SUBDIVIDISG PHARMACEUTICAL PRODUCTS BY HANDIN 1893
AT
PLANTOF MERCK& COMPANY
Contributions of Medicinal Chemistry An Outline of Early and Recent Accomplishments and Objectives of the Future C. R. ADDINALL had been unconsciously applied for the control HROUGH the Dark Ages, chemistry was kept alive by &Ier& & company, I ~ ~ . of , the infective organisms of various diseases in the traditional usage of cinchona, ipecac, merthe search of the alchemists Rahway, N. J. wry, antimony, and other products was proved for the philosopher’s stone and the elixir of and recognized, together with the limitations life, a dual aim that faintly foreshadowed the imposed by the crude nature of the drugs. The rapid developfundamental concepts which underlie the medicinal chemistry ment of organic chemistry in the hands of Liebig, Kekul6, of today. The practitioners of this ancient art ,msociated Baeyer, and their schools furnished chemical methods for the themselves with the apothecaries of the times who dispensed identification of the active principles of these drugs, and for the various medicines, charms, and poisons in popular vogue. the development of the growing list of synthetic compounds Paracelsus, one of the fathers of chemistry and a reformer in of therapeutic value discovered as a result of deliberate rethe development of internal medicine, reoriented the aims of search. the practitioners of these arts when he declared: “Alchemy is It has been said, with a great deal of truth, that modern not for making gold and silver; it is for making the supreme civilization with all its use of the inventions and discoveries sciences and to direct them against disease and for human of the physical sciences would be impossible were it not for the welfare.’, His suggestions slowly came to fruition (2nd chemprotection which the science of medicine affords. Only the istry gradually developed hand in hand with pharmacy until resources and organization available through modern medical the beginning of the nineteenth century. science can protect mankind from the increased danger of The premature discoveries of bacteria by Leeuwenhoek, epidemic disease due to the spread of up-to-date transand of vaccination by Jenner, had come and gone when, in portation facilities, and behind this medical science must 1820, Pelletier and Caventou isolated quinine. Within a be the support of an efficient national chemical industry. few years the preparation of the alkaloids from cinchona From colonial days onward, the rapidly expanding bark, the seeds of nux vomica, coca leaves, and the gum chemical concerns of the nation have contributed to its of the opium poppy became commercial practice in Europe physical well-being in times of peace and of war. The infant and in the United States. The time was then ripe for the dechemical industries founded around Boston, New York, and velopment of those pharmaceutical enterprises from whose Philadelphia and in Delaware, t o supply the needs of the roots have sprung the nationally known concerns now engaged colonies for salt, glass, potash, fertilizers, lime, iron, naval in the manufacture of medicinal chemicals. stores, gunpowder, and medicinals, grew with the expansion For thousands of years drugs had come into use through and development of the country. The founders and descendempirical observation, but gradually, about the middle of the ants of these old-established firms realized the necessity for conlast century, changes in therapeutic methods, based on the tinual improvement of their processes and established and new knowledge of the causes of disease, began to take place. Through the work of Pasteur, Koch, Lister, and their suemaintained research organizations. These chemical concerns increased in number and expanded their business, so that cessors it became apparent that infections were due to the inthrough their efforts and facilities, the United States had made vasion of the body by living organisms, and the preventive definite and striking advances in the manufacture of chemimedicine born of this concept gave a new direction to the therapeutics of infectious disease. The specific action that cals even before the World War. This was particularly true
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A Painting by Peter Paul Rabens (1577-1640)
Paracelsus
Theophrastus Bombast von Hohenheim (1490-1541), who gave himself the name Paracelsus, probably to indicate his superiority over Celsus, was a Swiss by birth. While primarily a medical man, Paracelsus was largely responsible for the departure from the Gelenic pharmacopeia in favor of the chemical or “spagyric” medicines, being the first to proclaim the doctrine that the life processes are chemical in nature. However, he was not a chemist, and was only slightly interested in “the beggerlie arte of Alcumystrie.” Throughout his entire life Paracelsus was a great student of all branches of natural history, as well as of the Hermetic mysteries, although something of a charlatan. He lectured at various uni\ ersities, having been one of the first (in Germany and Switzerland) to abandon Latin and to use German for his talks. For his time, he was a prolific writer. The original painting of which our illustration is a reproduction is in the Royal Art Gallery in Brussels and must have been painted by the famous Flemish painter, Rubens, not less than sixty years after Paracelsus’ death. (Alchemical and Historicsl Printtl)
