: and Ila, and there- effect of phenethyl is more generally obtained. We 7 have found a,lsn t h a t further substitution, now on the aromatic ring of the phenethyl radical, produces still further benefits. ;in extensive program based o i l these findings has led to selcctioii of ethyl 1-(4~rniiriopheneth~-lj-4-phe1~ylisonipecotate (I) most promising candidate for further study.
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n-t.yo (+)-3-iiietliq-loctsnedioic acid. 1;ig. l,-MeItiiig poiiit-coinposition diagrams for the >)-stems ( !-3-meth~-loctariedioic acid-( )-3-thioloctanedioic acid (circles, dashed line), and (t)-3-1netliylocta1iedioic acid-( - )-a-thioloctaxledioic acid (triangles, solid line).
+
+
(4) R. P Linstead, J . C. L u n t a n d €3. C. 1- TVeedon. J Chrir!. 3333 (1960) ( 9 ) S S t a l l b e r g - s t e n h ~ ~ e.n , (101Rj.
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as
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LThen 9-aniinophenethyl chloride hydrochloride6 was allowed to react with ethyl 4-phenylisonipecotate "carbonate"7 in alcohol with added sodium bicarbonate there was formed a base which could be precipitated from ether solution as a dihydrochlo$ 1 ) R . L. Clark, el al , THISJ O V R K A I , , 75, 4!10? (1953). ( 2 ) T v e are indebted t o Dr C . A . IVinter f o r this o h s c r v a t i o n . flcnilh (:3) 0. J . Braenden, S . B Eddy and H. I-Ialbach, A i ~ i l LVovlii Oii: , 13, R:37 ( 1 9 2 5 ) ; A. Rurger. l l e d i ' i n l l Cheiniilry, VoI I , p . 17'1 (19.51); 0. Schaumann, .lrcIz p x b Pnlizol Phnrmnhol , 196, 109 (I$i4(11 See. however, R . X Millar a n d R. P. Stephenson, J3,.ll J . P h n v r n n c d Ciierrrolherapy, 11, 27 ( 1 9 3 ) w h i c h appeared xfter subrnissiov of thls
communication. ( 4 ) 6 .U n n a . J P h o ~ w ~ ~ c IoLl p. . Thri rip , 79, 27 (1943); A. 1'. Green, G E;. Ruffell and E. K'aIton, J Pitsii m i i c y owii P h a i n r i r c o l . . 6 , 390 (19.74) Sohc>tka, f b r , 62, 2 l ! J l I 1
2343
BOOKREVIEWS
May 20, 1956
ride. Purification by crystallization from niethanol-ether and then methanol gave material of m.p. 280-287” dec. Anal. Calcd. for C~zH2802Nz.2HCl: C, 62.12; H, 7.11; N, 6.39. Found. C, 61.97; H, 6.97; N, 6.71. Determination of pKa values in aqueous ethanol gave values of 3.7 and 7.5. Absorption measurements oin the ultraviolet a t pH 7 gave 2330A., E% 293; 289OA., E 7 , 34.5. Treatment of the free base (I, m.p. 53”) with acetic anhydride-acetic acid a t 90-100” and conversion t o the salt gave the Nacetyl monohydrochloride, m.p. 264-265” ; Anal. Calcd. for C24H3003N2.HC1:C, 66.88; H, 7 . 2 5 ; N, 6.50. Found: C, 67.16; H, 7.57; N, 6.39. Ethyl 1- (4-aminophenethyl)-4-phenylisonipecotate is a potent analgesic with high oral activity and relatively mild side reactions. Mild anti-acetylcholine and antihistaminic activity has been observed in both isolated organs and in intact animals. I n animals, the compound approaches morphine in analgesic potency and is several times more active than meperidine (ethyl l-methyl-4phenylisonipecotate) . Unlike meperidine, it is a good antitussive agent against experimental cough in guinea pigs and dogs. The side reactions in animals such as general de-
pression and sedation, depression of respiration and lowering of blood pressure, are considerably milder than those produced by morphine, and somewhat milder than those of meperidine. The new compound does not produce nausea, vomiting or constipation in animals. The acute oral and subcutaneous toxicity of the compound, as measured in mice, is of the same order as meperidine, but it is somewhat more toxic on intravenous administration. After subcutaneous injection into rats, a bound form, probably the N-acetyl derivative, was found in the tissues. The synthetic N-acetyl derivative has analgesic activity of the same order as the parent compound when tested in rats. Ethyl 1-(4-aminophenethyl)-4-phenylisonipecotate has been given the generic name anileridine. Preliminary results in man by oral and parenteral administration indicate an analgesic potency a t least twice that of meperidine. J O H N ~YEIJLARD CONTRIBETION FROM THE PETERD . ORAHOVATS ASD DOHME ALAXP. SULLIVAN, JR. MERCKSHARP RESEARCH LABORATORIES GEORGEPURDCE MERCKAXD Co., INC. FREDERICK K . HEATH KARLPFISTER, ~ R D RAHKAY, N. J. RECEIVED -%PRIL 5, 1056
