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Vol. 15, No. 9
INDUSTRIAL A N D ENGINEERING CHEMISTRY
Recent Contributions of Chemistry t o Medicine By Ernest H. Volwiler Ttm ABBOTTLABORATORIES, CHICAGO, ILL. 6
EDICIKE as an art is gradually giving way to medi- than dyes, which have been found to have a wide applicacine as a science, but the process is a slow one tion, first as reagents in bacteriology, and later in the clinical which can never be completed, for the successful treatment of disease. As early as 1887 certain dyes were physician must be somewhat of an artist in his work, as well found to possess bacteriostatic action, but it was not until as a keen scientist. The transformation toward the scientific 1912 that Churchman,’,* and later Simon and Wood2 side has been considerably accelerated began a systematic study of these during the last twenty years, owing largecompounds. It was found in the ly to the application of many of the prinrather extensive series investigated by ciples of the various branches of chemisthem that the triaminotriphenylmethane try and physics, which the medical prodyes possess the greatest antiseptic or fession has gladly accepted and wisely bacteriostatic action, and that this is deemployed. Biochemistry, with the rependent upon the auxochromic amino lated branches of science that it ingroup as well as upon the triphenyl volves, is the key to the door through nucleus itself. Acid dyes are in general which most modern success in medicine much less effective than basic dyes, and is being obtained, and the information the effect of alkyl groups is uncertain. which it has placed a t the disposal of A much greater variety of dyes has rethe physician has led to marked changes cently been studied by Browning and in the types of substances which he Cohen3and by Norton and Davis.4 Their administers. work indicates the need for much more study, for we are as yet unable to deterThe history of drugs and their use mine what nuclei or groups are essential indicates many substances which are for the production of antisepsis. Among nearly if not quite as toxic to the host as the dyes which have proved most effito the parasite. One service which modcient toward the pneumococcus-streptoern chemistry is rendering consists in coccus group of bacteria are brilliant replacing the old, crude, ‘(shot-gun” green, gentian violet, and crystal violet. mixtures by compounds which, although The successful cure of pneumonia has yet still somewhat toxic, are limited in action to be discovered, and it is not unlikely to a few specific effects that are fairly well that such work as this may lead to the understood. Practically every drug in E. I3 VOLWILER successful solution of the problem. use to-dav is to some extent a aoison: It is in the treatment of syphilis and gonorrhea that dyes to speak ‘bf a drug as being “nontoxic” is to ignore the fact that the therapeutic effects of substances cannot be limited have been most extensively investigated. Ehrlich and his strictly to the conditions which it is intended to relieve or collaborators studied the use of trypan blue and of acrito the destruction of an invading organism-there certainly flavine as specifics for syphilis, but the results were not will be side effects which will affect more or less undesirably particularly encouraging. It was later found,5 however, the healthy, normal tissues. The end in view, but not the that acriflavine (trypaflavine) is almost unique among bacpath to follow, is usually well defined; the therapeutic effi- tericidal agents, inasmuch as its action is enhanced in the ciency must be raised to the utmost, and the side effects presence of serum, instead of being retarded. This led to its extended use as.& remedy for gonorrhea, .particularly in eliminated as nearly as possible. It must be admitted that the present state of our knowl- Great Britain and America. Incidentally, it is said that edge of the maintenance of health and the treatment of during the war acriflavine was almost universally used in disease is still quite unsatisfactory. Even after the diag- the German army in the treatment of wounds. The success of acriflavine has naturally led to the synnosis of a disease has been correctly made, the remedy available for its treatment is often ill-chosen and unsuited. In thesis of a great many modifications of it; only two, which the final analysis, the actions of all drugs must be referred were developed in Germany, need be mentioned hereto the cells themselves, concerning whose nature and reactions our knowledge is very fragmentary. Owing t? the cells’ complex structure, there can be but little hope that it eventually will be possible to express the action of most drugs in terms of definite chemical reactions; but it is perhaps not beyond our reach to determine why particular compounds ACRIFLAVINE FLAVIZID exert certain actions upon the cells, and how these actions NHa , may be enhanced or retarded. I Recent years have brought about some important advances in the treatment and prevention of disease. A few of these .will be briefly sketched in the following paragraphs.
