A Key to PHARMACEUTICAL AND MEDICINAL ... - ACS Publications

The Literature of Analgesics LEO J. STEVENS

Downloaded by 5.62.155.77 on September 4, 2016 | http://pubs.acs.org Publication Date: January 1, 1956 | doi: 10.1021/ba-1956-0016.ch001

Smith, Kline & French Laboratories, Philadelphia, Pa.

Relief of pain has been one of the oldest and most widely studied problems of medical art and related sciences—pertinent documentation is found even in papyri of the ancients. The historical development of the literature of analgesics is set forth; specialized analgesic literature and a number of the more important, recent reviews on the subject are mentioned. Some recent advances are briefly reviewed with special em phasis given to the chemical aspects, to the bioaction, and in some cases, to the clinical experiences made with selected drugs.

In modern times new anesthetic agents, analgesics, hypnotics, nerve sections, and laboratory studies on the physiology and psychology of pain have gone a long w a y toward making the relief of pain a widely studied and thoroughly investigated scientific problem. The word " a n a l g e s i a " entered the medical, chemical, and related literature w i t h the discovery and isolation of morphine by Serturner i n 1803 (63, 6U). It is by definition the absence of sensibility to pain which is physiologically due to a r a i s i n g of the pain threshold. Anesthesia—pain relief by loss of feeling—was introduced into the medical literature w i t h the discovery of ether by S i r Humphrey Davy, C. W . Long, W m . Morton (35), and others (8, 35), i n the early part of the 19th century. The use of cocaine by the Viennese opthalmologist, Roller, i n 1884, opened new vistas i n the field of pain relief (U6-J+8). Since then the synthesis pharmacology, and clinical use of local anesthetics have occupied a large portion of the literature. The Oldest Literature of Pain Relief

The Old Testament (52) and the Talmud contain reference to the ancient practice of inducing sleep by artificial means when otherwise sleep would not come because of pain. I n Homer's Odyssey (9th century, B.C.) we find that Helen of T r o y put some drug into wine to " l u l l a l l pains and anger and b r i n g f orgetf ulness to every sorrow" (35, 41). This is certainly one of the oldest references to the use of an analgesic, although its nature is not known. Perhaps i t was opium. The collection of opium itself was first described by Diagoras of Melos around 380 B . C . and by Theophrastus about the t h i r d century, B . C . Herodotus, a Greek historian, knew about a Scythian custom " o f inhaling the fumes of hemp" to overcome pain and induce sleep, another example of a very old use of a narcotic—Indian hemp, now known as hashish, is illegally used as a smoke f o r its intoxicating effects. Dioscorides, a physician i n Greece who lived i n the middle of the first century, mentions the use of mandragora, an herb of the nightshade family, as a pain-killing agent; the root of the plant was boiled i n wine and administered p r i o r to surgical operations (15, 35). One of the first references to analgesic pills was made by Celsus d u r i n g the first century, A . D . , i n his " D e M e d i c i n a " (13, 55, 66). In the literature of medieval times, the term " l a u d a n u m " is ascribed to the physician and alchemist Paracelsus (14931541). A n o i l for surgical anesthesia was described by Hugo de Lucca as early as the 13th century. It contained opium, the juices of Hyoscyamus, hemlock, and mandragora. Giambattista P o r t a , a surgeon of Naples, used a n essence made of Hyoscyamus, nightshade, poppy, and belladonna (37). Shakespeare, who was f a m i l i a r w i t h the narcotic effects of various drugs, i n " C y m b e l i n e " makes the court physician, Cornelius, prescribe a drug w h i c h : 3

A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

A D V A N C E S IN

4

CHEMISTRY SERIES

W i l l stupefy and dull the sense awhile, but there is No danger i n what show of death it makes, More than the locking up the spirits a time, To be more fresh, reviving. (65) A t present the literature of pain relief, under its various headings, has grown tremendously (Tables I and II). In fact, information on these subjects is not limited to a specialized literature of pain relief (except for limited numbers of more recent publications dealing exclusively w i t h this problem) but one may say that the literature of analgesics is now p a r t of the chemical, physiological, pharmacological, and clinical literature, and chemists who want to obtain information on analgesics must use the same methods that have to be applied i n other literature searches.


Table I.

