CHEMICAL CONSTITUTION 
 
 AND 
 
 PHYSIOLOGICAL ACTION 
 
 BY 
 
 PEOF. DR. LEOPOLD SPIEGEL 
 
 (BERLIN) 
 
 TRANSLATED WITH ADDITIONS 
 FROM THE GERMAN 
 
 BY 
 
 C. LUEDEKING AND A. C. BOYLSTCXN" 
 
 (PH.D., LEIPSIC) (A.M., HARVARD 
 
 NEW YOEK 
 
 D. VAN NOSTEAND COMPANY 
 
 25 PAEK PLACE 
 
 1915 
 
COPYRIGHT, 1915 
 
 BY 
 D. VAN NOSTRAND COMPANY 
 
 THE SCIENTIFIC PRESS 
 
 ROBERT DRUMMOND AND COMPANY 
 
 BROOKLYN. N. Y. 
 

 FOREWORD 
 
 THE action of chemical agents upon the animal organ- 
 ism, and particularly upon man, is of the greatest 
 importance and interest. Far too little has been done 
 toward systematizing our knowledge of this subject, 
 and there is no doubt that this field offers an enormous 
 opportunity for useful research. 
 
 The purpose and scope of the present treatise have 
 seemed sufficiently distinct from other works, and of 
 sufficient importance to justify its translation. We have 
 also attempted to bring the work up to date by a con- 
 sideration of some of the more recent literature. 
 
 The borderlands between the formerly distinct sciences 
 are becoming of more and more importance as each 
 science progresses. The relation between chemical con- 
 stitution and physiological action is of such fundamental, 
 and far-reaching significance that a general idea of the 
 work which has already been done should be of interest 
 not only to the physiological chemist and to the searcher 
 for new synthetic therapeutic agents, but also to the 
 physician who must prescribe the use of such com- 
 pounds. For real, rational scientific medicine must be 
 founded upon a knowledge of this subject, and in order 
 that a steady progress shall be made, a systematic 
 knowledge must replace haphazard and empirical in- 
 formation. 
 
 iii 
 
 346420 
 
iv FOREWORD 
 
 This work is presented with the hope that it may 
 aid not only in the search for new synthetic therapeutic 
 agents, but also in a more thorough understanding of the 
 action and the reasons for the action of many of the com- 
 pounds which are already in use. 
 
CONTENTS 
 
 PAGE 
 
 FOREWORD iii 
 
 GENERAL CONSIDERATIONS 1 
 
 INORGANIC COMPOUNDS 24 
 
 ORGANIC COMPOUNDS 43 
 
 (a) Aliphatic Series 43 
 
 Aldehydes and Ketones 50 
 
 Acids and Derivatives 54 
 
 (&) Aromatic Series 63 
 
 Hydroaromatic Compounds 72 
 
 Inner Disinfection 77 
 
 (c) Nitrogen Compounds 80 
 
 Ammonia and Simpler Derivatives 80 
 
 Ammonium Bases 96 
 
 Cyclic Bases and Alkaloids 100 
 
 Atropine Cocaine Group 103 
 
 Opium Alkaloids and Relatives 118 
 
 Veronal Group 128 
 
 Quinine and Relatives 133 
 
 Purine Group 144 
 
 Hydrazine and Hydroxylamine 149 
 
 Hyponitrous Acid Derivatives 151 
 
 RESUME 152 
 
 v 
 
CHEMICAL CONSTITUTION AND PHYSIO- 
 LOGICAL ACTION 
 
 GENERAL CONSIDERATIONS 
 
 Descriptive chemistry has brought forth an enormous 
 number of chemical compounds, and has showed us 
 their properties. The similarity of certain compounds 
 which could be brought into genetic relationship, if not 
 actually converted one to another, made possible the 
 grouping of such bodies into series. This led to a 
 classification of the chemical elements which directly 
 explained reactions common to all the members of a 
 series. General discrepancies which were observed were 
 explained by assuming not only different valences for 
 the different elements in combination, but also a vary- 
 ing valence for a single element. Finally, the analogies 
 between these series of elements were found to be related 
 to the weight of the hypothetical atoms, and this re- 
 sulted in the development of hypotheses connecting 
 atomic weights with chemical and physical properties. 
 The most perfect expression of such relations to-day is 
 the periodic system of the elements. There were only 
 timid attempts in the field of inorganic chemistry to 
 explain the properties of compounds by discovering not 
 only the kind and number of atoms in a combination, 
 but also the manner in which they were joined the 
 
2 GENERAL CONSIDERATIONS 
 
 constitution of the compounds. The most powerful 
 impulse to this work came from the knowledge of the 
 carbon compounds. For in these bodies a few elements 
 form countless compounds whose properties range from 
 those of a harmless brilliant dye to those of an apparently 
 insignificant but really powerful poison alkaloid. In 
 such a chaotic labyrinth it was impossible to find a path 
 without the Ariadne thread of constitutional interpre- 
 tation. 
 
 Organic chemists were therefore first in this work, 
 systematically propounding and elaborating hypotheses, 
 which were later applied to inorganic compounds. 
 
 Real scientific chemistry begins, at least in the organic 
 field, with the determination of the influence of consti- 
 tution upon the various properties of the compounds. 
 
 The primary object of investigation is to ascertain 
 the effect of the inner structure upon chemical and phys- 
 ical phenomena such as chemical reactivity, melting- 
 point, boiling-point, heat of combustion, refractivity, 
 dielectric constant, etc. 
 
 Especial interest was early excited by the color of 
 substances and particularly the property of imparting the 
 original or a modified color to animal and plant fibers. 
 
 Only in recent times has it been attempted to connect 
 the chemical constitution of compounds with those 
 properties which are most delicate and most important 
 to man that is, with their effect upon the animal 
 organism. 
 
 Of course the idea of finding a connective relation 
 between chemical and physiological properties of com- 
 pounds is by no means new. This thought naturally 
 arose with the earliest chemical considerations which 
 were directed to substances of especial importance and 
 interest to man, whether their qualities were injurious 
 
GENERAL CONSIDERATIONS 3 
 
 or remedial. Then appeared the genius of Paracelsus, 
 who directed chemistry into new courses with the sig- 
 nificant expression, " The real object of chemistry is 
 not to make gold, but to prepare medicines." (Von 
 Meyer, History of Chemistry, 2d ed. from 2d German 
 ed.) 
 
 He announced a proposition that has a decided smack 
 of modern times when he said "The healthy human 
 body is a combination of chemical substances; when 
 this suffers any change, diseases arise, which' accordingly 
 can be cured only by chemical remedies." 
 
 The further advancement we owe next to the latro- 
 chemical school, which proceeded along the course which 
 Paracelsus had laid. This school, under de la Boe Sylvius, 
 attempted to make all the science of medicine applied 
 chemistry. ,The pity is that in this development there 
 sprang up beside really far-reaching and fundamental 
 ideas the most vague and speculative phantasies and 
 imaginings, which could not fail to discredit the whole 
 science of chemistry for some time, particularly so in 
 investigating the curative effects of compounds. 
 
 Chemical and physiological knowledge was in too 
 undeveloped a condition for us to expect a great deal 
 of productive work from those times. In order that 
 we may evaluate the effect produced upon life functions 
 by the substances artificially ingested into the organism 
 it is quite necessary, according to our present ideas, 
 that we postulate that these substances enter into reac- 
 tion with the constituents of the cells which transmit 
 the effect to the whole organism. Then it becomes at 
 once evident to the chemist that such an Interaction 
 depends not only upon the structure of the ingested 
 reagent, but quite as much upon the structure of the 
 cell substances. 
 
4 GENERAL CONSIDERATIONS 
 
 Thus we arrive at the discouraging conclusion that 
 for a full and complete solution of our problems, for 
 a sure and definite knowledge of the action of foodstuffs, 
 medicines or poisons, it is quite certainly essential that 
 we know the constitution of the cell substance and the 
 significance of this constitution in the various physio- 
 logical functions. Until this is known we must remain 
 in the dark. At all events to-day, when the chemical 
 constitution of one of the interacting materials that 
 is, the ingested substance, is known with a probability 
 that borders upon certainty, we are facing our problem 
 with views quite different from those which were cur- 
 rent in the days of Paracelsus, Van Helmont and Sylvius. 
 We may even allow ourselves to hope that these very 
 relationships to whose investigation we are here devoted 
 may become a means of assured progress in the deter- 
 mination of the ultimate nature of the cell substances 
 themselves. For the behavior of a substance toward 
 known reagents gives us quite generally a clue to the 
 presence of groups whose reaction characteristics we 
 know. 
 
 At any rate if we were to limit ourselves even 
 to-day to our investigation of the actions and effects 
 of only those substances whose constitution may be 
 considered to be wholly and perfectly cleared up in all 
 details, our field would be comparatively small. For 
 we must remember that it is in a series of substances 
 whose constitution has so far defied all attempts at 
 solution where we find some of the physiologically most 
 active material. But there are fortunately many per- 
 tinent relationships that can be established even with 
 our very limited knowledge of constitutional structure, 
 just as is the case in pure chemistry. For example, 
 it is not at all necessary to know the structure of aro- 
 
GENERAL CONSIDERATIONS 5 
 
 matic hydrocarbons in order to conclude definitely after 
 noting the varying behavior of their nitro derivatives 
 on the one hand, and the corresponding amines formed 
 by reduction of these nitro bodies on the other hand, as 
 compared with the corresponding diazonium salts, that 
 the amino group on the aromatic nucleus plays an 
 important and especial role in the reactions involved. 
 In the same manner in the case of physiologically active 
 substances we can easily trace the influence of various 
 substitutions, although the actual constitution and 
 occasionally even the empirical composition of , the main 
 body of the compound may be entirely unknown to us. 
 In the cases of some substances the living organism is 
 an indicator of such remarkably great delicacy that it 
 far transcends all chemical reagents and reminds us 
 strongly of the sensitiveness of the electroscope in the 
 detection of radioactive substances. For example, the 
 living organism demonstrates most clearly changes of 
 this sort in the formation of specific anti-bodies from 
 the normal components of the animal body. Such 
 changes could not even be surmised by any chemical 
 reagents, although there can be no question that for 
 their fundamental causes they must be referred to alter- 
 ation of the chemical and stearic structure of complex 
 molecules. 
 
 As we have already noted, material ingested from 
 without enters into relationship with the body materials 
 in the performance of the various body functions. In 
 general the more these ingested substances differ from 
 those of the body and the greater the effect observed 
 by the introduction of the most minute quantities, so 
 much the more easily may these relationships be deter- 
 mined. Both of these conditions are well satisfied in 
 the case of those substances which are in part injurious 
 
6 GENERAL CONSIDERATIONS 
 
 to the body as poisons and in part beneficial as med- 
 icines. We shall therefore essentially restrict ourselves 
 to a consideration of these substances in the following 
 treatise. 
 
 First of all let us consider what quantities of foreign 
 substance introduced into the body are capable of being 
 recognized by a definite effect. Hydrocyanic acid is 
 fatal for man in doses of 0.05 gm., and its effects are 
 very clearly discernible in doses of 0.0005 gm. Strych- 
 nine, which is fatal for adult man in doses of 0.10 gm. 
 to 0.12 gm., shows a very marked effect even in doses 
 of 0.003 gm. Pilocarpine is utilized in a therapeutic 
 way for man in quantities of 0.005 gm. Let us for a 
 moment consider these small quantities to be distributed 
 only in the blood, which in an adult human being is 
 estimated at 5.5 kgm. We then find the following 
 concentrations in the blood for doses that are effective : 
 
 Hydrocyanic acid 1 : 11,000,000 
 
 Strychnine 1 : 1,800,000 
 
 Pilocarpine 1 : 1,100,000 
 
 Now for some of the particularly delicate chemical 
 reactions the following limits of sensitiveness have been 
 found: 
 
 AgN0 3 and HC1 1 : 1,000,000 
 
 BaCl 2 and H 2 SO 4 1 : 400,000 
 
 A further consideration of the above figures makes 
 it seem improbable that the quantities of the poisons 
 mentioned are so uniformly distributed in the organism 
 as is assumed in the calculation. We are rather led to 
 the view that a localization or concentration takes place 
 at those parts that are affected, in somewhat the same 
 manner as a woolen thread can concentrate and make 
 
GENERAL CONSIDERATIONS 7 
 
 distinctly visible a very slight and uncertain color in 
 a solution. And indeed it has been possible by intra- 
 vital staining with proper dye-stuffs to furnish proof 
 of such a localization within the organism. Thus, for 
 example, methylene blue imparts a particularly intense 
 color to the nerve endings, certain cells of the pancreas 
 and a definite category of muscle fibers endowed with 
 particular functions. 1 At the same time it has been 
 possible by means of this same coloring-matter to estab- 
 lish differences in chemical characteristics of the cells 
 which absorb it. It is taken up in* part as a leuco base 
 and in part is transformed into a compound which 
 regenerates methylene blue only on treatment with 
 hydrochloric acid. 2 The power of coloring gray nerve 
 matter is possessed by only a small number of dyes, 
 especially basic dyes. All dyes that contain a sulphonic 
 acid group are in this respect entirely ineffective and 
 of the acid dyes containing hydroxyl as the auxochrome 
 group alizarine alone is effective. 
 