Contributions of Medicinal Chemistry An Outline of Early and Recent Accomplishments and Objectives of the Future C . K. ADDINALL HHOUGII the I.)ark Ages, had been unconsciously applied for the control chemistry was kept alive by ] ~ 1 , . . ~ k company, xne., of tlie infective organisms of various diseases in the search of t.he alchemists the tradibional usage of cinchona, ipecac, merRaliway, N. J. for tlie pliilosopher’s stone and tho elixir of cory, antimomy, and other products was proved life, a dual aim that faiiitly foresiiadowed the aiid recognized, together with the limitations fundamental concepts wlrieti underlie tlie modiciiral chemistry imposed by the crudenature of t,hedrugs. Tlie rapid develop of today. The praotilioners of this ancient art associated ment of organic chemistry in tlie hands of Liebig, Kekulb, theniselves vith the apothecaries of the times who dispensed J h y e r , aiid their schools furnished chemical methods for the t,hevarious medicines, cliarnis, arid poisuns in popular vogue. identificn,tiiin of the active principles of these drugs, and for I’wacclsus, one of t,l!e fathers of chemistry and R reformer i n tlie development of the growing list of synthetic coinpounds tlre development of int,eriial medicine, reoriented the aims of of therapclltic valor discovered as a result of deliberate ret.he practitioners of these arts when lie declared: “Alctieniy is search. It has been said, witli a grent deal of truth, that modern not for making gold and silver; it is for making tlie sapreme sciences and to direct them against disease and for Iiumali civilization with all its use of the inventions and discoveries adfare.” His suggest.ions slowly came to friiit.ioii m d chemof tlie physical sciences would be impossible were it, not for the istry gradually developed !land in Iiand with piiuriiiacy until protection which the science of medicine affords. Only tlre t,lie beginning of the nineteenth century. resoiiroes and organization available through modern medical 1910premiture discoveries of Lmct,eria by I~euweniiock, science can protect mankind from the increased danger of aiid of vaccination by Jenner, had come arid golie when, in epideniic diseae due to the spread of up-to-date trans1820, Pelletier and Caventou isolated quinine. Wit.liin a portation facilities, and behind this medical science must few years the preparation of the alkaloids from cinchona be the support of an efficient national cliemical industry. Prom colonial days onward, the rapidly expanding hark, the seeds of nux vomica, coca leaves, and the gum chemical concerns of tlie nation have contributed to its of theopium poppy became comniercial practice in Europe physical well-being in times of peace and of war. The infant and in the United States. The time was then ripe for the development of those pharmaceutical enterprises from whose chemical indiistries founded aroimd Boston, Xew York, and roots have sprung the nalionally known concerns now engaged Philadelphia and in Delaware, to supply tlre needs of t,he in the manufacture of medicinal chemicals. colonies for salt, lass, potash, fertilizers, lime, iron, n a d For thousands of years drugs had come into use througli stores, gunpowder, and medicinals, grew with the expansion empirical observation, but gradually, ahout the middle of the and development of tile country. Tlie founders and deseondlast century, changes in therapeutic metliods, based on the antsof theseold-established firms realized the necessity for connew knowledge of the causes of disease, began to take pluce. tinual improvement of their processes and cstablislied and Through the work of Pasteur, Koch, I’ister, and their suemaintained research orgaribations. These chemical concerns cessors it hecame spparent that infectioiis vere due to the inincreased in number and espanded their business, so that vasion of the body by living organisms, and the prevent,ive throuph their t;Xurts and facilities, tlie United States had made medicine born of this concept gave a new directiun to the definite and striking advances in the manufacture of chemitherapeutics of infectious disease. The specific action that cals even before the World War. This was particularly true
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INDUSTRIAL AND ENGINEERING CHEMISTRY
Vitamins In recent years the recognition of diseases due t o the lack of substances normally present in the body has led to the need for intensive research into the constitution and possible methods for the synthesis of these potent substances. The recognition of a beriberi-like condition in his barnyard fowls by Eijkmann during the last few years of the nineteenth century, and the realization by Funk in 1911 of the cure of experimental beriberi in fowls fed with rice bran, were observations which have been followed by far-reaching advances in our knowledge of those essential dietary factors we now know as “vitamins.”