Modern Journals Devoted to Problems of Anesthesia and

Name Anesthesiology Anaesthesia

of

Anesthésie

analgésie

Acta

et

Journal

Anaesthesiologica

British Journal of Current Researches and Analgesia Der Anaesthesist

Belgica Anaesthesia in Anesthesia

Quarterly Apparently discontinued i n 1944

Abstracts, Special Texts, and Review Articles

United Nations Bulletin of Narcotics A l s o see (6, 36, 39, 40, U9, 50, 57) a

3 times a year

Georg Thieme, L e i p z i g

Name Anesthesia Abstracts Chemical Abstracts Chemisches Zentralblatt Biological Abstracts Excerpta Medica Current List of Medical Literature Quarterly Cumulative Index Medicus Quarterly Reviews Annals of the New York Academy of Sciences Vol. 51 : "Newer Synthetic Analgesics"

Quarterly Bimonthly Bimonthly

Osterreichische Gesellschaft f u r Anaesthesiologie, V i e n n a ; S p r i n g e r Verlag, Berlin Società I t a l i a n a d i Anestesiologica A s s o c i a c i o n A r g e n t i n a de Anestesia, Buenos A i r e s

Minerva Anestesiologica Revistw argentina de anestesia y analgesia Revista brasileira de anestesiologia Schmerz Narkose-Anaesthesie

Table II.

Society, Author, Publisher The A m e r i c a n Society of Anesthesiologists A s s o c i a t i o n of Anaesthetists of G r e a t B r i t a i n and Ireland Société Française d'Anesthésie et d'Analgésie Société Belge de C h i r u r g i e , Bruxelles ( p a r t of A c t a C h i r u r g i c a B e l g i c a ) J o h n Sherratt & Son, A l t r i n c h a m , E n g l a n d I n t e r n a t i o n a l A n e s t h e s i a Research Society

Analgesia

Published Bimonthly Quarterly

Society,

0

Publisher

B u r g e r s P u b l i s h i n g Co., M i n n e a p o l i s A M E R I C A N C H E M I C A L SOCIETY

Akademie^Verlag G.m.b.H.

W i l l i a m s & W i l k i n s Co. A r m e d Forces M e d i c a l L i b r a r y American Medical Association C h e m i c a l Society, L o n d o n , 1948, 1951 lished November 1948. N e w Y o r k A c a d e m y of Sciences, Conference on N e w e r S y n t h e t i c Analgesics, M a y 1948 p u b -

f o r a d d i t i o n a l review

articles.

Some Recent Developments Revealed in the Literature of Analgesics

In the field of synthetic analgesics, the prime requirement has always been to find potent, nonhabit-forming drugs of low toxicity. This task has fallen short of the goal, but i t has made significant advances. W i t h the possible exception of the salicylates, antipyrine, pyramidon, and aspirin, a l l introduced i n the late 1800's, and metopon introduced i n 1936, no true synthetic analgesic was reported before Eisleb and Schaumann developed demerol (l-methyl-4-phenyl-piperidine-4-carboxylic acid ethyl ester hydrochloride) (19). Schaumann postulated that demerol, i n its structure as a 4-phenylpiperidine deriva tive, constitutes a part of the morphine molecule (56). Well-known i n various coun tries under different names, its nonproprietary name is Meperidine. Demerol is used clinically i n obstetrical and other analgesia i n doses of 50 to 150 mg., orally or intramuscularly. Unfortunately, it is habit-forming U , 38). Structures, Syntheses, and Analgesic Activities. Eisleb condensed AT-bis-(p chloroethyl)-methylamine w i t h benzyl cyanide; the piperidinonitrile thus obtained was hydrolyzed and the carboxylic acid formed esterified w i t h ethyl alcohol ; the hy drochloric salt of this ester is demerol (17, 18).