 Phenomena of this sort, at first noted only as interesting 
 facts, were utilized later, particularly by Ehrlich, as 
 a basic starting point for a comprehensive tracing out 
 of physiological action. We must tarry for a moment 
 while on this interesting point. The first question which 
 naturally arises is how we can recognize a localization 
 when we are dealing with substances other than those 
 we have just discussed that is, with substances whose 
 presence cannot be plainly detected by the eye, as 
 is the case with coloring matters. When we have under 
 consideration the living being, then, of course the hypoth- 
 esis that such localization is the cause of the general 
 physiological effect, helps us out of our difficulty. By 
 
 1 Ehrlich, Leyden-Festschrift, Vol. I. 
 
 2 Herter, Z. physiol. Chem., 42, 493 (1904). 
 
8 GENERAL CONSIDERATIONS 
 
 careful study of the physiological effects we can deter- 
 mine when the ingested foreign substance has become 
 localized if we know the seat of the function that has 
 been affected. Thus we may learn the organ upon which 
 this function is dependent and so the brain centers 
 and nerve fibers concerned in the effect. For all such 
 information as this we are of course indebted to the 
 present state of development of anatomy and phys- 
 iology. Naturally we must determine by experiment 
 in the individual case whether the influence is to be 
 traced to the organ 'itself or to the brain center that 
 controls it, or whether the nerve fiber that connects 
 the two has been affected. Further observations can 
 be made in the post mortem examination of the affected 
 individual. Some substances leave at the seat of their 
 localization distinct evidences in the form of histological 
 changes; for example, the ecgonine derivatives in the 
 parenchyma of the liver (Ehrlich) and curare in the nerve 
 fibers (Cavallie). The localization of other substances 
 can be detected directly by staining or by the addition of a 
 proper reagent. Thus, for example, it is possible to trace 
 the iron absorption from the intestines by the intestinal 
 epithelial cells, the lymphatic glands, etc., by treating 
 the organs under suitable conditions with ammonium 
 sulphide or with potassium ferrocyanide. Thus, also 
 it is possible to ascertain the distribution of aniline 
 in the organism by means of l-2-naphthoquinone-4- 
 sulphonic acid. 1 The further development of physio- 
 logical and histological anatomical methods will very 
 probably bring to light many other possibilities in this 
 field. 
 
 We may add that the localization of the toxines, 
 immuno bodies, etc., which are so exceedingly sensitive 
 i Ehrlich and Herter, Z. physiol. Chem., 41,^379 (1904). 
 
GENERAL CONSIDERATIONS 9 
 
 in their reaction, can quite frequently be directly demon- 
 strated by means of solution of the corresponding anti- 
 bodies. 
 
 Now this selective power, which has already been 
 determined for a great number of substances and which 
 we can reasonably expect to exist for many others, 
 may depend upon either physical or upon chemical 
 causes. 
 
 Ehrlich compares the power of resorption possessed by 
 individual organs for certain substances to the shaking- 
 out process for alkaloids from their aqueous solution by 
 means of organic solvents, such as ether, benzol, ligroin, 
 etc. If we bear in mind that the liquids circulating in 
 the body (blood and lymph) are essentially aqueous in 
 character, but that the organs of vital importance, 
 such as blood corpuscles, brain and nerves, are dis- 
 tinguished by a content of fatty or wax-like substances, 
 such as lecithines and cholesterines, then many physi- 
 ological effects suggest the comparison. Hans Meyer 1 
 as well as Overton 2 have shown that at least in the 
 case of the neutral narcotics we have to do with more 
 than a mere comparison, as here the degree of action 
 increases in the same ratio as the quotient: 
 
 Solubility in fat : solubility in water. 
 
 There had previously been recognized relationships 
 between the fat content of the brain and the degree 
 of narcosis 3 that led von Bibra and Harless to the 
 assumption that the essential feature of narcosis is the 
 extraction of fat substances from the brain. This view 
 
 1 Hans Meyer, Arch. exp. Path. Pharm., 42, 109 (1899) and 
 46, 337 (1901). Baum, ibid., 42, 119 (1899). 
 
 2 Studien iiber die Narkose, Jena, 1901. 
 Kochmann, Biochem. Zentr., 4, 689 (1906). 
 
10 GENERAL CONSIDERATIONS 
 
 has more recently been supported by the experiments 
 of Reicher. 1 Further, Hermann has shown that all 
 narcotics of the fatty series can dissolve red blood cor- 
 puscles, and has explained this phenomenon as an extrac- 
 tion of their fat-like substances. At the same time he 
 calls attention to the coincidence of this process with 
 the presumptive occurrence of narcosis. Reicher, on 
 the other hand, had pointed out that the narcotic power 
 of a substance is inveresly proportional to its solubility 
 in water. 
 
 The theory of Overton and Hans Meyer may be summed 
 up in the following theorems propounded by them: 
 
 (1) All primarily indifferent substances that are sol- 
 vents for fat and fat-like bodies must act as narcotics 
 upon living protoplasm cells if they can be absorbed 
 by the cells. 
 
 (2) The action must appear first and strongest in those 
 cells in whose composition these fat-like substances pre- 
 dominate and in which they are especially essential 
 contributors to the cell-function in the nerve cells, 
 therefore, before all others. 
 
 (3) The relative power for action of such narcotics 
 must be dependent on the one hand upon their mechan- 
 ical affinity for fat-like substances and on the other 
 hand their lack of affinity for the remaining cell sub- 
 stances that is, principally water. So we can say 
 their power depends upon the degree of their partition 
 between water and the fat-like substances. 
 
 This theory is borne out and substantiated by the 
 finding of similar relationships in other than the fatty 
 series; but we cannot say that solubility in fat alone 
 is the cause of narcosis. For such a conclusion as 
 that would very apparently imply that the neutral 
 1 Reicher, Z. klin. Med., 65, 235 (1908). 
 
GENERAL CONSIDERATIONS 11 
 
 fats should be counted among the most powerful of 
 narcotics. So we must conclude that aside from these 
 factors of solubility there must be taken into account 
 some chemical factors of no less importance. 
 
 Kochmann with perfect justice raises the objection 
 that if the theory of Meyer is entirely valid all nar- 
 cotics that act on the central system would of neces- 
 sity act upon the peripheral nerves, at least temporarily 
 paralyzing them, because they are very decidedly rich 
 in lipoids, even if not to such an extent as is the brain. 
 But, according to Gradenwitz, 1 this is not the case. 
 
 Now there are very definite observations that point 
 to the presence of chemical action in narcosis. 
 
 The objection may very properly be made to the theory 
 of von Bibra and Harless that the rapid return to the 
 normal state contradicts it. This is Kochmann's argument. 
 
 Neverthless the fact which they have established re- 
 mains that is, that the quantity of fat capable of 
 being extracted (from the brain during narcosis) is 
 less than the quantity that can normally be extracted. 
 Therefore, if this fat has not been removed from the 
 cells, it must have undergone a change through the 
 action of the narcotic. Moore and Roaf 2 have shown 
 that chloroform and other anaesthetics combine with 
 protoplasm to form unstable compounds, and they 
 presume that the formation of such compounds is the 
 cause of the intoxication. The possibility of the for- 
 mation of such compounds by the union of substances 
 supposedly incapable of chemical combination has been 
 thoroughly discussed by Heymans and de Buck. 3 
 
 1 Gradenwitz, Dissertation, Breslau, 1898. 
 
 2 Moore and Roaf, Proc. Roy. Soc., 73, 494 (1904); and 77, 
 86 (1906). 
 
 3 Heymans and de Buck, Arch, intern, pharmacodyn., 1, 1 (1894). 
 
12 GENERAL CONSIDERATIONS 
 
 So Kochmann fairly propounds the question: does 
 the solubility in the fat perhaps merely serve as a means 
 to an end? It may be absolutely necessary only in order 
 that the narcotic may enter the cell without being an 
 etiological causative factor. In view of this discussion 
 we must decide that the power to dissolve in fat is essen- 
 tial as the chief cause for the entry of the narcotic into 
 certain organs. Therefore this factor within a given 
 group of substances related in action will determine the 
 degree of their activity. 
 
 A treatment similar to the one we have made concern- 
 ing solubility may also be applied to osmotic pressure 
 and to surface tension in order to explain physiological 
 differences in action of various substances. Nothing 
 could be more desirable than to subject to mathematical 
 treatment the complicated situation which we have in 
 the action of foreign substances in the organism. But 
 as yet we should have to deal with too great a number 
 of variables at one time, and until some of the rela- 
 tionships that are still almost unknown to us shall have 
 been positively established, such a treatment can hardly 
 be applied. A premature attempt of the sort, which 
 frequently results in treating as negligible factors the 
 clear deductions of physiological observations, can only 
 lead to discredit of the mathematical method. 
 
 Loew l assumed a direct chemical union of the proto- 
 plasm with the so-called substituting poisons, supposing 
 the labile amino and aldehyde groups of the protoplasm 
 to be active in effecting such a union. In such a case 
 then, the poisonous substances to be considered must 
 have certain groups which are capable of reaction with 
 these amino and aldehyde groups even in very dilute 
 
 1 Loew Ein natiirliches System der Gif twirkungen, Stuttgart 
 (1893). 
 
GENERAL CONSIDERATIONS 13 
 
 solutions. Such an explanation seems to be, at least 
 in some instances, quite plausible. For example, hydrox- 
 ylamine and the hydrazines, which are well-known alde- 
 hyde reagents, are powerful poisons for vegetable and 
 animal organisms, while the ketoximes, in which the 
 reaction group is bound, are only in exceptional cases 
 more poisonous than the related ketones. Moreover, 
 aniline, which reacts with aldehyde with far greater 
 difficulty than does phenylhydrazine, is also, as we should 
 expect, far less poisonous. In the case of a few poison- 
 ous bodies having a tertiary nitrogen, a reduction with 
 the formation of an imino group and consequently 
 greater chemical activity increases their poisonous effects. 
 In this connection may be mentioned the reduction of 
 pyridine to piperidine. It is quite presumable also that 
 in this category should be placed those bases whose 
 power for action may be diminished by the entry of 
 alkyl groups. This is particularly the case when an 
 acid radicle is introduced into an amino group. In 
 other cases, however, this hypothesis fails and is not 
 supported by the facts. Erhlich will not admit this 
 hypothesis at all for ingested foreign poisons, because 
 in his very numerous experiments in this direction he 
 was never able to establish that there had been a chem- 
 ical union of such bodies. In fact, he found that the 
 various poisons could, without exception, be again ex- 
 tracted from the tissues by means of neutral, chemically 
 inactive solvents. Further, he opposes the Loew theory 
 with the following arguments. 
 
 (1) The return from a condition of narcosis to the 
 normal condition is rapid in the case of most of the 
 substances under consideration. 
 
 (2) When dye-stuffs (such as fuchsine) which are 
 capable of reacting with aldehyde to suffer a distinct 
 
14 GENERAL CONSIDERATIONS 
 
 color change are used, there is no occurrence of such 
 change. 
 
 Ehrlich, however, assumes a real chemical union in 
 the case of toxines of high molecular weight and in 
 the case of substances such as food-stuffs which are 
 capable of assimilation, and in such cases he maintains 
 that the specific haptophoric groups of the substance 
 combine with the receptors or side chains of the pro- 
 toplasm. For foreign substances, he concludes as a 
 result of his investigations, that there is such a union 
 
 CR 2 ^ 
 
 only in the case of dimethylenimine ^>NH and for 
 
 CH/ 
 
 the structurally analogous dimethylene oxide | 
 
 CH 
 
 because these substances effect a lasting and peculiar 
 change in the tissue. 
 
 Although we must acknowledge that the objections to 
 the theory of Loew are in part justified, nevertheless, 
 they themselves are not beyond criticism nor wholly 
 free from fault. It is safe to presume that there are a 
 number of substances that would show an action on the 
 tissues similar to that of dimethylenimine. In fact, 
 according to Ehrlich's investigations, cocaine and most 
 of the other ecgonine derivatives cause a characteristic 
 foamy degeneration of the liver cells, and a more deli- 
 cate microscopic technique has shown that cocaine and 
 stovaine, which acts similarly, develop in the localities 
 of their action certain well-marked structural changes. 1 
 It will, therefore, without doubt, be necessary to widen 
 the circle of exceptions to the Ehrlich law, and among 
 these exceptions are most certainly to be included, 
 
 ^antesson, Skand. Arch. Physiol, 21, 35; Chem. Zentr., 
 1908, II, 145. 
 