M
DYESI N MEDICINE I n the last decade probably no other series of substances has shown more promising progress in the therapeutic field
RIVANOL
namely, flavizid and rivanol.
Rivanol was discovered by
* Numbers refer to bibliography a t end of article.
Septernb er, 1923
I N D UXTRIAL A N D EXG1 hTEERING CHEiMIXTRY
MorgenrothG who is noted for his work on quinine derivatives for the treatment of pneumonia. It appears valuable in the treatment of streptococcic infections, although the work with both it and flavizid is too incomplete to justify final judgment as to their true value. American investigators have begun work in some interesting and altogether new series of dyes, which are of importance inasmuch as they may lead to other even more vduable compounds. Two phthaleins containing mercury, wcurochrome -220 and flumerin, HOHg
HOHg
I
I
1
I
CoH4COeNa MERCUROCHROME
C6H6COzNa FLUMERIN
have been studied by White and his collaborator^.^ Mercurochrome is being employed as a general antiseptic, while flumerin has been suggested for use as an antisyphilitic. Sodium-p-hydroxymercuri-o-nitrophenolate (mercurophen), investigated by Schamberg, Kolmer, and Raiziss,8 has proved vduable as a general antiseptic. There can be no doubt that the use of dyes in medicine constitutes an important step in the evolution of modern therapeutic measures, but they will be superseded as soon as other non-dyeing compounds of equal or greater efficiency can be developed. I n the present state of bacteriological and clinical knowledge, the staining qualities of dyes give a good method for following their action, but indications are not lacking that there are other substances which do not possess the objectionable dyeing or staining qualities, but which, nevertheless, may be equally efficient.
TREATMENT OF SYPHILIS Eternal vigilance and most vigorous therapeutic measures constitute the only hope of eradicating or even controlling syphilis, which is to-day probably the world’s greatest scourge. It is interesting to note that mercury was used in its treatment almost from the time of its appearance in Europe, but mercury in its varied forms has up to the present proved at best a rather dangerous drug to employ. Probably no advance in medicine has exceeded in importance the discovery of the arsphenamines by Ehrlich in 1910. Ehrlich’s work constitutes the first extended investigation in the field of chemotherapy or the correlation of chemical constitution and physiologic action to produce specific desired therapeutic effects. As=-=As
OH
OH
ARSPHENAMINE
OH OH NEOARSPHENAMINE
It Beems probable that if the perseverance and care taken in the development of these compounds of arsenic were to be applied to the study of other diseases, a number of them would be passing into the category of rare maladies. On account of the prevalence and difficulty of contro1.of syphilis, however, it cannot even be stated that it is on the decline; but the use of the arsphenamines has assuredly been of great value in checking its ravages. An immense amount of research has been carried on in all civilized countries during the last decade in the attempt to develop products superior to the arsphenamines, but up
907
to the present the main progress, in which chemists of the United States have had a most prominent part, has come in decreasing the toxicity and increasing the safety of the arsphenamines, rather than in the discovery of new compounds in other series. Recently Voegtlins has focused attention upon sulfarsphenamine, one of the compounds related to arsphenamine, prepared by Ehrlich and his collaborators, but apparently discarded by them. Since it is a bisulfite derivative instead of the sulfoxalate compound (neoarsphenamine), it is less susceptible to the formation of toxic oxidation products and is giving promise of some valuable therapeutic application. Jacobs and Heidelberger,lo in an admirably systematic series of investigations, have developed the sodium salt of LV-phenylglycineamide-p-arsonic acid, called tryparsamide, which has proved valuable in the treatment of African sleeping sickness, a trypanosome disease related to syphilis. The compound was deemed of little value in the treatment of syphilis, partly because of the danger of producing blindness, but recent clinical experiments indicate that it may have a place in the treatment of neuro-syphilis, a form of tertiary syphilis. It may also be said that sulfarsphenamine has very recently given promise in this same field. Although arsenic administration for syphilis has held the limelight, the simultaneous or separate use of mercury has by no means been abandoned, and other metals are finding use. Apparently, the arsphenamines clear the blood stream of the spirochetes with remarkable rapidity and the simultaneous use of mercury preparations prevents the organisms from finding lodgment in the tissues. Recently disodiummercurisalicylacetate (mercurosal) has been placed upon the market as an antisyphilitic. A number of investigators, particularly in American universities, aided and encouraged by the United States Interdepartmental Social Hygiene Board, are carrying on important work with mercury compounds. Moreover, bismuth compounds, for example, sodium potassium tartrobismuthate, introduced by French pharmacologists and physicians, have attracted a great deal of attention, particularly for use in those cases where arsenic and mercury are not well tolerated qr where they are ineffective. I n efficiency, compounds of arsenic, bismuth, and mercury are saidL2to bear the approximate relative ratio 10: 7 :4. The most promising treatment of trypanosome diseases, such as syphilis and African sleeping sickness, has heretofore seemed to involve the administration of compounds of metals, such as arsenic, but the recent work in Germany indicates that eventually purely organic compounds may be equally promising, if not even more so. Owing to the conditions brought about by the war, the nature of these substances has been carefully guarded, but they are apparently complex aromatic amides synthesized from naphthalenesulfonic acids, phosgene, and nitrobenzoic acid, or similar intermediates :
Loas@~soaH OH
XH. [ C O D i Y H ] , .