STEVENS—THE LITERATURE OF ANALGESICS /CHaCHaW CH N

C H e

H CHCN+CH CH - C H ti.tm I JT CI NaNHj 3

r

• OT CHWai N(CH ) 2

3

3 2

2

n

CH,

\

_

6H CH(GH )N(CH3)

/

8

3

CH(CH )CH N(CH )

8

CaHeMgW

3

e

3

8

C H MgCl a

8

Ok \

/

CH CH(CH )N(CH ) a

3

3

2

The synthesis takes its start from diphenylacetonitrile, which is condensed with 2-chlorodimethylaminopropane under the influence of sodamide. A s this chloramine A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

A D V A N C E S IN CHEMISTRY SERIES

6

undergoes immediate cyclization to an ethyleneimine under these conditions, and the latter may react w i t h diphenylacetonitrile i n two ways, depending upon the cleavage of its three-membered r i n g , two isomeric nitriles are formed. A f t e r separation of the isomer, one nitrile yields amidon on treatment w i t h a G r i g n a r d compound, while the other results i n isoamidon upon similar treatment (60). The structural rela tionship of amidon to morphine (7) may be seen i n the structural formulas.


Morphine Fragment

Amidon

The work of Grewe (30, 31), of the U n i v e r s i t y of K i e l , has contributed greatly to the old problems of the morphine synthesis and structure. Grewe found a rela tively simple way to synthesize a basic structure analogous to morphine which he called ΛΤ-methylmorphinan ; their interrelationship (33) may be seen i n the struc t u r a l formulas (34).

Morphine

iV-Methylmorphinan

The Grewe synthesis was carried out by condensing cyanoacetic ester and cyclohexanone-carboxylic ethyl ester i n the presence of ammonium acetate, glacial acetic acid, and benzene. The condensation product was hydrolyzed w i t h concentrated hydrochloric acid and the unsaturated dicarboxylic acid formed was heated w i t h ammonium carbonate to form 1,3-dihydroxytetrahydroisoquinoline. Through chlorination w i t h phosphorus oxychloride, the two hydroxy groups were removed and the dichloro compound formed was dechlorinated to yield 5,6,7,8-tetrahydroisoquinoline. The latter was methylated on the nitrogen and the reaction product i n teracted with benzylmagnesium chloride. Hydrogénation of the hexahydroisoquinoline derivative formed yielded 2-methyl-l-benzyl-l,2,3,4,5,6,7,8-octahydroisoquinoline which was cyclized to ΛΓ-methylmorphinan using 5 0 % phosphoric acid (30, 31). A n isomeric iV-methylisomorphinan was prepared by Gates i n a different w a y (28). ΛΓ-methylmorphinan has analgesic effects ; however, its 3-hydroxy derivative was found to have potent analgesic properties. It seems that a tertiary nitrogen and the hydroxy group i n the 3 position favor analgesic activity; the oxygen bridge of morphine does not seem to be essential (30, 31). Schnider and Grussner (59), of Hoffmann-LaRoche, synthesized 3-hydroxy-A/-methylmorphinan i n a manner similar to the Grewe synthesis. Its hydrobromide has been marketed as Dromoran and is used as an analgesic i n doses of 2.5 to 5 mg., subcutaneously. Dromoran's analgesic effects i n humans are somewhat better than those of morphine; the average duration of analgesia produced by Dromoran is somewhat longer than that produced by similar doses of morphine sulfate (45). It also causes habituation (22). The synthesis of morphine has been the dream of organic chemists for a long time. It was finally accomplished i n 1952 by M a r s h a l l Gates and G i l g Tschudi (27) of the U n i v e r s i t y of Rochester, although parts of this total synthesis had been re ported previously (23-25, 28, 29). The i n i t i a l material of the total synthesis was 2,6-dihydroxynaphthalene from which, i n a complicated 10-step synthesis, 5,6-dimethoxy-4-cyanomethyl-l,2-naphthoquinone was prepared (23-25, 28, 29). A complete presentation of these steps was given by M a r s h a l l Gates before the 13th National Organic Chemistry Sym posium, A M E R I C A N C H E M I C A L SOCIETY, June 15, 1953, at A n n A r b o r , M i c h , (see page 8 ) . A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