GENERAL CONSIDERATIONS 15 
 
 according to Ehrlich's own beautiful researches, the 
 compounds or combinations of trivalent arsenic in their 
 behavior toward trypanosomes. 1 
 
 The most weighty of the reasons adduced by Ehrlich 
 in support of his contention is the fact that the poi- 
 sonous substances can be removed from the tissues 
 by means of neutral solvents. But even supposing a 
 chemical union, this phenomenon can be explained by 
 the law of mass action by assuming that the various 
 protoplasm compounds are easily dissociated in the 
 solvents. This would at the same time explain the 
 evanescence of the narcosis. 
 
 In fact, we find in Overton's work some results that 
 indicate such a behavior. For example, if we place 
 certain cells in a strychnine solution, there is formed 
 within the cells a precipitate of strychnine tannate. 
 This formation is proportionate to the concentration 
 of the alkaloid in solution, and if this concentration is 
 decreased by sufficiently diluting the solution, the pre- 
 cipitate will disappear. Accordingly, a chemical union 
 of the poisons would seem quite probable if their removal 
 from the tissues proceeded only according to laws other 
 than those that hold in the case of ordinary mixtures 
 of substances. And, in fact, this is supported by in- 
 vestigations of Straub 2 who found that certain effects 
 of alkaloids are dependent upon a preliminary storage 
 in the sensitive cells. He also found that inactive 
 alkaloids are either destroyed or are not stored up in the 
 cells. Straub proved such a storage effect in the case 
 of veratrine, and he further showed that here the par- 
 tition coefficients differ from those demanded by the 
 diffusion law. Denarcotization is also . effected by the 
 
 1 Ehrlich, Ber., 42, 30 (1909). 
 
 2 Straub, Pfliiger's Arch., 98, 233 (1903). 
 
16 GENERAL CONSIDERATIONS 
 
 blood and tissue fluids much more strongly than we 
 should expect according to this law. Therefore, we 
 must consider the fixation of the poison on the proto- 
 plasm and its removal as a reversible reaction which 
 may be represented by the following equation: 
 
 Plasma + poison solution^ poison plasma + water. 
 
 Other instances of chemical fixation have already 
 been mentioned in the discussion of the Overton-Meyer 
 theory. 
 
 However this conflict of opinions as to the mechan- 
 ism of the action may be decided, this at least is certain: 
 The production of an effect at any desired place in the 
 organism necessitates such a chemical constitution of 
 the ingested substances as to make possible their local 
 fixation, whether it be of a chemical or of a physical 
 nature. When there is such a structure of the material, 
 this acts, we may say, as a grappling hook by means of 
 which the effective groups can be attached or hooked 
 on to the substance of the tissue. 1 
 
 It is necessary, of course, to avoid the previous accu- 
 mulation in the protoplasm of such groups as have the 
 same or a similar selective tendency as the substance 
 we desire to bring into action. Otherwise our efforts 
 at directive medication would be fruitless. This dis- 
 cussion clearly emphasizes the great practical value of 
 research upon the mode of action of the different sub- 
 stituting groups and upon the group characteristics 
 which enable them to react upon or become attached 
 to the different body organs. It is also apparent that 
 the synthesis o medicinal preparations depends upon 
 the scientific advance of such considerations. 
 1 Ehrlich, Leyden-Festschrift. 
 
GENERAL CONSIDERATIONS 17 
 
 A research of this sort is conducted in two different 
 ways. At first it was naturally directed to substances 
 that had been determined in an empirical manner to be 
 physiologically active. These were of course natural 
 substances, principally plant products. The first object 
 was to isolate from the raw product whether drug or 
 coal tar, those chemical components which constituted 
 the active principles. This course has been pursued 
 for many decades since the isolation of morphine from 
 opium, and is still being pursued to-day. Such activities 
 have been remarkable for the energy which has been 
 spent in them and for the resulting successes. Coin- 
 cident with such work, particularly in later years, has 
 been the work of unraveling the chemical constitution 
 of the active principles obtained. Then followed the 
 attempt to determine what particular parts of the mole- 
 cule, what special groups, were responsible for the 
 specific physiological action. For example, it is extremely 
 interesting and valuable from a chemical standpoint to 
 have the total synthesis of an alkaloid. But it is far 
 more important from the standpoint of practical medi- 
 cine to be able to modify such a body so as to deprive 
 it of undesirable or unpleasant effects while still retaining 
 its essential physiological properties or to increase or 
 strengthen the desired effect, or lastly, to combine this 
 with other desired effects which are lacking in the 
 original substance. These efforts must be carried still 
 further in order to make ourselves independent of the 
 original substances of nature, and to make in their stead 
 artificial substances, similar, but constituted as simply 
 as possible. 
 
 At the beginning of this work it was natural that it 
 should be mainly directed toward the thoroughly known 
 effects of substances traditionally offered us by nature. 
 
18 GENERAL CONSIDERATIONS 
 
 But soon the investigators were ready to leave this path 
 to explore physiological effects with which the older 
 observers were necessarily quite unacquainted. How 
 much there may be that is physiologically not only 
 interesting, but indeed valuable in the almost count- 
 less numbers of compounds which the speculative inves- 
 tigation and experimentation of the chemists have given 
 us since Wohler's synthesis of urea! Enormous as these 
 possibilities are, they must continue to multiply to far 
 greater numbers in the future. 
 
 The second direction in which effort has turned for 
 quite a period of time is the determination of the phys- 
 iological behavior of many active chemical groups, 
 some of them long known and some newly discovered. 
 It is to be urgently desired from both a practical and 
 a theoretical standpoint that this work will be con- 
 ducted in a much more comprehensive and thorough 
 way than hitherto. For, up to the present time, this 
 work has been usually done by pharmacologists either 
 directly employed or supported by chemical factories, 
 and it has been carried out merely with a view to its 
 practical exploitation. Such work has had no real 
 scientific aim and purpose. The theoretical develop- 
 ment of the subject demands more thorough methods of 
 investigation. The pursuit of vaguely suggested and 
 often undesired effects can be successfully carried on 
 only by the cooperation of the chemist and the phys- 
 iologist. Thus only will the theoretical views on the 
 influence of constitution be placed upon a secure and 
 safe foundation. And it is almost self-evident that 
 such investigation will be followed by an immense amount 
 of information of practical value, at least in a general 
 understanding and conception of the subject. Such 
 investigations are of sufficient importance for the wel- 
 
GENERAL CONSIDERATIONS 19 
 
 fare of mankind to warrant the foundation and support 
 by state authorities of institutions properly equipped 
 and independently endowed to carry on the work. The 
 pharmacological university institutions which are car- 
 rying the burden of education with their few and 
 underpaid professors are entirely inadequate to cope 
 vigorously with this problem. 
 
 The greatest care and painstaking detail are of course 
 paramount in importance in the development of this 
 science. There must be the most thorough reliability 
 in the work of the chemist in unraveling the structure 
 of the compounds which he has prepared as well as 
 in the work of the physiologist and physician in inter- 
 preting the symptoms which are provoked. The tech- 
 nique of the work is as yet in its developmental stage, 
 and still leaves much to be desired. We may hope that 
 in time many an obscure and hitherto inexplicable 
 phenomenon will find its explanation. 
 
 Especially is the greatest care also demanded in 
 judging and interpreting the results of experiments. 
 For example, it happens occasionally that a faint sug- 
 gestion of an effect in the initial substance is very con- 
 siderably increased by the introduction of a new group. 
 The almost self-evident inference is that this new group *^ 
 is in itself responsible for such an increment in the 
 observed effect. But this conclusion may be quite 
 erroneous, since the influence of the new group may 
 essentially depend upon the fact that it neutralizes 
 another effect which predominated in the initial sub- 
 stance, or that it, so to speak, paralyzes the action 
 of a group that obstructed the prominence of the de- 
 sired effect. Thus, for example, there is formed from 
 the mildly anaesthetic benzoyl ecgonine, 
 
20 
 
 GENERAL CONSIDERATIONS 
 
 HCOOH 
 
 by alkylation the powerfully active cocaine; but ben- 
 zoyltropine, 
 
 N CH 3 CHOGOC 6 H 5 
 
 is also powerful in its anaesthetic effect. Therefore, we 
 can conclude that the alkylation of the carboxyl group 
 in benzoylecgonine does not impart the anaesthetic prop- 
 erties to the compound; but it does neutralize the 
 inhibitory qualities of the carboxyl group. There is a 
 similar relationship between arecoline II and arecaidine I : 
 
 I ARECAIDINE 
 CH 
 
 H 2 C/\C COOH 
 
 H 2 C/\C C 
 H 2 GIJCH 2 
 
 
 II ARECOLINE 
 CH 
 
 11: 
 
 2 G/\C.COOCH 3 
 
 
 jCL JCH 2 
 \/ 
 
 N 
 
 k 
 
 N 
 G 
 
 It must be clear that in such cases only the most 
 painstaking consideration of analagous cases in the 
 greatest possible variety can' lead us to a correct inter- 
 pretation of results. 
 
 Great care is likewise necessary in quantitative com- 
 parisons of effects. The mode of distribution must be 
 carefully taken into account. For example, we must 
 
GENERAL CONSIDERATIONS 21 
 
 consider that differences in solubility may often account 
 wholly or in part for deviations from the expected local- 
 ization possibilities of a drug or poison. Add to this 
 the fact that probably in the case of every substance 
 ingested we must admit that a certain quantity is nec- 
 essary before any effect will be noticeable. Comparisons 
 of intensity of effect should be made only after passing 
 this initial quantity. Especially is this consideration of 
 importance in cases where the ingested substance is nor- 
 mally present in the organism. Under such conditions 
 a certain adjustment of the normal organism has been 
 already established for the material in question. 
 
 It is, of course, only in exceptional cases that we 
 find monotropic substances. By this we mean sub- 
 stances that are limited in action to one organ, or still 
 more correctly, to one element of one organ. New 
 difficulties and new complications in judging the relative 
 strength of effect arise from the differences in the points 
 of attack or action of substances upon the complicated 
 higher organisms. The attempt has been made in more 
 recent times to avoid this difficulty as far as possible 
 by making the experiments on the lowest life forms, 
 such as the unicellular organisms of bacteria, paramsecia, 
 yeast, sea urchin eggs, red blood corpuscles, etc. As 
 one would expect, the results obtained in this manner 
 are very well comparable among themselves. But it is 
 clear that in order to reach conclusions which are applic- 
 able to the higher animal organisms from the results 
 with these lowest forms, it would be necessary to make 
 an enormous number of different experiments on the 
 most divers cell kinds. For there have been observed 
 the greatest differences imaginable in/ the effects of 
 some groups upon warm- and upon cold-blooded animals. 
 Not only that, but there have been found differences 
 
GENERAL CONSIDERATIONS 
 
 of behavior in the most nearly related species. For 
 example, the extraordinary diminution of the poisonous 
 effect of p-aminophenyl arsinic acid by acetylization 
 whije observed in the case of the mouse is only slight 
 in the case of other animals. In the case of the mor- 
 phine derivatives, the only experimental results that are 
 comparable with the effects on the human organism 
 are those obtained on the organism of the cat. We 
 must mention here the quite valuable investigations that 
 have been made on isolated organs retained in their 
 state of normal functions by means of an artificial cir- 
 culation of blood. 
 
 But there are sometimes individual differences even 
 in the same animal kind. That such is the case even in 
 the lower forms of life is shown by the occurrence of 
 some trypanosome types that are immune to poisons 
 through an established tolerance. In the higher forms 
 of life and particularly in man, this phenomenon is 
 very strongly pronounced and very varied. It is known 
 under such names as idiosyncrasy, tolerance and im- 
 munity. Some substances have been observed to act 
 differently under normal physiological conditions and 
 under pathological conditions. Thus, quinine will re- 
 duce the temperature of a fever patient from 3 to 4, 
 while the temperature of a normal person is only slightly 
 lowered. Salicylic acid is powerfully active in this 
 direction in cases of acute articular rheumatism, while 
 it is but slightly active in other febrile affections and is 
 inactive upon the normal body. 
 