BAYER-205
(possible iormula)
1
CO.
i
1 2
“Bayer-205” appears to be of value in the treatment of African sleeping sickness, but is apparently not applicable for use in human syphilis. It is interesting that the immense amount of excellent work which has been done by scores of investigators of many nations, with good facilities at hand, has produced comparatively little aside from advances in the production of the arsphenamines of high quality and potency. Nevertheless,
INDUSTRIAL A N D ENGINEERING CHEMISTRY
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Vol. 15, No. 9
a broad and sound basis is being laid from which we may reasonably expect to develop the “lucky accident’’ that will constitute the next big step in our progress toward the elimination of syphilis. Whether this advance will come along the line of purely organic compounds, or whether compounds of metals such as arsenic will continue to be the best remedies, cannot a t present be predicted.
twenty years ago Overton’’ and M e y e P showed that in a given series there is a more or less close relationship between physiological activity and the partition coefficients of the compounds between fats and water, and they illustrated this relationship by experiments upon a number of hypnotics which were known a t that time. The physiological testing of hypnotics is not always entirely satisfactory and no doubt this difficulty could in some cases be overcome by simulHYPNOTICS AND SED.4TIVES taneously carrying out physico-chemical tests as suggested It-cannot be said that the power of producing sleep is by Overton. If a physician were asked to choose the most valuable inherent in any certain combination of groups, inasmuch as there is a wide variety of nuclei, both inorganic and organic, single drug a t his disposal, morphine would probably be his which may form the basis of hypnotic compounds. Most choice. This drug has a host of uses, one of which is as a modern hypnotics. belong to the organic series; among the hypnotic. The elucidation of the structure of morphine first of these to be used was chloral hydrate. Other products has been the object of an immense amount of work, parwhich have come into use are based upon the nuclei of ure- ticularly by Knorr, Pschorr, Freund, Vongerichten, and more recently by Gulland and Robinson,lg but even to-day thane (I, VIII), sulfonmethane (11), halogen-substituted acid ureides (111), pyrimidine (IV), hydantoin (V), homo- we are not quite sure of the structure of certain portions of its complex molecule. Morphine is a dangerous drug t o phthalimide (VI), and diketotetrahydroxazole (VII). use, not only because of its toxicity, but also because of the degrading habit formation which it induces. Doubtless CHI\ /SOzCzHa some portions of the molecule of morphine are useless and C NHzCOOCzHj harmful, and it is most likely that it is possible to synthesize CH3/ ‘SOzCzHs more simple organic compounds which would produce the I-URETHANE 11-DIETHYLSULFONEDIMSTHYL- effect desired without the drawbacks inherent in the naturally METHANE (SULBANOL) occurring alkaloid. Cocaine is being gradually replaced in this manner by synthetic local anesthetics, and the value of CO-NH a similar substitution for morphine would be inestimable. co I CZH5‘CCONHCONHz Surgical operations cannot usually be performed under CZH5/ 1 CzHs/ 1 1 the ordinary hypnotics in doses in which they may be safely Br CO-NH employed. What would be desirable is a safe hypnotic which, ACID (BARIII-~-BROMODIETHYLACETYLUREA I V - DIETHYLBARBITURIC while producing a natural sleep in which the normal body (ADALIN) BITAL, VERONAL) functions are undisturbed, will a t the same time render the patient insensible to pain. It is not unlikely that in the realm of synthetic chemistry some day will be discovered a product which more closely approximates the ideal hypnotic anesthetic. 0
V-PHENYLETHYLHYDANTOIN (NIRVANOL)
VI-DI€THYLHOMOPHTHALIMID€~~
BENZYL ESTERS
Few better illustrations of how the chemist proceeds in his attempts to discover the physiologically active nucleus I NHzCOOCHaCCla of a naturally occurring drug, and then follows it up by synCzHa/C\CO--NH thesizing a more simple and effective substitute, can be had VII-PHENYLETHYLDIKETOTETRA- VIII-TRICHLOROETXYLURETHANE than the development by Macht20 of the use of benzyl esters HYDROXAZOLE14 (VOLUNTAL) 15 to relieve the pain caused by the rhythmic contractions of An examination of the structures of these compounds indi- involuntary muscle. Papaverine, one of the alkaloids of the cates that their activity is based upon the presence of one opium group, contains a substituted benzyl radical, and reasonor more of the following atoms or groups: (1) alkyl groups, ing