S T E V E N S — T H E LITERATURE OF ANALGESICS

7

CI

Dechlorination

t

[

(1) flUI". (2) C H CH MgW

|j

e

e

2

$,6, 7,8-tetrahydroisoquinoline GH C H


2

00

e

e

, C H s

2e e c

Hydroge- y nation

H

• 3 Œ

Ring c l o s u r e y cone.H P0 ,150° 3

4

2-Methyl-l-benzyl-l,2,3,U,5, 6,7,8-octahydroisoquinoline N-CH

3

N-Methylmorphinan

The naphthoquinone was subjected to the diene reaction w i t h butadiene to form 3,4-dimethoxy-9,10-dioxo-13-cyanomethyl-5,8,9,10,13,14-hexahydrophenanthrene. This was hydrogenated over copper-chromium oxide to give a ketolactam, which on Wolff-Kishner reduction and remethylation yielded another lactam. Reduction of the lactam w i t h lithium aluminum hydride, followed by methylation w i t h formalde hyde-formic acid, gave dZ-/3-A -dihydrodesoxycodeine methyl ether (26). The racemate was resolved w i t h L ( + )-dibenzoyltartaric acid; the d-p-A -dihydrodesoxycodeine methyl ether, on hydration w i t h dilute sulfuric acid, yielded β-dihydrothebainol methyl ether. On vigorous treatment w i t h potassium hydroxide i n diethylene glycol, demethylation occurred to yield /3-dihydrothebainol. Oxidation of /3-dihydrothebaino by a potassium ieri-butoxide-benzophenone system gave /3-dihydrothebainone. Bromination of this w i t h 2 moles of bromine, followed by treatment w i t h 2,4-dinitrophenylhydrazine, yielded a dinitrophenylhydrazone. Cleavage of the hydrazone w i t h acetone and acid produced 1-bromothebainone. This substance was converted by catalytic hydrogénation to dihydrothebainone hydrate. Bromination of the latter w i t h 3 moles of bromine, followed by treatment w i t h dinitrophenylhydrazine, pro duced 1-bromocodeinone dinitrophenylhydrazone. On cleavage of this hydrazone, 1bromocodeinone resulted. 1-Bromocodeinone was converted by lithium aluminum hydride i n tetrahydrofuran solution into codeine. Codeine was demethylated to morphine, using pyridine hydrochloride as described by Rapoport and his coworkers (53, 54). Thus, 146 years after the discovery of morphine by Serturner, the first total synthesis of morphine was carried out. 6

e

Miscellaneous Analgesics. Aralkylamines have received attention as potential analgesic agents; of these, some sympathomimetic amines—e.g., epinephrine and ephedrine—have been reported to exhibit a pain-threshold-elevating action (21, 51, 58). More recently, a series of aminophthalidylalkanes, of which 1-amino-l-phthalidylpropane was the most active (32, 66), was found to exhibit analgesic activity (20, 67). Aralkylamines and aminophthalidylalkanes have not achieved any clinical importance. A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.


A D V A N C E S IN CHEMISTRY SERIES


S T E V E N S — T H E LITERATURE OF ANALGESICS

9

[-CH-CH -CH 2

3


A n interesting structure and rather unorthodox for an analgesic is 1,4-bisdiethylaminomethylnaphthalene hydrochloride. Reported by Badger and coworkers, i t i s claimed to have the same activity as demerol (3).

A series of potent analgesics, some of them as active as morphine i n the r a t , has been discovered by B r i t i s h workers of the Wellcome Research Laboratories ; they a r e 3-tert-amino-l,l-(2'-thienyl)-l-butenes, where R = M e , E t ; N R = N < [ C H ] > C H , or N < [ C H ] > C H , or N < [ C H ] > 0 (1). 2

2

2

4

2

2

2

3

4

B u c h i and coworkers (11) recently prepared several series of 3,5-dioxopyrazolidine derivatives. Some of them showed, i n animal tests, analgesic effects on the order of pyramidon—e.g., l-phenyl-3,5-dioxopyrazolidine.

Of several attempts to use the concept of quaternary carbon and tertiary nitrogen i n /3-relationship as a feature of analgesic potency, the interesting compound of Schwartzman (61, 62) should be mentioned. According to E d d y (16), this material, a l,l'-spirocyclohexyl-(?)-amino-3'-dimethylaminoindane, is stable and nearly twice as active as codeine (5, 16).

IT

N ( G H

3

) ,

F i n a l l y , l,4-di-(2-pyrazyl) -piperazine, a " b i s s e d " compound w i t h a n allegedly high analgesic potency, should be mentioned (14).

Acknowledgment

The author would like to acknowledge the valuable a i d and suggestions offered by Glenn E . U l l y o t and James F . K e r w i n , among others. A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.