VOL. 27, NO. 5
present in the rice polish, a yield many times larger than those previously reported. The process has been developed on a factory scale up to a thousand fold concentration of the vitamin. Vitamin B concentrates are now marketed containing approximately 2000 ChaseSherman units per ounce and, therefore, six to eight times more concentrated than either wheat germ or rice polishings. The pure crystalline vitamin B1 is also commercially available. After he had worked out a successful method for the isolation of larger yields of crystalline vitamin B1, Williams was able to publish, in January of this year, an account of the sulfite cleavage of the vitamin into two recognizable products which enables him to suggest a structural formula represent-
LOCATION OF PHARMACEUTICAL MANUFACTURERS (PROPRIETARY MAXUFACTURERS I X CIRCLES) FROM THE CENSUS OF
The brilliant work of Szent-Gyorgi, Haworth, and Reichstein made possible the isolation, investigation, and synthesis of the antiscorbutic vitamin C which is now marketed in the pure form, prepared either from natural sources or synthetically, and now available for the treatment of typical scorbutic syndrome and for the purposes of investigation of obscure avitaminoses. In a recent series of lectures Szent-Gyorgi has not only pointed out that the vitamins may be useful remedies in certain diseases hitherto not found amenable to medical treatment but has suggested that protection against disease may depend on the level of the vitamin content of the organism. That such effects may be produced is arousing great interest and is leading t o a thorough investigation into the part played by vitamins in the metabolic processes of plants and animals. Of the six vitamins which are known to be separate entities, the absence of which from the diet causes some special disease or functional defect, two a t least, vitamins C and D, have been artificially prepared in a state of complete purity, and the chemical nature of another, vitamin A, has been clearly established. Recently, a method for obtaining larger yields of the crystalline antineuritic vitamin B has been worked out by Williams in the Department of Physiological Chemistry of Columbia University. The progress of isolation of the vitamin from the raw material, rice polish, was gaged a t every step by injection tests on polyneuritic rats. The method, which entails absorption on fuller’s earth, extraction with quinine sulfate, purification by extraction with barium hydroxide, and subsequent fractionation with phosphotungstic acid, gives consistent yields of antineuritic vitamin hydrochloride of approximately 5 grams per ton of rice polish. This represents a recovery of about 25 per cent of the amount
1930
ing the probable configuration of the vitamin. Thus once more, by ceaseless effort on the part of the academic investigator with the cooperation of the medicinal chemical industry, a substance has been dragged from obscurity and raised from the level of an “active principle” to the standing of a definite compound whose separate preparation will enable its action t o be individually studied and the results of its deficiency to be more clearly recognized.
Hormones The hormones, that group of relatively simple compounds produced in definite parts of the body and carried by the blood or lymph to other parts whose structures are thereby modified or regulated, have recently taken a prominent POsition among the substances of importance in medicinal chemistry. As the distinguished investigator Butenandt has so clearly stated, the chemical investigation of hormones begins with attempts to prepare the hormone under investigation in the form of a chemically pure, simple substance. The solution of this problem is bound up with the existence of a suitable starting material and of a quantitative test for the hormone, and its goal is reached when the hormone is obtained in well-formed crystals, the simple nature of which can be settled beyond doubt with the help of modern physical and chemical methods. In 1927 Aschheim and Zondek discovered that the estrusproducing hormone was excreted in the urine in mammalian pregnancy; and after it had been found that a simple benzene extract of the urine gave large amounts of the hormone in a high state of purity, investigators throughout the world succeeded in obtaining the hormone in crystalline form. Up to this time no one had any idea as to what group of organic
M A Y . 19%
INI~IJSTHI.41~ AND ENGINEERING CHEMLYTIIY
in tire field of medicinal clieniistry on account of dlie large output of quinine and opium preparations.