from this fact, Macht investigated the action of simple (2) halogen atoms, (3) ketone or aldehyde groups. Never- benzyl esters, such as the benzoate. They were found to theless, there are so many factors involved and the compounds possess an action similar to that of papaverine, less complishow such wide variations in activity that a correlation be- cated by undesirable side actions, and the products are tween their constitution and their sleep-producing properties cheaper than papaverine. This discovery was soon followed is still impossible. Urethane and voluntal are mild in action, by the introduction of a large number of other benzyl esters, of low toxicity, and require to be given in comparatively such as the succinate, stearate, fumarate, phosphate, acetyllarge doses; whereas the others are stronger in action and salicylate, etc., all of which possess more or less important more toxic, but are effective in smaller doses. The sulfon- advantages over the benzoate. It was soon discovered by methane series (sulfonal, trional, and tetronal) was a t one Wildman,21 however, thdt benzyl ethers produce the same time extensively used, but the compounds were found to relaxant action on smooth muscle, and recently KammZ2 have deleterious action upon the heart and other organs. has indicated that the effect exerted by benzyl compounds Probably no hypnotic has ever come into as extended use is not specific for the benzyl group, but that other more or all over the world as barbital. Since some new alcohols less unrelated radicals produce the same action. The value have recently become available, other dialkylbarbituric of benzyl.compounds in medicine has by no means been acids have been prepared and of these the n-butylethyl and definitely decided. Hailed a t first by many of the uninthe isoamylethyl compounds seem to be best, exceeding by formed assbeing perfect substitutes for not only papaverine several times the activity of barbital itself.l6 but for morphine also, they have in many cases proved disApparently, the investigations of hypnotics have not been appointing and their use has now practically fallen into cercorrelated closely enough with the physico-chemical methods tain well-defined channels, where only extended clinical available for testing and comparing the products. Over application can finally determine their true value. C6HS\
/o-co
September, 1923
INDUSTRIAL A N D ENGINEERING CHEMISTRY
909
Insulin is obtainable by the careful and rather complicated extraction of the Islets of Langerhans, small bodies which The lack or superabundance of certain substances occurring exist in conjunction with the pancreas and which are intiin the body may produce most profound changes and ab- mately concerned with the metabolism of sugar. By daily normalities in our well-being and physical appearance. These injection of a solution of insulin even hopeless cases of diasubstances usually occur in very small amounts in the various betes may be so relieved that the patient can return to a glands of internal secretion, and, in general, little is known fairly normal existence. h’ot only are we ignorant of the concerning either their mode of action or their chemical composition of insulin, but we do not even know whether identities. Epinephrine (adrenaline), the blood-pressure rais- the active constituent is a protein or not. Scores of bioing constituent of the suprarenal glands, is better under- chemists have labored diligently with it during the last stood chemically and physiologically than any of the others. two years, but their efforts have tended mainly toward the Its structure is definitely known, owing to the painstaking isolation of a fairly pure and safe extract; the surface of its chemical investigation has not even been scratched. and excellent investigations of three chemists in AmericaTo these few- naturally occurring therapeutically valuable Abel, Aldrich, and Takamine-and not only is the pure naturally occurring product available, but its synthesis has products can be added a host of others, and we know far been solved and the synthetic product is now used by physi- too little about any of them. Th? vitamins are almost as cians side by side with the epinephrine obtained from supra- much of an enigma as ever. Digitalis is used daily as a heart renal glands. Nearly all the analogous products which have stimulant, as is strophanthin, but their chemical natures been synthesized are much less active or are entirely in- cannot at present even be inferred. Morphine has already active, but it has recently been stated t h a t an analogous been mentioned, but of most of the alkaloids we know far naphthalene derivative is forty times more active than less than