10

ADVANCES IN CHEMISTRY SERIES

Bibliography (1) Adamson, D. W., and Green, A. F., Nature (London), 165, 122 (1950). (2) Avison, A. W. D., and Morrison, A. L., J. Chem. Soc. (London), 1950, pp. 1471, 1474, 1478, 1510. (3) Badger, G. M., Cook, J. W., Donald, G. M. S., Graham, J. D. P., and Walker, T., Nature, 162, 21 (1948). (4) Batterman, R. C., and Himmelsbach, C. K., J. Am. Med. Assoc., 122, 222 (1943). (5) Beckett, A. H., J. Pharm. and Pharmacol., 4, 425-47 (1952). (6) Bentley, Κ. W., "The Chemistry of the Morphine Alkaloids," Clarendon Press, Oxford, 1954. (7) Bergel, F., and Morrison, A. L., Quart. Revs. (London), 2, 349-82, (1948). (8) Bigelow, H. J., Boston Med. Surg. J., Nov. 18, 1846. (9) Bockmühl, M. and Erhardt, G., Ann., 561, 63 (1949). (10) British Intelligence Objectives Subcommittee, BIOS Rept. 116 (1945). (11) Büchi, J., Ammann, J., Lieberken, R., and Eichenberger, E., Helv. Chim. Acta, 36, 75-86 (1953). (12) Burger, Α., General Anesthetics, Local Anesthetics and Analgesics, "Medicinal Chemistry," Vol. I, p. 181, Interscience, New York, 1951. (13) Celsus, "De Medicina." (14) Denton, J. J., and Howard, K. L. (to American Cyanamid Co.), U. S. Patent 2,459,367 (Jan. 18, 1949). (15) Dioscorides, "De Medicina Materia Librum," Vol. 4, p. 76. (16) Eddy, N. B., J. Am. Pharm. Assoc., 39, 245-50 (1950). (17) Eisleb, O. (to Winthrop Chemical Co.), Ger. Patent 679,281, U. S. Patent 2,167,351 (July 1939); Ber., 74, 1433 (1941). (18) Eisleb, O., Med. u. Chem. Abhandl med. chem. Forschungestätten I. G. Fa benind., 4, 213 (1942). (19) Eisleb, O., and Schaumann, O., Deut. med. Wochschr., 65, 967 (1939). (20) Fellows, E. J., and Cunningham, R. W., Federation Proc., 4, 119 (1945). (21) Fellows, E. J., and Ullyot, G. E., Analgesic Aralkylamines, "Medicinal Chem istry," C. M. Suter, ed., Wiley, New York, 1951. (22) Fraser, H. F., and Isbell, H., Pharmacol. Exptl. Therap., 100, 128-35 (1950). (23) Gates, M., J. Am. Chem. Soc., 72, 228-34 (1950). (24) Gates, M., and Newhall, W. F., Experientia, 5, 285-6 (1949). (25) Gates, M., and Newhall, W. F., J. Am. Chem. Soc., 70, 2261-3 (1948). (26) Gates, M., and Tschudi, G., Ibid., 72, 4839-40 (1950). (27) Ibid., 74, 1109-10 (1952). (28) Gates, M., Woodward, R. B., Newhall, W. F., and Künzle, R., Ibid., 72, 1141-6 (1950). (29) Greenberg, L. Α., "Antipyrine, a Critical Bibliographic Review," Monographs of Institute for Study of Analgesic and Sedative Drugs, Hillhouse Press, New Haven, Conn., 1950. (30) Grewe, R., and Mondon, Α., Chem. Ber., 81, 279-86 (1948). (31) Grewe, R., Mondon, Α., and Nolte, E., Angew. Chem., 61, 442 (1949). (32) Gross, Martin, "Acetanilid, a Critical Bibliographic Review," Monographs of Institute for Study of Analgesic and Sedative Drugs, Hillhouse Press, New Haven, Conn., 1946. (33) Gross, Martin, and Greenberg, L. Α., "The Salicylates," Hillhouse Press, New Haven, Conn., 1948. (34) Gulland, and Robinson, Mem. Proc. Manchester Lit. & Phil. Soc., 69, 79 (1924-25). (35) Gwathmey, J. T., "Anesthesia," 1st ed., Appleton, New York, 1914. (36) Hewer, C. L., "Recent Advances in Anaesthesia and Analgesia," 7th ed., Churchill, London, 1952. (37) Hewitt, F. W., "Anesthetics and Their Administration," 4th ed., p. 3, Macmillan, London, 1912. (38) Himmelbach, C. K., J. Pharmacol. Exptl. Therap., 75, 64-7 (1942). (39) Holmes, H. L., "The Morphine Alkaloids. The Alkaloids, Chemistry and Physi ology," ed. by Holmes and Manske, Academic Press, New York, 1950-52. (40) Holmes, H. L., and Stock, G., "The Morphine Alkaloids," Academic Press, New York, 1950-52. (41) Homer, "Odyssey," Vol. 4, p. 220. (42) Isbell, H., J. Pharmacol. Exptl. Therap., 97, 182-9 (1949). (43) Kaegi, H., and Miescher, K., Helv. Chim. Acta, 32, 2489 (1949); Swiss Patent 218,517 (1949). (44) Kaufmann, H. P., "Arzneimittel-Synthese," p. 99, Springer Verlag, Berlin, 1953. A Key to PHARMACEUTICAL AND MEDICINAL CHEMISTRY LITERATURE Advances in Chemistry; American Chemical Society: Washington, DC, 1956.