 Now, it will be quite evident that conditions are very 
 complicated indeed when one wishes to act upon living 
 organisms such as injurious parasites within another 
 living being. Inner disinfection by chemical means 
 in bacterial affections has remained, as is shown in 
 
GENERAL CONSIDERATIONS 23 
 
 the case of the phenols, a pious hope, a consummation 
 devoutly to be wished for. It is quite true that the 
 specific serum therapy will have to be referred for its 
 ultimate reasons to chemical effects, although the eluci- 
 dation of the chemical processes herein involved is still 
 in its very infancy. But we already know that in some 
 cases of serum therapy we have to deal with the con- 
 comitant action of lecithins and other lipoids, and per- 
 haps soaps. The conditions seem to be more favorable, 
 however, in the battle against animal parasites, where 
 iodine, arsenic, and mercury compounds and certain 
 dye-stuffs have been shown to be efficient in doses not 
 injurious to man. In the case of dye-stuffs particularly 
 there has been established a distinct relationship between 
 constitution and effect upon the organism. 
 
 Some substances do not act as such for themselves, 
 but only through secondary products, which are formed 
 from them in the organism. The knowledge of such 
 transformations forms an important field of our study, 
 a field, however, which we can but casually touch upon 
 in this treatise. 
 
INORGANIC COMPOUNDS 
 
 In the action of inorganic substances we have to deal 
 with other considerations besides the local effects such as 
 are produced especially by free acids and alkalies. There 
 is above all the effect of the water, and in the case of 
 salts, since these are either used in solution or dis- 
 solved in the body, there are the various conditions 
 dominant in solutions. The salts in part dissociate 
 into their ions, and these, together with the undissociated 
 salt, are the cause of osmotic pressure. According as 
 the solution is hypotonic or hypertonic it will either 
 cause a flooding of the tissues or will effect an abstrac- 
 tion of water from them. In the case of hypertonic 
 solutions, we have to deal with salt action in its proper 
 sense, which manifests itself preponderatingly in an 
 increase of diuresis. 1 Further, the ions are the cause 
 of. specific effects. Blake 2 in his investigations, which 
 extended over several decades, determined that these 
 effects are due essentially to the electropositive com- 
 ponents. By directly introducing the substances into 
 the circulatory systems of living animals, he arrived at 
 the following conclusions: 
 
 (1) The action depends only upon the kations, and 
 has only very slight connections, if any, with the anions. 
 
 (2) In the same isomorphous group the activity bears 
 a distinct relationship to the atomic weight, the in- 
 
 1 Sollmann, Am. J. Physiol., 9, 13, 454 (1907). 
 
 2 Blake, Compt. rend., 1839; Proc. Roy. Soc., London, 1841; 
 Am. J. Sci., 1874; Ber., 14, 394 (1881). 
 
 24 
 
INORGANIC COMPOUNDS 25 
 
 tensity of activity increasing with the atomic weight. 
 The following groups are qualitatively equivalent: 
 
 (a) Li, Na, Rb, Tl, Cs, Ag, (K and NH 4 do not 
 
 fall in this series) ; 
 (6) Mg, Fe, Mn, Co, Ni, Cu, Zn, Cd; 
 
 (c) Ca, Sr, Ba; 
 
 (d) Th, Pd, Pt, Os, Au. 
 
 Blake characterizes these group effects in detail as 
 follows : 
 
 (a) Monovalent elements exert a powerful astringent 
 or contracting action upon the capillaries of the lungs. 
 They circulate through the nerve centers in greater 
 concentration than through the lungs, and they exer- 
 cise no appreciable effects upon the body capillaries. 
 
 (b and c) The salts of all divalent elements cause no 
 contraction of the capillaries of the lungs. They are, 
 however, detrimental to the heart action, and if ad- 
 ministered in sufficient quantity inhibit it entirely. 
 In smaller quantities the substances of the magnesium 
 group (6) act directly upon the hsemogastric nerve, 
 and presumably they act indirectly, by a reflex action, 
 upon the intestine nerve (nervus splanchnicus). The 
 members of the calcium group (c) act upon the spinal cord, 
 causing spasmodic contractions of the voluntary muscles. 
 
 (d) The salts of the trivalent and tetravalent metals 
 act principally upon the inhibitory as well as upon 
 the vasomotor centers of the medulla oblongata. For 
 the different valences of the same element there are 
 characteristic differences in the compounds. In general, 
 with increase in valence of the element there is an in- 
 crease in the number of organs affected. Thus, ferrous 
 compounds affect fewer organs than ferric, etc. 
 
 Blake later arranged the elements in isomorphous 
 
26 
 
 INORGANIC COMPOUNDS 
 
 series, according to their atomic weights and the degree 
 of their toxicity. The following is his table, the atomic 
 weights being taken by him from the international 
 table for 1908: 
 
 Group. 
 
 Element. 
 
 Atomic weight. 
 
 Lethal dose for 
 1 kgm. of animal 
 body. 
 
 (a) 
 
 Lithium. 
 
 7 03 
 
 1 2 
 
 
 Rubidium 
 
 85 5 
 
 12 
 
 
 Caesium 
 
 132 9 
 
 12 
 
 
 Silver 
 
 107 93 
 
 028 
 
 
 Gold. 
 
 197 2 
 
 003 
 
 n 
 
 Magnesium 
 Iron (II) 
 
 24.36 
 55.9 
 
 0.97 
 32 
 
 
 Nickel 
 
 58 7 
 
 18 
 
 
 Cobalt 
 
 59 
 
 17 
 
 
 Copper. 
 
 63 6 
 
 17 
 
 (c) 
 
 Zinc 1 
 Cadmium 2 
 
 Calcium 
 Strontium 
 Barium.. 
 
 65.4 
 112.4 
 
 40.1 
 87.6 
 137 4 
 
 0.18 
 0.085 
 
 0.50 
 0.38 
 08 
 
 (d) 
 
 Aluminum 
 
 27 1 
 
 007 
 
 
 Iron (III) . 
 
 55 9 
 
 004 
 
 
 Yttrium 
 
 89 
 
 004 
 
 
 Cerium (III) 
 Cerium (IV) . . 
 
 140.25 
 140 25 
 
 0.005 
 062 
 
 
 Thorium 
 Lanthanum 
 
 232.5 
 138.9 
 
 0.034 
 0.025 
 
 
 Didimium 
 
 142 
 
 017 
 
 
 Palladium 
 Platinum 
 
 106.5 
 194.8 
 
 0.008 
 0.027 
 
 
 
 
 
 We may add that uranium with the high atomic weight of 238.5 is ex- 
 ceedingly poisonous. Kobert, Arbeiten, 5, 1 (1890). 
 
 1 Gallium with an atomic weight of 70 is according to Rabuteau slightly 
 more active than zinc. Rabuteau, Compt. rend. soc. biol., 35, 310 (1883). 
 
 2 Compare Athanasiu and Langlois, Ibid. 47, 391, 496 (1895). 
 
INORGANIC COMPOUNDS 27 
 
 As before mentioned, potassium occupies, according 
 to Blake's investigation, an exceptional position, which 
 he, as in the case of nitrogen, connected with deviations 
 observed in the behavior of the spectrum. Sodium, on 
 the other hand, does not fit into the series in a quanti- 
 tative way. This exception on the part of sodium may 
 be explained by the odd and peculiar position of that 
 element as a special sub-group of the alkali metals in 
 the Mendelejeff system. There is also another point 
 of view, which we shall reach later, which will enable 
 us to understand this peculiarity. Potassium and am- 
 monium share with the other monovalent kations the 
 property of acting upon the capillaries of the lungs. 
 At the same time, they possess like the calcium group, 
 with which they are both isomorphous, the property 
 of contracting the voluntary muscles. Potassium is at 
 the same time a powerful cardiac poison. 1 This same 
 property is also observed to a certain degree to be 
 possessed by caesium and rubidium. In this case then, 
 the intensity of action increases with diminishing atomic 
 weight. Therefore, contrary to the original formulation of 
 Blake, but in accordance with the demands of the periodic 
 system, potassium shows properties in common with the 
 other alkali metals (excepting sodium) . Furthermore, quite 
 in accord with these facts, the " typical " element lithium 
 has only the faintest suggestion of the cardiac effect. 2 
 
 Binet has carried out a more exhaustive investigation 
 of the alkalies and alkaline earths 3 According to his 
 experiments, both groups in common cause in the central 
 nervous system a diminution of susceptibility for exci- 
 tation and they also cause a disturbance in the power 
 of contraction of the muscles. Preceding the latter effect 
 
 1 Astolfoni, Arch, intern. Pharmacodyn., 11, 381 (1903). 
 
 2 Botkin, Zentr. med. Wissensch., 1885, No. 48. 
 
 3 Binet, Compt. rend., 115, 251 (1892). 
 
28 
 
 INORGANIC COMPOUNDS 
 
 there are to be observed disturbances in respiration and 
 in heart action. In the case of warm-blooded animals, 
 these may cause death before the first general effects men- 
 tioned above become appreciable. There are found some- 
 times also (particularly in the case of barium and lithium) l 
 disturbances in the alimentary canal. Besides these 
 differences we observe strikingly characteristic and dif- 
 ferent effects for the chemical groups of the metals. 
 Thus, the alkalies cause stoppage of the heart in diastole 
 besides a motor inactivity through a general relaxation 
 of the muscles. The alkaline earths, on the other hand, 
 stop the heart in systole. Magnesium resembles the 
 alkali group in that it stops the heart in diastole, but 
 it is distinguished from that group in causing an early 
 paralysis of the peripheral nervous system. In the 
 case of mammals, barium is the most poisonous element 
 of the group for heart action and respiration. It is 
 further characterized by contraction effects. Calcium 
 acts predominantly upon the central nervous system, 
 producing a state of rigidity with retention of reflex 
 excitability and sensibility. 
 
 Lusanna 2 investigated the action of metallic chlorides 
 upon respiration and contractility in the faradic exci- 
 tation of the frog muscle, using solutions isotonic with 
 a 7 per cent sodium chloride solution, and arrived at 
 the following results : 
 
 
 Respiration 
 depressed. 
 
 Respiration 
 not affected. 
 
 Respiration 
 increased. 
 
 Contractility destroyed 
 Contractility not affected. . . 
 
 Ca, Hg, Cu 
 Ni, Co 
 Li, Mg 
 
 K 
 
 Na, Sr 
 
 NH 4 , Ba 
 
 1 Good, Am. J. med. sci., Feb., 1903. 
 
 2 Bull. soc. meU, 1907, No. 4. 
 
INORGANIC COMPOUNDS 29 
 
 According to Hebert 1 thorium, cerium, lanthanum, 
 zirconium, aluminum, and magnesium are posionous for 
 fish, plants, aspergillus niger, yeasts and soluble ferments. 
 The toxicity increases from magnesium (atomic weight 
 24.36) to lanthanum (138.9), to cerium (140.25), to chro- 
 mium (52.1), to aluminum (27.1), to thorium (232.5). 
 There can be seen no relation whatever in this case 
 between toxicity and atomic weight. 
 
 There have rather recently been discovered in the case 
 of magnesium, some very peculiar effects which remind 
 one of certain alkaloids. According to Meltzer 2 solutions 
 of magnesium salts injected either subcutaneously, intra- 
 venously or directly into the canal of the spinal cord 
 cause anaesthesia and retard respiration. Upon admin- 
 istering large amounts, the tonus of the vasomotor 
 center is impaired and somewhat before this the tonus 
 of the pneumogastric center is so affected, and there 
 is observed a deep general stupefaction with relaxation 
 of all the muscles. Of practical importance is the 
 statement of Meltzer that a deep general narcosis can 
 be obtained with quantities that do not influence heart 
 action, blood pressure, or respiration. According to 
 different authors, 3 we have to deal with a curare-like 
 action on the motor nerve ends while the sensory nerves 
 are said to be not at all affected. On the contrary, 
 Delhaye, 4 found that the diminution of excitability is 
 manifested more quickly and more intensely in the 
 sensory than in the motor nerve system that in the 
 former it is central and that it is curare-like only in 
 
 1 Hebert, J. physiol. path, gen., 9, 217 (1907). 
 
 2 Meltzer, Berl. klin. Wochenschr., 43, No. 3 (1906); Meltzer 
 and Auer, Am. J. physiol., 21, 449 (1908). 
 
 3 Wiki, Soc. biol., 60, 1008 (1906); Bardier, Soc. biol., 62, 
 843 (1907). 
 
 4 Delhaye, Bull. soc. roy. sci. med. nat., Brussels, 1908, 72. 
 
30 INORGANIC COMPOUNDS 
 
 regard to the motor endplates. According to him the 
 injurious effect of this treatment upon respiration and 
 upon the kidneys (resulting in a diminution of the 
 quantity of urine and the appearance of albumin and 
 cylinders in the urine), must preclude its therapeutic use. 
 