BOOK REVIEWS An Introduction to Paper Electrophoresis and Related Methods. By MICHAELLEDERER,Institut du Radium Paris. Elsevier Publishing Company, 2330 Holcombe Boulevard, Houston, Texas. 1955. xii 206 pp. 16 X 23.5 cm. Price, $7.75. For those investigators who are not familiar with the field of electrophoresis and who are interested in applying the new and simple procedures on filter paper t o a specialized problem, this is a very welcome book. There are certainly many people in such a category because of the widespread applications ranging from the separation of isotopes t o the classification of blood proteins in human disease. This broad range of subjects is well covered in Doctor Lederer’s book and it is apparent t h a t he has had a long and diversified experience in this field. The book is written in a clear and simple manner supplemented by many illustrations and is easily read by the novice. I n addition, there is sufficient theoretical background along with a very complete and extensive bibliography to make it a useful volume t o experienced workers. One might wish that the author had been more critical of the various procedures for carrying out paper electrophoresis, particularly in view of his own experience, so t h a t the reader could better evaluate the method t h a t he should apply. This is a most difficult problem because all the techniques of paper electrophoresis work fairly well and no one unbiased observer has had sufficient experience with the whole group t o really classify them. A relatively small portion of the book is devoted to electrophoresis in other supporting media besides filter paper. T h e section on gels is quite complete h u t this whole subject is developing so rapidly a t the present time t h a t any attempt a t a review is almost immediately outdated. Despite these natural limitations, this work should be a valuable addition t o a n y laboratory applying or interested in applying electrophoretic methods. ?“E ROCKEFELLER INSTITUTE FOR AIEDICAI, RESEARCH WITHSTREETAND YORKA L ~ E S U L I I H N R Y G. Z ( U S K E I . XElV Y O R K 21, x E \ V YORE;
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B. Basic Processes of Gaseous Electronics. BY LEONARD LOEB. Cniversity of California Press, Berkeley 4, California. 1955. xvii 1012 pp. 16 X 24.5 cm. Price, 813.50 I n the first edition of his classic “Conduction of Electricity through Gases” (1903), J. J. Thomson wrote: LVith the discovery and study of Cathode rays, Kiintgen rays and Radio-activity a new era has begun in Phl-sics, in which the electrical properties of gases have played and will play a most important part. . , Searly a half-century later, however. II. D. Sinyth (writing in the American Scientist in 19471, after affirming the origin of many great discoveries of the modern period of physics in studies of dischaiges in gases, remarks that: the innumerable series [of experiments] on the discharge of electricity through gases . been going on now for nearly a hundred >-ears,has us the fluorescent lamp and other devices, but has still not told us what happens in a n electrical discharge in gases. The truth of this melancholy observation is amply attested in L. B. Loeb’s most recent book, a dishearteningly massive tome which may quickly give mental indigestion to any but the most expert and tenacious render. Although great progress has certainly been achieved-thus, contemporary techniques in electronics have, just in the past decade. virtually revolutionized the experimental approach, :tnd greatly enhanced the accessibility of many loug-studied phenomena-the analysis of numerous important aspects of gaseous conduction still ends in 3 bewildering morass of complexity. “Gaseous electronics,” incidentally, is the a p t designation used t o replace “electrical discharges in gases” in this triumphant modern era. The plan of the book is separately t o treat various basic pheriornena which are important in gaseous conduction, such a s drift velocity, diffusion a n d recombination of charge carriers. arid olily t1ic.11t o dcal wit11 tlic properties uf discliarge.. tiieniwl\.c~. ‘l‘lic (Iivi\ioii uf
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