STEVENS—THE LITERATURE OF ANALGESICS


(45) (46) (47) (48) (49)

11

Keutmann, E., and Foldes, F. F., New England J. Med., 244, 286-8 (1951). Köller, C., J. Am. Med. Assoc., 117, 1284 (1941). Röller, C., Wien. med. Wochschr., 1884. Ibid., 85, 17 (1935). Krueger, Hugo, Eddy, Ν. B., and Sumwalt, M., "Pharmacology of the Opium Alkaloids," Parts 1 and 2, Suppl. 165 to Public Health Reports, U. S. Public Health Service, 1941-43. (50) Lee, John, "Partial Structures Related to Morphine," in Medicinal Chemistry, ed. by C. M. Suter, Wiley, New York, 1951. (51) Maxwell, Chinese Med. J., 42, 694 (1928). (52) Old Testament, Holy Bible, Genesis ii, 21. (53) Rapoport, H., and Bonner, R., J. Am. Chem. Soc., 73, 5485 (1951). (54) Rapoport, H., Lowell, C. H., and Tolbert, Β. M. Ibid., 73, 5900 (1951). (55) Robinson, "Victory over Pain," Schumann, New York. (56) Schaumann, O., Arch. exptl. Pathol. Pharmakol., 196, 109-36 (1940). (57) Ibid., 216, 48-77 (1952). (58) Schmidt, Med. Klin. (Munich), 8, 1485 (1912). (59) Schnider, O., and Grüssner, Α., Helv. Chim. Acta, 32, 821-8 (1949); Swiss Patents 252,755, 254,106 (1949). (60) Schultz, E. M., Robb, C. M., and Sprague, J. M., J. Am. Chem. Soc., 69, 188-9 (1947). (61) Schwartzman, L. H., J. Org. Chem., 15, 517-24 (1950). (62) Schwartzman, L. H., and Forrest-Woods, G., Ibid., 17, 492-504 (1952). (63) Sertürner, F. W. Α., Ann. chim. et phys., 5 (2), 21 (1817). (64) Sertürner, F. W. Α., J. Pharmaz. Aerzte, Apotheker u. Chemiker, 14, 47 (1806). (65) Shakespeare, Wm., "Cymbeline," Act I, Scene IV., line 34. (66) Tainter, M. L., Ann. Ν. Y. Acad. Sci., 51, 3-11 (1948). (67) Ullyot, G., Stehle, J., Zirkle, C., Shriner, C., and Wolf, F. J., J. Org. Chem., 10, 429 (1945). (68) U. S. Dept. Commerce, Office of Publication Board, Rept. PB-981, 96-A (1945). (69) Ziernig, Α., and Lee, J., J. Org. Chem., 12, 911-14 (1947).

RECEIVED September

13, 1954.


A Key to PHARMACEUTICAL AND MEDICINAL ... - ACS Publications

Recommend Documents