 The fundamental characteristic effect common to man- 
 ganese, iron, nickel, and cobalt, according to Wohlwill, 1 
 is the production of capillary hypersemia of the stomach 
 intestinal tract, and a consequent change in blood 
 pressure. This together with a direct action on the 
 central nervous system is probably responsible for the 
 nervous symptoms exhibited under treatment with these 
 substances. The manner in which these metals act is 
 very similar to the action of arsenic. But they differ 
 from arsenic in that they are not resorbed by the stomach 
 and intestinal tract. 2 
 
 It is already apparent from what has been said, 
 that the Blake laws are not universally valid. This 
 is particularly noticeable in the case of the action of 
 anions, an action which is practically denied by Blake. 
 He himself, however, made a note of the difference in 
 behavior of sodium orthophosphate and the pyrophos- 
 phate which like the metaphosphate is poisonous. He 
 sought to explain this difference by attributing it to 
 greater hydrolytic dissociation, resulting in the liberation 
 of a larger amount of free alkali. But this explanation 
 will not hold. Differences similar to those found in the 
 phosphoric acids also occur in the case of the vanadic acids. 
 
 Blake's negative results never referred to the halogens 
 and cyanogen, although their specific effects are in- 
 contestable. According to Bouchardat and Cooper, 3 
 
 1 Wohlwill, Arch. exp. Path. Pharm., 56, 404 (1907). 
 2 Shumoff-Sieber, Biochem. Ztr., 2, 190 (1906). 
 3 Frankel, Arzneimittelsynthese, 2d Ed., p. 5. 
 
INORGANIC COMPOUNDS 31 
 
 the general tendency with the halogens is a diminution 
 of effect with increase of atomic weight. But the rela- 
 tionship is different in the case of the sodium salts. 
 For here the fluoride is most poisonous. Then follow 
 in order the iodide, bromide and chloride. Their com- 
 parative toxicity may be judged by the following toxic 
 doses: fluoride, .02 gm.; iodide, 8 gms.; bromide, 10 
 gms.; chloride, 40 gms. 
 
 There is an essential difference in action between the 
 halogen salts and the sulphates in that the former are 
 easily resorbed, while the latter are resorbed only with 
 decided difficulty with the result that the sulphates 
 exhibit a specific saline action in the form of a purgative 
 effect. 
 
 According to Pauli 1 all ions act upon albuminous 
 substances, but there is an antagonism or opposition 
 between the two kinds. The kations precipitate such 
 substances, while the anions exhibit a counter effect. 
 The purgative action is related to this capacity for 
 precipitating albumin. Thus, the purgative effect in- 
 creases from the slightly astringent and laxative alkali 
 salts to the heavy metal salts, which cause caustic and 
 gastroenteritic effects. 2 . Among the anions themselves 
 also, the counterprecipitation and accordingly the anti- 
 purgative tendency varies, the halogens being most 
 active in this respect. And of the halogens iodine is 
 most effective, although it is exceeded by sulphocyanide. 
 
 For salts of the alkaline earths the anions can be 
 arranged in the order of the counter precipitation effect 
 as follows: SCN>I >Br>NO 3 >C1 >C 2 H 3 O 2 . For 
 salts of the alkalies the arrangement is reversed, viz.: 
 C 2 H 3 O2>Cl>N.O3>Br>I>SCN. The kations may be 
 
 1 Pauli, Munch, med. Wochschr., 50, No. 4 (1903). 
 
 2 Hofmeister, Arch. exp. Path. Pharm., 24, 247 (1888). 
 
32 INORGANIC COMPOUNDS 
 
 arranged in the order of their precipitating power as 
 follows: Mg>NH 4 >K>Na. 1 
 
 But we must remark here that the total specific 
 action upon the organism does not necessarily accord 
 with the ion effect. This is strikingly illustrated by 
 the action of alkaline earth ions in regard to the SCN 
 action. The alkaline earths are not themselves precip- 
 itants. Nor are the sulphocyanides of the alkalies. 
 Yet the two acting together will cause precipitation 
 of proteids. In living animals that have been moderately 
 dosed with sulphocyanides a subsequent dosage of 
 barium causes an acute sulphocyanide poisoning, while 
 strontium causes a hardly perceptible increase in the 
 sulphocyanide action and calcium has no effect at all. 2 
 
 In some other poison effects polyvalent kations can have 
 an action antagonistic to that of the monovalent kations. 
 
 A certain concentration of sodium ions is necessary 
 for the contractive action of frog muscles, 3 the Medusa 
 Gonionemus, 4 and fibers or strips of the heart muscle 
 of Chrysemis Marginata. 5 But if the sodium ions (or 
 in their place lithium, rubidium, or calcium ions) alone 
 are present, then they have a poisonous effect. If 
 frogs' muscles are suspended in a pure 7 per cent solu- 
 tion of sodium chloride, they attain in about an hour 
 a state of rhythmic spasms or convulsions that con- 
 tinues for twenty-four hours or longer. 6 Teleostier Fun- 
 dulus and its impregnated eggs die quickly in a pure 
 sodium chloride solution on account of the osmotic 
 
 1 Pauli, Hofmeister's Beitr., 5, 27 (1904). 
 
 2 Pauli and Frohlich, Wien Akad. Ber., 115, III, Abt., June, 
 1906. 
 
 3 Overton, Pfluger's Arch., 92, 115, 346 (1902). 
 
 4 Loeb, Am. J. Physiol., 3, 383 (1900). 
 
 5 Lingle, ibid., 4, 265 (1900). 
 
 6 Loeb, Festschr. fur Fick (Beitr. z. Physiol.), p. 101 (1899). 
 
INORGANIC COMPOUNDS 33 
 
 pressure of the sea water. 1 Gonionemus likewise stands 
 a diminution of osmotic pressure better than a pure 
 NaCl solution of normal pressure. This poisonous action 
 of the sodium ions can be overcome by the addition 
 of comparatively small amounts of trivalent kations. In 
 the case of Fundulus and Gonionemus the poisonous 
 
 effects are wholly destroyed by Ca, Ba, Sr, Mg, Pb, 
 it ii 
 
 Co, Fe, Zn, Mn, Cr, Al, while they are in part removed 
 ii n 
 
 by U and Th. There is no such action at all by Hg, 
 
 in 
 
 Cu, Cd, Ni, and Fe. 2 In the case of the frog muscles, 
 the rhythmical convulsions or spasms are not stopped 
 by Ba, Zn, Cd, and Pb, but they are stopped by K, 
 notwithstanding the fact that it is monovalent. 3 And 
 further, in the case of Fundulus and Gonionemus, the 
 presence of K ions is necessary, besides that of the 
 divalent ion for a complete restitution of the normal 
 function. The reason for this necessity of a definite 
 equilibrium of ions must probably be found in the action 
 of the ions upon those colloids which are necessary for life. 4 
 Herbst 5 makes the observation that for the develop- 
 ment of the eggs of Fundulus Mg ions are necessary as 
 well as Na, K and Ca. Furthermore, he finds that the 
 anions are not negligible, since chlorine, sulphuric acid, 
 and carbonic acid ions are also necessary. To a lim- 
 ited degree, however, substitution of these ions by 
 
 1 Loeb, Am. J. Physiol., 3, 327 (1900); Pfliiger's Arch., 80, 229 
 (1900). 
 
 2 Ibid., Am. J. Physiol., 6, 411; Pfliiger's Arch., 88, 68 and 93, 
 246 (1902). 
 
 3 Ibid., Pfliiger's Arch., 91, 248 (1902). 
 
 *Hoeber, Biochem. Zentr., 1, 497 (1903); Hoeber and Gordon, 
 Hofmeister's Beitr., 5, 432 (1904). 
 
 5 Herbst, Arch. f. Entwickl. Mechanik, 17, 306 (1904). 
 
34 INORGANIC COMPOUNDS 
 
 chemically related ones may be made. Thus, for exam- 
 ple, 8203 may to some extent be used to replace SO-*, 
 Br to replace Cl, and Rb or Cs for K. Moreover, in 
 some processes a certain excess of hydroxyl ions is 
 necessary. 
 
 The hsemolytic action of human blood serum is un- 
 affected by the addition of sodium chloride, potassium 
 chloride, or lithium chloride, but it is destroyed by 
 salts of the alkaline earths and also by an N/8 con- 
 centration of potassium sulphate. 1 
 
 Mathews 2 emphasizes the importance of both ions, 
 but interprets the results as a consequence of the dif- 
 ferent solution pressures and not of the different valences. 
 According to his theory the poisonous effect of any 
 given salt is inversely proportional to the sum of the 
 solution pressures of the ions. 
 
 In interpreting the results of such investigations we 
 must always consider that the poisonous effect of some 
 salts may be prevented by a certain saturation of the 
 cells with other and harmless salts. Thus, according 
 to Lesne and Richet fils, 3 sodium chloride administered 
 either simultaneously or previously protects the organ- 
 ism to a very considerable degree from the injurious 
 effects of potassium iodide, ammonium chloride, and 
 even of some salts of alkaloids. But this does not 
 hold true for all salts, and in many instances no appre- 
 ciable results could be found in this direction. 4 
 
 We must also bear in mind that a tolerance already 
 
 1 Hektoen, Zentr. Bakteriol., 35, 357 (1904). 
 
 2 Mathews, Am. J. PhysioL, 10, No. 6 (1904); compare Pond, 
 ibid., 19, 258 ,(1907). 
 
 8 Lesne and Richet fils, Arch, intern, pharmacodyn., 12, 237 
 (1903). 
 
 4 Lesne, Richet fils and Noe", Soc. biol., 57, 99, 238 (1904). 
 
INORGANIC COMPOUNDS 35 
 
 established in the organism which is being used for 
 experimentation on the effects of various inorganic 
 salts, plays a very important part in the results obtained. 
 To this fact, perhaps, may be attributed the exceptional 
 position of sodium in the series, for this element consti- 
 tutes the principal inorganic component of the fluids (or 
 humors) of the body. In this connection we may also 
 note, that, as we should expect, herbivora can stand potas- 
 sium salts far better than can carnivora. In the case 
 of calcium, the lower the stage of development of the 
 animal kind, tjie greater is the tolerance toward this 
 element. Also it is found that tolerance for calcium 
 is more easily established in youthful individuals than 
 in fully developed ones. For all substances which nat- 
 urally occur in the organism there may be assumed a 
 certain initial value or concentration which must be 
 passed before the effects are really comparable or meas- 
 urable. 
 
 Quite in agreement with the assumption of ionic 
 effect or action in these physiological studies is the great 
 importance of the degree of dissociation which is very 
 decidedly pointed out by the investigations of Dreser * 
 and of Kronig and Paul 2 upon the bactericidal action 
 of mercury salts. 
 
 From all this discussion it is self-evident that the 
 action of the individual elements is very largely de- 
 pendent upon the form of combination in which they 
 act. The powerfully toxic effect of free phosphorus 
 disappears at once when the substance is combined with 
 oxygen, as even phosphorus suboxide is entirely lack- 
 ing in toxic effect. 3 Arsenic is most toxic in its hydro- 
 
 1 Dreser, Arch. exp. Path. Pharm., 32, 456 (1893). 
 
 2 Kronig and Paul, Zeitschr. physik. Chem., 21, 414 (1896). 
 
 3 Robert, Therap. Gegenw., 5, 59 (1903). 
 
36 INORGANIC COMPOUNDS 
 
 gen compounds and oxygen compounds, the trioxide 
 having, of course, a particularly intense effect. The 
 phosphonium and arsonium compounds have essentially 
 the curare-like action of the organic quarternary am- 
 monium salts. Finally, the compounds of the cacodyl 
 type produce a characteristic arsenic effect proportional 
 to the ease with which the organism can oxidize them 
 to arsenic trioxide. 1 
 
 The complex ions containing cyanogen with iron have 
 an action not at all similar to their action as more 
 simple ions. This point is clearly shown by the fer- 
 rocyanides, ferricyanides, and sulphocyanides. Further- 
 more, the different action of a single element with different 
 valences may find its explanation in the difference of 
 the corresponding ions*. 
 
 Above all, although the ionistic conception has been 
 sufficiently justified by other experiences, we must men- 
 tion the difference in behavior ordinarily to be looked 
 for when an element is bound up in organic non-elec- 
 trolytes. The specific action of an element in such a 
 condition can only be expected after its transition into 
 the ionic state, and, therefore, it must generally come 
 into play in a slow, mild, and continuous manner. 
 
 An example of such an effect has already been men- 
 tioned in the discussion of the cacodyl compounds. 
 
 The same explanation seems to hold in the case of 
 compounds which have been recently accepted and 
 much used of the type of p-aminophenyl arsinic acid. 
 This substance is found in trade under the name of 
 Atoxyl, and was formerly erroneously supposed to be 
 meta-arsenous acid anilide. 
 
 While we are discussing the organic arsenic compounds 
 it may not be out of place to devote some space to a 
 iKobert, I.e.; Martinet, Bull. gen. Therap., 155, 70 (1908). 
 
INORGANIC COMPOUNDS 37 
 
 consideration of a little of their history, and the path 
 which has led to that most recent compound which 
 has caused tremendous excitement even outside the 
 scientific world salvarsan. 
 