Present Status The high position held today by the niediciiral elieniical eornpanies among industrial organiaations is due, in large degree, to the improved ethical status of the chemical industry in general and of the iiiedicinal chemical industry in particular. The ethical st,atrdards of the leading mnnuEact,rn-ers, ditring the last ceritury, liave been unifornily high. T1:eir insistence upon the high quality and uniformity of their pmducts; the observance of sound and equitable trade prac:tices; tlie ~nairiteiianceof competent research organizations, and their cobperatioti with hospitals, cliiiics, and with privately and puhlirly endmwd research institutions, liave nude possible enormous eoiitributioiis to the alleviation of hiinan Iiealth. suffering and the saieguarding of ~iiil~lic Tlrrough the facilit,ies of these organizations tlie better kmiwii and old estal~lislied nit:di~:inalclieiiiical coiirprrnds tiavr tiern piirified aiid staodardised. By the labors of t,lie researdi: wiitrol, and faot,ory clieniiits in t,liese i:iinoeros there are iir)i~-avnilable, for medicinal uses, d i e i n i d s wliich conform tn the standards established by t.lie ti. S. Pliarniacopria niitl remedies wliich stand accepted by the Council on r i d Clieniistry of the American Medical Associainher of these liouses have estabof tiieir owii for their laboratory tied the niaxirririni limits of impurities t,a be foiiiid io their reagent grades of clieruieals suitable for researell work of tlie lriglicst order. Tlie need for research undertaken in the spirit of free inquiry, often with no immediate practical or ~mrbablcresult otber than the increase of fundamental knowledge, l i a s been recogiiined and provided for by a nrirnber of well-known concerns. T l i e establishment of nrw research laboratories by Eli Lilly & Company, a t Indianapolis, Ind.>in 1834, and by Xerck & Company at Itahway, N.J., in 1933, is evidence of the recent, important development of research facilities in the field of medicinal chemistry. The achievements of the modern researell Inboratories were well exemplified a t the Fourteenth Exposition of Chemical Industries in 1933 by the exhibition of a group of new developments, eommercialised during the four preceding years, under the arresting dit,ln "Cliildren of the Depression." These
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developments were eitlier esaeiitially new or greatly improved as the result of research, and each had been successfully established duriiig those four depression years. Among them were new vitamin products; a recently developed product for the x-ray examination of the urinary tract; a general anesthetic with a higher potency and a more favorable safety ratio than ether; a new synthetic with a hormone-like action, antagonistic to that of adrenaline, and a iiew barbiturate, etc. h iresli source for betaine hydrochloride was publjshed; details were given of the large-scale production of bromine and iodine from domestic brines; and new processes for the commercial production in the United States of antipyrine, the well-known analgesic and antipyretic, were disclosed.
Alkaloids Tile gradual trend of organic cliemistry back to a niore detailed study of naturally occurring substances lias led to intensive work on the active principles contained in plants. Almost daily, new alkaloids and glucosides are being isolated and exaniined with a view to determining their composition srid attempting their synthesis. The unsolved questions of striict,iire of the rildcr kiiowri alkaluids are being reconsidered, new derivatives with more berrcfinial effects are being made, arid the more linrnifiil specifics are gradually being replaced. Just ns the searcli for a substitute for eoeaine resulbed in the finding of procaine, an effect.ive local auesthetic devoid of addicting qualities, so today coijperative research is being carried on by tlie Satiiiiial Jksearuh Couucil and the liniversities of Virginia and Michigan iii r:oiijurictionu;itlivarious I x a n c l m of the government service in an endeavor to find mine drug to replace niorphiiicsome substitute possessing many of ita mlun1)le niedicinal propert,ies but not leading to :ddir:tion. Tile intaisive work of Lyndun Small and his r~ollnboratorshas already result,cd in the assigument to the gwerutnent of IJ. S. Patent No. 1,880,977for the preparation of it morphine derivative, diliyr~rudesoi?nnorpliine D, which is about t,lrree tinies as toxic as morphine, but exerts an analgesic act,ion a t least ten times greater aiid a general depressant effect some thirty or forty times as great. In these rvmtruetive cobperative efforts the investigators have been aided by manufacturers of incdicinal chemicals who recogiiise the necessity for close cobperation with workers engaged in scientific investigations sunnorted bv academic or wblielv endowed irwt,itutions