we do of it. An interesting development in the epinephrine itself.23 treatment of leprosy has come through the use of salts or esters of the acids of chaulmoogra oil, obtained from the seed l\c/H of a tropical tree. Leprosy is a disease to which lower animals are not susceptible and the investigations of its cure in man have lagged because proposed remedies could not be pharmacologically tested. It is not claimed that the salts or esters of two of the acids of chaulmoogra oil-namely, 1’ chaulmoogric acid and hydnocarpic acid-are really satisHO n H factory for the treatment of leprosy, but they represent the EPINEPHRINE(ADRENALINE) THYROXIX best means at present available. These acids differ from any previously known fatty acids in containing a five-memTo Xenda1l24 we owe the greater part of our rather ex- bered carbon ring. The dotted lines in the formulas inditended knowledge of the active principle of the thyroid cate that the points of attachment of the bonds are unknown. gland. It is well known that a deficiency or excess of this H H active constituent produces the most marked effects, not only upon the health of an individual, but also upon his HC-- k--C- CHz-(CHz)uCOOH HC---$----C CHz(CH2)&OOH physical characteristics. Certain localities, such as Italy, I I I Switzerland, and o ~ Great r Lakes region, show a remarkable HzCCHz HzCCHa prevalence of certain diseases, often goiter, and it has been CHAULMOOGRIC ACID HYDNOCARPIC ACID shown that the water in these communities is deficient in iodine. Kendall and his collaborators by their remarkable CONCLUSION work have not only isolated the pure active substance (thyThe foregoing brief discussion includes only a few of the roxin) of the thyroid and indicated its structure, but they have made good progress toward its synthesis. Some of types of substances employed in medicine. There are, of the difficulties encountered may be imagined when it is noted course, many other series which have found application for that the thyroxin molecule is not only quite complex in itself, specific purposes in medical practice, and the chemical and but also contains several asymmetric carbon atoms. When physiological problems connected with them are just as this problem is solved, it will be of interest to determine important and needful of solution as any of those indicated what portions of the molecule are actually essential; that in the foregoing discussion. The tendency, of course, is to press on to discover products of therapeutic value in new iodine must be present is certain. Our knowledge of the products occurring in the other fields, but the old ones must not be abandoned until our glands of the body is also far from being complete. The knowledge about them is far more complete than a t present. tiny pituitary body, lying a t the base of the brain, is the The practice of medicine can be placed upon a more rational source of a blood-pressure raising substance which has long basis by a clearer understanding of the relationships existing been in use to control hemorrhage, etc. AbelZ5at one time between chemical constitution and physiological action, believed that histamine (4-imidazolylethylamine) occurred and a closer cooperation between the chemist, pharmacologist, in some combination to constitute the active principle, but bacteriologist, and clinician. It seems that endowed inthis belief seems no longer tenable26 and we are almost as stitutes for chemico-medical research, such as the Rockefeller much in. doubt as ever as to its true nature. The successful Institute in New York City, have the greatest opportunities solution of the problem promises ample reward to the investi- for performing the fundamental research necessary to lay a sound basis for future progress. Until there is such a basis, gator who can accomplish it. Probably no discovery since that of the arsphenamines there will always be products introduced on the market which has attracted so much immediate attention as that of insulin, should never be there, and other products of real value will used in the treatment of diabetes. Here again the long and be passed by without real trial. As recently pointed out by painstaking labors of many biochemists needed only the Hirschfelder, cooperation by the manufacturer is needed final touch of a keen investigator to make a needed and so that leads suggested by the pharmacologist may be properly valuable product available-this touch being supplied by utilized; but equally important is the need of obtaining comthe Canadians, Banting and Best27 and their collaborators. plete pharmacological tests of substances which have been NATURALLY OCCURRING PRODUCTS
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A