 As early as 1837 Bunsen observed that cacodylic acid 
 seemed to be less toxic (for frogs) than inorganic arsenic 
 compounds. But Lebahn showed in 1869 and H. Schulz 
 in 1879 that cacodylic acid, dimethyl arsinic acid 
 (CH 3 )2AsOOH and also diphenyl arsinic acid are deadly 
 poisons for warm-blooded animals, although slower in 
 action than the inorganic arsenic compounds. Hefter, 
 Kobert, and others arrived at the conclusion that such 
 compounds act in proportion to their mineralization in 
 the organism. There were various such compounds pre- 
 pared and introduced for use; but the one which served 
 as the starting-point for Ehrlich's investigations is the 
 afore-mentioned Atoxyl. It was soon observed that the 
 various compounds prepared did not act entirely as if 
 their effect depended upon mineralization alone. In fact, 
 they were observed to have specific effects against infec- 
 tious diseases. This was first observed in the case of 
 trypanosome diseases. Thereupon arsenic returned to 
 the first application which it had as a popular remedy 
 against recurrent fevers or malaria. Its usefulness against 
 sleeping-sickness and other trypanosome diseases was 
 determined in the French colonies by Laveran and Mesnil. 
 Thomas, and later Robert Koch used atoxyl for com- 
 bating the sleeping-sickness. A serious hindrance to 
 its usefulness, however, was the pronounced side-effects 
 and the slowness and uncertainty of the cure. It was 
 then to be hoped that the effect upon the parasites 
 might be increased and the effect upon the host de- 
 creased. The necessary changes in the constitution of 
 atoxyl were made clear when Ehrlich and Bertheim 
 
38 INORGANIC COMPOUNDS 
 
 discovered that the constitution ascribed to atoxyl was 
 incorrect and that it is the mono-sodium salt of the long- 
 known p-aminophenyl arsinic acid, NH2CeH4As03H 2 , 
 which is designated arsanilic acid. The first step in 
 the variation of amino compounds is usually to introduce 
 acid radicles. The introduction of acetyl gave a prep- 
 aration called arsacetine, the sodium salt of acetyl arsan- 
 ilic acid. This was effective and little toxic for some 
 animals, particularly mice; but was not suitable for 
 use upon man. A better compound was found when 
 the acetyl radicle was attached to the amino group 
 by means of the methyl instead of carboxyl. This 
 gave arsanilacetic acid, AsOsH 2 C6H4 NHCH 2 COOH. 
 It was then found that trypanosomes in vitro were not 
 killed by this compound, but by its reduction products, 
 and that probably, as in the organic compounds of 
 pentavalent arsenic, the real effect is due to a reduction 
 in the organism to trivalent arsenic. Among such tri- 
 valent arsenic compounds which were found to be power- 
 ful against protozoa, but only slightly toxic for the 
 higher organisms are the derivatives of amino-phenyl- 
 arsen-oxide, NH 2 CeH4 AsO, and derivatives of diam- 
 ino arsenobenzol, NH 2 CeH4 As = As CeH4 NH 2 , 
 particularly arsenophenyl glycine, 
 
 As C 6 H 4 NH CH 2 COOH 
 As C 6 H 4 NH CH 2 COOH 
 
 The next step that was taken was a further introduction 
 of substituents in the benzol ring. It was found that 
 ortho substitution of most groups impaired the effect; 
 but halogen increased it. About the next advance was 
 to try some of the trypanocides upon spirillae diseases. 
 Atoxyl was tried upon cases of syphilis. Its close 
 
INORGANIC COMPOUNDS 39 
 
 derivatives were also tried, but in general the side effects 
 are too great, compared with the advantageous action. 
 The benzol sulpho derivative of atoxyl, however (which 
 is called Hectine) , and the mercury salt of arsanilic acid 
 are said by some to be effective. It was next found 
 that a powerful spirillocide was obtained by replacing 
 with hydroxyl the amino group of di-para-aminoarsen- 
 obenzol. This gives para-arsenophenol. Then the most 
 effective substance was found by introducing amino 
 groups in the ortho position to the hydroxyls in arseno- 
 phenol. This gives dioxy-di-amino-arsenobenzol, whose 
 hydrochloride is Salvarsan. 
 
 This compound is prepared by the nitration and 
 subsequent reduction of para-oxy-phenyl arsinic acid, 
 which is formed directly from phenol and arsenic acid. 
 It was hoped and at first supposed that in this sub- 
 stance we had an agent which at one fell stroke could 
 kill all the protozoa in the organism, and thus avoid 
 the possibility of some of them becoming immune. 
 But results have seemed to show that in some cases 
 either some spirochetse are relatively immune to the 
 arsenic from the start or they are protected from its 
 action by their location. Doubtless there are many 
 cases that are promptly and permanently cured by 
 salvarsan, as there are also many that are curable by 
 
40 INORGANIC COMPOUNDS 
 
 mercury. In other cases, perhaps it is necessary to 
 adopt a method previously indicated by Ehrlich namely, 
 that of combination therapy. 
 
 The disadvantages, which occasionally accompany the 
 use of salvarsan are attributed by Ehrlich to its in- 
 stability toward atmospheric oxygen. Neosalvarsan is 
 the result of an attempt to avoid this deterioration due 
 to the attack of oxygen. Salvarsan was combined with 
 sodium methanal sulphoxalate. This compound dis- 
 solves readily in water with a neutral reaction to litmus, 
 seems to be less toxic and more easily tolerated than 
 salvarsan, and produces less injurious side effects. 
 
 In cases where the element itself in non-ionized form 
 is active, as for example in the case of iodine, it seems 
 that the effect is dependent upon a dissociation or 
 breaking down into elementary form, which is somewhat 
 similar to ionization. 
 
 But sometimes it seems to be just certain organic 
 compounds of inorganic elements that exercise a peculiar 
 and specific effect. In such cases, of course, for the 
 attainment of this particular effect, the use of such 
 compounds is from the beginning clearly indicated and 
 to be expected. For example, such is pre-eminently 
 the case for many iodine compounds. After a sub- 
 stance containing iodine had been extracted from the 
 thyroid gland and had been recognized as its active 
 constituent then iodothyrine, iodogorgonic acid, etc., 
 obtained from this secretion were used to obtain the 
 specific effects desired. 
 
 The advantages of the halogenized fats (lodipine, 
 Bromipine), and of the salts of the halogenized fatty 
 acids (Sajodine, Sabromine) may be due essentially to 
 their milder and long continued action on account of 
 the necessity for a preliminary ionization. There is, 
 
INORGANIC COMPOUNDS 41 
 
 however, the possibility that their advantage may be 
 dependent upon a condition more favorable to resorp- 
 tion and assimilation. Such favorable conditions for 
 assimilation have also been assumed to hold for organic 
 iron compounds and also in various compounds through 
 which phosphorus is introduced into the organism. 
 Through such an assumption a special importance or 
 efficiency has been claimed for the lecithins, glycero- 
 phosphoric acids, and particularly for Phytin, which 
 is a double calcium and. magnesium salt of anhydro- 
 oxymethylene-diphosphoric acid. Whether or not all 
 these assumptions will hold must be considered to be 
 still an open question. 
 
 It is undoubtedly possible to cause the metals to ^ 
 penetrate further into the tissues if they are in com- 
 bination in organic molecules than if they were in the 
 form of electrolytes, because of the precipitating effect 
 that such electrolytes have upon albuminoids. Thus, 
 they may be employed to obtain results in otherwise 
 unreachable places. 1 The importance of many com- 
 pounds of this class depends upon this property or 
 ability for penetrating the tissues in an unprecipitated 
 condition. In this connection may be mentioned as 
 an example the wide use of certain organic silver com- 
 pounds such as Argyrol. 
 
 A special place in the science of medication is occupied 
 by colloidal solutions of the metals. Since all influence 
 of the anions is eliminated in such a case we may per- 
 haps expect a particularly clear and undisturbed effect 
 of the kations. It cannot yet be decided whether it 
 is upon this fact that the professed great efficacy of 
 these solutions in infectious diseases depends, or whether 
 there is at the same time a catalytic effect. 
 
 Compare Pauli, Wien. klin. Wochschr., 17, 558 (1906). 
 
42 INORGANIC COMPOUNDS 
 
 At all events it is quite certain that all varieties of 
 metal colloids are not equivalent. Luzzatto 1 has made 
 tentative experiments upon the influence of various 
 colloids upon the resorption of medicinal substances. 
 1 Luzzatto, Arch, fisiol., 1905, II, 10. 
 
ORGANIC COMPOUNDS 
 
 Aliphatic Series 
 
 According to Lauder Brunton and Cash, hydrocar- 
 bons act quite generally upon the nerve centers. In 
 the aromatic series this action is principally confined 
 to the motor centers, while in the aliphatic series it 
 affects essentially the sensory centers. In the case of 
 the aliphatic series there is a very pronounced narcotic 
 and anaesthetic effect, whether the application is sub- 
 cutaneous or by inhalation. According to a law pro- 
 pounded by Richardson 1 this effect increases (in the 
 paraffine series) with the increase in carbon content 
 of the molecule. Coincident with this narcotic effect, 
 and in marked contradistinction to that caused by 
 substances of the morphine group, there is observed a 
 reduction of the reflex excitability. 
 
 Naturally the increase in effect of the members of the 
 series with increase of carbon content finds its limit 1 
 in the physical properties of the substances. The high 
 boiling paraffines of high molecular weight are practically 
 without any action on the orgahism. This is easily 
 understood, since substances of the paraffine series are 
 hardly capable of resorption and consequently their 
 entry into the organs is possible only by evaporation, 
 and is therefore dependent upon their vapor tension. 
 
 1 Richardson, Med. Times and Gaz., 1871. 
 
 43 
 
44 ORGANIC COMPOUNDS 
 
 For a given carbon content unsaturated hydrocarbons 
 act more powerfully than saturated hydrocarbons. Thus, 
 for example, ethylene is much more active than ethane. 
 In this connection we must observe that the double 
 bonds in a cyclic system have less effect upon the in- 
 tensity of action than do the double bonds in an open 
 chain. 
 
 For example, let us consider the three hydrocarbons, 
 
 Pentane, CH 3 CH 2 CH 2 CH 2 CH 3 
 
 CH 
 Pental, 
 
 CHj 
 
 and, 
 
 Cyclopentadine | ;>CH 2 
 
 =CK 
 ;> 
 / 
 
 Of the three we find pental to be most active, 
 cyclopentadine second, and pentane least active. 
 
 Pental is perhaps the only body of this series which 
 has found practical application. And we may remark 
 that it exhibits a grouping which has also demonstrated 
 its efficiency in other series. This grouping is an arrange- 
 ment of alkyl groups about a center. As we shall soon 
 note, the ethyl group is in general considerably more 
 powerful in its effect than the methyl group. Now then, 
 we should expect to be able to increase the activity of 
 this body considerably by replacing the methyl by ethyl 
 groups and also still further by the replacement of hydro- 
 gens by alkyl radicles. 
 
 In its fundamental character the narcotic action of 
 the monobasic alcohols and their ethers, neutral esters, 
 ketones, aldehydes and halogen derivatives is the same as 
 for the hydrocarbons themselves. But the intensity of 
 this action paries widely and is quite decidedly deter- 
 
ALIPHATIC SERIES 45 
 
 mined by the nature of the compound and the sub- 
 stituting group or element. 
 
 The halogen derivatives, and particularly the chlorine 
 derivatives, show a very considerably greater hypnotic 
 action than do the hydrocarbons. This increase in 
 power depends, in the first place, upon the halogen 
 content and is proportional to it. Thus, methane has a 
 barely perceptible narcotic action. Monochlormethane 
 is weakly narcotic, dichlormethane is still more powerful, 
 and chloroform and carbon tetrachloride, as is well 
 known, are both very powerfully active. Other effects 
 besides the narcotic action also increase with increasing 
 halogen content. 
 
 A depression of the heart and vascular activity is 
 hardly noticeable in the case of the hydrocarbon. But 
 it is plainly apparent with the halogen derivatives and 
 is proportional to the halogen content. Thus, Zoepffel l 
 found that the pulsations of a frog's heart were stopped 
 after the administration of chloroform in only one- 
 fourth the molecular concentration that was necessary 
 for the same effect with dichlormethane. 
 
 Dichlormethane and carbon tetrachloride do not fall 
 perfectly into the series because they produce powerful 
 side-effects, manifested by convulsive spasms of such 
 violence that the narcotic action is forced into a position 
 of secondary importance. This special action, also, 
 bears a definite relation to constitutional differences in 
 composition. For, if we conceive of the halogen deriv- 
 atives of the hydrocarbons as being the halogen acid 
 esters of the corresponding hydroxyl bodies, then, as 
 Brissemoret 2 showed, we can find a concordance between 
 the actions of the hydroxyl compounds, as well as their 
 
 1 Zoepffel, Arch. exp. Path. Pharm., 49, 89 (1903). 
 
 2 Brissemoret, Bull. gen. Therap., 153, 657 (1907). 
 
46 ORGANIC COMPOUNDS 
 
 alkyl ethers. Thus, formaldehyde and its acetals cor- 
 respond to dichlormethane, while we have carbonic 
 acid and its esters corresponding to carbon tetrachloride. 
 Upon examining the other two classes of compounds, 
 we find that methyl alcohol and methyl ether corre- 
 sponding to monochlormethane, and ortho formic acid 
 and its esters corresponding to chloroform, are, without 
 exception, real anaesthetics or hypnotics. 
 
 In the ethane series there are additional differences 
 to be noticed, and these may be referred to the dis- 
 tribution of the chlorine atoms between the two carbon 
 atoms. Thus, ethylene chloride and ethylidene chloride, 
 although they both have the empirical formula C2H4C12, 
 show certain marked differences in narcotic effect and 
 also in side effects. 
 
 The bromine derivatives show actions quite similar 
 to those of the chlorine derivatives. Ethyl bromide 
 has found application as an inhalation anaesthetic, and, 
 although bromoform is not sufficiently volatile for this 
 purpose, it has nevertheless been used for mitigating 
 the paroxysms of whooping cough. 
 
 According to Binz, 1 iodoform taken internally acts as 
 a narcotic and hypnotic. Mulzer, 2 however, denies that 
 this is the case for all animal organisms. Such an action 
 was observed by him for dogs, but not for rabbits. But 
 there comes strongly into play in the iodine-substituted 
 compounds another very important effect, and that is 
 their antiseptic action. This has been generally attrib- 
 uted to the demonstrable liberation of iodine from the 
 compound in the organism. 3 
 
 With the substitution of hydroxyl for a hydrogen in 
 
 j^ 
 
 1 Binz, Berl. klin. Wochschr., 32, No. 7 (1885). 
 
 2 Mulzer, Z. exp. Path. Ther., 1, 446 (1905). 
 
 3 cf. Schiirhoff, Arch, intern, pharmacodyn., 14, 427 (1905). 
 
ALIPHATIC SERIES 47 
 
 the hydrocarbons the conditions become exceedingly 
 interesting. With a single substitution we have, of 
 course, instead of the hydrocarbon a monatomic alcohol. 
 This increases the hypnotic action of the compound 
 sufficiently so that these alcohols are practically useful 
 hypnotics. In accordance with the Richardson law, we 
 find the action to increase with the length of the straight 
 carbon chain. So the longer the CH chain is, the greater 
 will be the increase in hypnotic effect when the monatomic 
 alcohol is formed. Furthermore, the secondary alcohols 
 show a greater hypnotic effect than the primary alco- 
 hols, and the tertiary alcohols exhibit a still more power- 
 ful action. In these latter, particularly even more than 
 in the secondary and primary alcohols, there is to be 
 observed a specific influence of the ethyl group. For 
 example, it requires the administration of as much as 
 4 gms. of trimethyl carbinol'to induce sleep, while evenj 
 2 gms. of ethyl-dimethyl carbinol will induce a sleep 
 lasting from eight to nine hours. And the adminis- 
 tration of only 1 gm. of tri-ethyl carbinol induces ten 
 to twelve hours of sleep. 1 But the practical applica- 
 tion of this latter substance for its hypnotic effect is 
 precluded, because of the side-effects consisting of dif- 
 ficulty in breathing when doses as large as 1 gm. are 
 used and a powerful excitation for lesser doses. Thus, 
 for practical purposes, the ethyl-dimethyl carbinol is the 
 only one of these substances available for inducing sleep. 
 
 This rather specific influence of the ethyl group which , 
 we shall later notice repeatedly seems to depend upon 
 the fact that it has a special relationship to the 
 nervous system. This has indeed been shown to be the 
 case by color experiments of Ehrlich and Michaelis. 2 
 
 1 Schneegans and v. Mering, Therap. Monatsh., 1892, 331. 
 
 2 Leyden-Festschrift. 
 
48 
 
 ORGANIC COMPOUNDS 
 
 They showed that nerves were colored by dyes con- 
 taining diethylamino groups, while they were not so 
 affected by the corresponding methyl compounds. We 
 must remark here, however, that this peculiarity of the 
 ethyl group holds only in comparisons with the methyl 
 group. Propyl groups we shall find equivalent to r or 
 even stronger than ethyl groups in a given series. But 
 we also find that the alkyl compounds of higher molec- 
 ular weight are excluded from practical application 
 not because their narcotic effect is too weak, but because 
 their undesirable secondary effect is too strong. Thus, 
 it appears from an investigation by Rather 1 that we 
 have the following relative toxic values as measured 
 by the paralysis of conductivity for centripetal stimulus 
 in a frog. 
 
 Point of stimulation. 
 
 CH 4 
 
 C 2 H 6 O 
 
 C 3 H 8 O 
 
 C4H, O 
 
 C 5 Hi 2 O 
 
 Ischiadicus 
 Cornea 
 
 1 
 1 
 
 3 
 3 
 
 18 
 30 
 
 36 
 90 
 
 120 
 225 
 
 Foot. 
 
 1 
 
 2 
 
 5 
 
 20 
 
 50 
 
 
 
 
 
 
 
 There is likewise found a regular increase in action 
 from methyl to ethyl to propyl alcohols in their action 
 upon ciliated tissue and motor nerve fibers 2 on the 
 development of moulds 3 and of sea urchin eggs. 4 
 
 In regard to that part of the influence which is due 
 to the physical properties of the substance, we must 
 refer to the general part of this work. 
 
 We have already noted that the substitution of hydro- 
 
 1 Inaugural-Dissertation Tubingen, 1905. 
 
 2 Breyer, Pfliiger's Arch., 99, 481 (1903). 
 
 3 Iwanhoff, Zentr. Bakteriol. (II), 13, 139 (1904). 
 'Fiihner, Arch. exp. Path. Pharm., 59, 1 (1908). 
 
ALIPHATIC SERIES 49 
 
 gen by halogen in the hydrocarbons increased the nar- 
 cotic power of the compound. The same condition 
 holds in the case of alcohols. 
 
 As a practical result of this knowledge we find a product 
 put upon the market by the Elberfeld Farbenfabriken 
 under the name of Isopral. This is trichlorisopropyl 
 alcohol. 
 
 When several hydrogen atoms of the hydrocarbon 
 are substituted by hydroxyl groups we must distinguish 
 two different sorts of results. In the first place, if the 
 substitution takes place on the same carbon atom, 
 then the narcotic effect is either maintained or strength- 
 ened. The aldehydes and ketones (if we disregard their 
 other properties) are decided narcotics. The same thing 
 is true, as we have already mentioned, for ortho formic 
 acid, acetic acid and their esters. But if the substitu- 
 tion takes place on different carbon atoms the result 
 is different. For the polyatomic alcohols as well as 
 the oxyaldehydes (aldoles) and the oxyketones are 
 lacking in hypnotic power, and this lack of power is 
 proportional to the number of hydroxyl groups present. 
 But the accumulation of alkyl groups about the carbon 
 atoms which bear the hydroxyl groups seems to effect 
 a compensation, or neutralizing of the action of the 
 hydroxyl groups. Thus, some pinacones have been 
 found to be active. Here again the favorable influence 
 of the ethyl groups is clearly noticeable. For example, 
 the dose of methyl pinacone, 
 
 GH 3 , y 
 
 >C(OH) C(OH)< 
 GH/ N CH 3 
 
 required to produce sleep is 10 gms., while only 2 gms. 
 are required in the case of methyl-ethyl pinacone, 
 
50 ORGANIC COMPOUNDS 
 
 /^TT 
 
 3 \C(OH) C(OH)/ 
 
 
 C 2 H 5 
 and finally, only 1.5 gm. of ethyl pinacone, 
 
 C(OH) 
 
 In general, the effect of the hydroxyl group remains 
 unaltered or at most only slightly modified when an 
 alkyl group is substituted for the " typical " hydrogen 
 atom, although such a substitution causes the sub- 
 stance to be more resistant toward the organism. Thus, 
 in a very general way we can see a similarity in the 
 action of ethers and acetals to the action of their funda- 
 mental compounds. But there is a series of important 
 exceptions to this general rule which, however, concern 
 chiefly the compounds of the aromatic series. 
 
 Aldehydes and Ketones 
 
 Even acetaldehyde shows a distinctly hypnotic action. 
 This effect is exhibited in a greater degree by the poly- 
 meric paraldehyde (C2H 4 0)3 which at the same time 
 causes less preliminary excitation than the simpler body. 
 The acetals are feeble sleep producers, and there is no 
 appreciable difference in this respect between methylal 
 and the ordinary acetal. Analogous to the difference 
 in behavior of acetaldehyde and paraldehyde is the dif- 
 ference between the corresponding sulphur compounds, 
 thioaldehyde and tri-thioaldehyde. 
 
 The influence of the substitution of halogens is again 
 very prominently shown in these compounds. Tri- 
 chloracetaldehyde, (Chloral) or rather, Chloral hydrate, 
 
ALIPHATIC SERIES 51 
 
 which is easily formed by the addition of water, is a very 
 strong narcotic. It was Liebreich who introduced this 
 first synthetic therapeutic agent (chloral hydrate) and 
 thereby gave a tremendous impulse to the modern 
 synthesis of such substances. He thought that its action 
 was dependent upon the splitting off of chloroform, 
 a reaction which is easily accomplished outside the 
 organism by means of alkaline liquids. Accordingly, 
 he considered as useful hypnotics all those compounds 
 which have three chlorine atoms, firmly enough bound 
 to one carbon atom to make possible the formation 
 of chloroform. Although this hypothesis resulted in 
 such a beautiful practical success, it can hardly claim 
 any advocates to-day. For it is very questionable 
 whether there are at all appreciable quantities of chlor- 
 oform produced in the organism from chloral hydrate. 
 The larger part of it, as von Mering has showed, is 
 converted into trichlorethyl alcohol, which conjugates 
 with glucuronic acid, with the resultant formation 
 of urochloralic * acid or trichlorethylglucuronic acid 
 (C2C1 3 H2-C 6 H9O7). Trichlorethyl alcohol itself acts 
 exactly like chloral. On the other hand, the trichlor- 
 acetic acid obtained by the oxidation of chloral is said 
 to be without hypnotic properties. Although there have 
 been observations to the contrary, they have been at- 
 tributed to impurities in the sodium trichloracetate 
 used, a substance which it is exceedingly difficult to 
 obtain in a pure state. Now trichloracetic acid will 
 split off chloroform as easily as will chloral, and under 
 similar conditions. So Liebreich's hypothesis must be 
 considered untenable. 
 
 Chloral has certain disagreeable effects, especially an 
 irritant action which depends upon the presence of the 
 aldehyde group. Therefore, it was natural to make 
 
52 ORGANIC COMPOUNDS 
 
 use of the capacity of this group for easy reaction and 
 to prepare compounds which it was hoped would be 
 devoid of these disagreeable side-effects. ' Such a series 
 of derivatives has been made, and the results of an 
 examination of these substances are interesting because 
 they support the assumption that the aldehyde group 
 participates in the action of chloral hydrate. For of 
 these derived bodies the only ones which had the desired 
 hypnotic action were those from which chloral could 
 be easily reproduced. The more stable ones were not 
 only less active as hypnotics, but were often strongly 
 toxic. The result is that attempts in this direction have 
 been fruitless, for in those cases where the desired hyp- 
 notic effect was attained the undesirable action of chloral, 
 especially the effects upon the heart and respiration, 
 was correspondingly pronounced. There are, however, 
 some of the compounds which have the advantage of 
 avoiding the disagreeable effect upon the stomach, 
 because the chloral splits off in the lower parts of the 
 digestive tract. We may thus classify the following 
 from the compounds which have been prepared : 
 1. As sufficing for hypnotic effect: 
 
 Chloralamide, CC1 3 CH(OH) NH CHO, or more 
 correctly chloral formamide, splits off chloral hydrate 
 slowly in the organism. 1 
 
 Chloralose or anhydro-gluco-chloral is a condensation 
 product of chloral and glucose. 2 
 
 The poison effects quite recently observed in the use 
 of this substance are said to be due to the fact that 
 there is formed beside the useful chloral, varying amounts 
 of another substance, parachloralose, which has no 
 hypnotic action, while it does produce nausea, rise in 
 
 1 v. Mering, Therap. Monatsh., 1889, 565. 
 2 Heffter, Ber., 22, 1050 (1889). 
 
ALIPHATIC SERIES 53 
 
 temperature, and a subsequent subnormal tempera- 
 ture. 1 
 
 Very similar to this seems to be the case in the con- 
 densation products of chloral with pentoses. 2 
 
 Dormiol or dimethyl-ethyl-carbinol-chloral is a con- 
 densation product of chloral and amylene hydrate. 3 
 Hypnal or monochloral antipyrine. 4 
 
 Compounds with the ortho forms, as 
 
 Chloran, an addition product of acetone-chloroform 
 with chloral, 
 
 /OH 
 
 CC1 3 CO C^-CH 2 GG1 3 . 
 \CH 3 
 
 2. As insufficient for hypnotic effect: 
 
 Chloral ammonium, or trichloraminoethyl alcohol, 
 CC1 3 -CH(NH 2 )OH.\ 
 
 Chloralimide, CC1 3 -CH=NH. 
 
 Chloralcyanohydrate, CC1 3 -CH(OH)CN, which de- 
 composes with difficulty with the formation of hydro- 
 cyanic acid. 
 
 Chloral acetone, CC1 3 - CH(OH) - CH 2 CO - CH 3 . 6 
 
 Monochlorurea and dichlorurea. 
 
 Chloralurethane, CC1 3 - CH(OH)NH CO 2 C 2 H 5 . 
 
 Chloral acetophenone, CC1 3 CH(OH) CH 2 - CO - C 6 H 5 , 
 which is converted in the organism to trichlorethylidene- 
 acetophenone, CC1 3 CH=CH CO C 6 H 5 . 
 
 Chloral acetophenoneoxime. 
 
 Of the higher homologues of chloral the butyl chloral, 
 
 1 Mosso, Chloralosio e Parachloralosio, Genoa, 1894. 
 
 2 Henriot and Richet, Semaine medic., 1894, No. 70. 
 
 3 Fuchs and Koch, Munch, med. Wochschr., 1898, No. 37. 
 
 4 Hertz, Therap. Monatsh., 1890, 243. 
 
 5 Nesbitt, Therap. Gaz., 1888, p. 88. 
 6 K6nigs, Ber., 25, 794 (1892). 
 
54 ORGANIC COMPOUNDS 
 
 , acts very much like ordinary 
 chloral. A condensation product of this body with 
 pyramidone which, put upon the market under the 
 name of Trigemin, has been recommended by Overlach 
 for use in cases of neuralgia, especially neuralgia of the 
 trigeminus. 
 
 The ketones in general possess hypnotic properties, 
 which appear most distinctly and prominently empha- 
 sized above the side-effects when there is an ethyl group 
 in the compound. Thus, dimethyl ketone causes, coin- 
 cident with a hypnosis like that observed in drunk- 
 enness, an excitation of the heart and a subsequent 
 paralysis of the central nervous systern.' But diethyl 
 ketone is a real and correct sleep producer with no 
 effect whatever on the heart action. Similar, but less 
 pronounced, is the action of dipropyl ketone. The 
 aromatic ketones, such as benzophenone, act less power- 
 fully than the aliphatic ketones, and, ranking between 
 the two in physiological activity, as we should expect, 
 are the mixed ketones of the type of acetophenone. 
 And in this series of compounds the intensity of the 
 action is essentially determined rather by the nature 
 of the aliphatic component group than by the aromatic 
 group. According to Fuchs and Schultze 1 the ketoximes 
 are more intense in hypnotic action than the related 
 ketones; but they have at the same time a harmful 
 effect upon the digestive system. 
 
 Acids and Their Derivatives 
 
 The fatty acids exhibit a hardly perceptible narcotic 
 
 action. Here, as in other cases, the carboxyl seems to 
 
 reduce the effect of the compound. For when this 
 
 1 Fuchs and Schultze, Munch, med. Wochschr., 51, 1102 (1905). 
 
ALIPATHIC SERIES 55 
 
 group is replaced, as by an alkyl or by an amide group, 
 the action is again more pronounced. There is to be 
 observed in this case, again, within certain limits, an 
 increase of effect with increased carbon content. Thus 
 for example, certain esters and amides of valerianic 
 acid are more active than the corresponding derivatives 
 of acids of lower molecular weight. Hans Meyer 1 was 
 the first to establish in the case of the aliphatic acid 
 amides the fact that their physiological activity in- 
 creased with their molecular weight and that at the 
 same time the compounds increased in solubility in ether 
 and fat. According to Harrass, 2 the administration of 
 amides is accompanied not only by a narcotic effect, 
 but also by phenomena similar to the spasmodic cramps 
 caused by ammonia, which latter, however, are cer- 
 tainly not due to the ammonia component alone. Both 
 effects are increased by alkylation on the nitrogen. 
 The only compound of this sort that has come into 
 practical use is valerianic acict diethylamide, which is 
 marketed under the name of Valyl. The introduction 
 of alkyl groups upon the carbon atom of acetanilide 
 results in only slightly active bodies; but if at the 
 same time the third hydrogen atom is replaced by a 
 halogen (e.g. bromine) there are formed some very 
 effective sleep producers, such as diethylbromacetamide, 
 ethylpropylbromacetamide, and dipropylbromacetamide. 
 The diethyl compound, 
 
 Br/ 
 
 is used under the name of Neuronal. 3 
 
 1 H. Meyer, Arch. exp. Path. Pharm., 42, 109 (1899). 
 
 2 P. Harrass, Arch, intern. Pharmacodyn., 11, 431 (1903). 
 
 3 Fuchs and Schultze, Munch, med. Wochschr., 51, 1102 (1905). 
 
56 ORGANIC COMPOUNDS 
 
 Under the name Adalin there has been introduced 
 brom-diethylurea, which is recommended as a sedative 
 and mild hypnotic, harmless to the heart and respira- 
 ation in therapeutic doses. Such an action could have 
 well been predicted for this compound. Although the 
 general hypnotic action of the aliphatic compounds 
 disappears when carboxyl is introduced, it reappears 
 when this group is covered by an alkyl or amide group. 
 Now the two things which increase this effect are the 
 accumulation of alkyl, especially ethyl groups, and the 
 introduction of halogen. Thus, although di-ethyl-aceta- 
 mide, 
 
 5 v 
 
 >CH.CO-NH 2 
 C 2 H/ 
 
 is too weak to be therapeutically useful, if bromine is 
 introduced in place of the remaining hydrogen, we 
 have Neuronal, 
 
 C 2 H 5v Mr 
 
 y c \ 
 
 C 2 R/ N CONH 2 
 
 which can be utilized as a hypnotic. It is to be noted, 
 too, that in general the urea derivatives are more power- 
 ful than the ammonia derivatives. Brom-diethyl-acetyl- 
 urea, 
 
 Br 
 
 C 2 H 5 // \X).NH. CO- NH 2 
 
 has the same relationship to Neuronal that urea has to 
 ammonia. Another representative of the group is Brom- 
 ural, which is an a-brom-isovalerianyl urea, 
 
 CH 3X /Br 
 
 >CH-CH< 
 CH/ \CO-NH. CO. NH 2 
 
ALIPATHIC SERIES 57 
 
 This is constitutionally different from Adalin in that 
 the bromine is attached to a different carbon atom 
 from that which carries the alkyl groups. Now in general 
 the methyl groups have less effect than ethyl; but the 
 active dose of Bromural is no greater than that of 
 Adalin. 
 
 So we may be safe in saying that the location of the 
 bromine seems not to be of great importance or at 
 least there is no one location which is essential. 
 
 These compounds are valuable additions to our thera- 
 peutic agents in that they are efficient but mild sleep 
 producers without particular anaesthetic action, and are 
 said to be well tolerated in cases of cardiac disease. 
 
 In the case of carbamide the alkylation of the nitro- 
 gen may result under proper conditions in bodies with 
 distinctly narcotic properties. As in the alcohol series 
 we again see here the significance of the tertiary alkyl 
 group. Although ureas into which have been intro- 
 duced one or even more primary alkyl groups are lack- 
 ing in physiological activity, nevertheless the tertiary 
 bodies are strongly active as for example tertiary 
 amyl urea, 
 
 /CH 3 
 
 /NH-Cf-CHs 
 C0< \C 2 H 5 
 
 N NH 2 
 
 and the tertiary heptyl urea which is very similar in 
 structure, 
 
 f 1 TT 
 
 /NH.C^C 2 H5 
 C0< \C 2 H 5 
 
 \MTT- 
 
 ^NH< 
 
58 ORGANIC COMPOUNDS 
 
 but more powerfully active. The tertiary butyl urea, 
 on the other hand, 
 
 /CH 3 
 
 / NH.Cf-CH 3 
 C0< \CH 3 
 
 X NH 2 
 
 is much less active. Therefore, we notice in these series 
 again the influence on the one hand of the accumulation 
 of alkyl groups and on the other hand the effect of 
 increasing the weight of these alkyl groups. Later we 
 shall return for a consideration of the urea derivatives 
 of alkylated acids (Veronal group). 
 
 With the urethanes, H^N-CO-OR we find a narcotic 
 effect by action upon the central nervous system with 
 the great advantage that all the important body func- 
 tions are undisturbed. Again in this series, more notice- 
 ably in the lower members, the intensity of effect in- 
 creases with the molecular weight of the substituting 
 alcohol. 1 The introduction of the acetyl into the amino 
 group reduces the toxicity of the compound. The activity 
 is greater in certain urethanes of secondary alcohols, 
 and again we must emphasize the effect of increasing 
 the number of alkyl groups present as, for example, 
 in the case of methylisopropylcarbinol urethane, 
 
 H 2 N CO OCH< /CH 3 
 
 which is sold under the name of Hedonal. 2 
 
 Nitro compounds possess general toxic properties that 
 are manifested in different ways. The nitrous acid esters, 
 
 1 Binet, Rev. medic, de la Suisse rom., 1893, 540, 628. 
 
 2 Dreser, Wien. klin. Wochschr., 12, 1007 (1899). 
 
ALIPATHIC SERIES 59 
 
 which are isomeric with them, are so essentially and char- 
 acteristically different in their physiological action that 
 this action may be used for purposes of differentiation 
 in cases of doubtful isomerism. This characteristic 
 action consists of a dilation of the blood vessels. But 
 there are observed differences of action which cannot 
 be explained by constitutional peculiarities or carbon 
 content, and are probably due to varying decomposition 
 products. 
 
 Even more marked are the differences in behavior 
 observed in isomers of the cyanide compounds. Hydro- 
 cyanic acid, which we may consider an isocyanide, 
 with perhaps divalent carbon HN=C, is about five 
 times as toxic as dicyanogen NEEC CEEN; but the 
 characteristics of the effect are the same for both that 
 is, paralysis of the respiratory center in the medulla 
 oblongata. Closely related to hydrocyanic acid are the 
 organic isocyanides (isonitriles or carbylamines) R N^C 
 or R N=C. According to Calmels, 1 methyl isonitrile 
 is more poisonous than anhydrous hydrocyanic acid, while 
 the ethyl compound shows a decided diminution in 
 toxicity, being only about one-eighth as poisonous. 
 
 The nitriles R C==N, on the other hand, although 
 also poisonous, are essentially different in action from 
 hydrocyanic acid. Acetonitrile inhibits the reflex exci- 
 tation and acts on some animals by inhalation as an 
 anaesthetic. Brissemoret 2 states that the only exci- 
 tation is in the stomach and intestinal tract. According 
 to Verbruegge 3 the toxicity of these compounds increases 
 with their molecular weight. 
 
 1 Calmels, Compt. rend., 98, 536 (1884). 
 
 2 A. Brissemoret, Soc. de biol., 60, 54 (1906). 
 
 3 Verbruegge, Arch, intern. Pharmacodyn., 5, 161; Reid Hunt, 
 ibid., 12, 447, 
 
60 ORGANIC COMPOUNDS 
 
 In the cyanic acid compounds and thiocyanic com- 
 pounds isomerism does not result in any essential dif- 
 ferences of effect. Their action is somewhat similar 
 to that of hydrocyanic acid, but very much weaker. 
 The derivatives which contain oxygen seem to be more 
 poisonous than the corresponding sulphur compounds. 
 We may remark here, too, that in some instances the 
 esters show toxic effects which are barely perceptible 
 or not at all noticeable in the free acids and in their 
 metal salts. 
 
 Cyanogen in complex compounds seems to manifest 
 its toxic effect only when there is a possibility of splitting 
 off hydrocyanic acid in the organism, as, for example, 
 in the case of sodium nitroprusside. 
 
 We have repeatedly called attention to the influence 
 which the accumulation of alkyl groups has upon the 
 sleep-producing effect of substances. We have also 
 noted the superiority of the ethyl over the methyl 
 group in such compounds. Both of these points are 
 again plainly brought out by the action of the group of 
 sulphones. Their effect was at first accidentally discov- 
 ered by Baumann and Kast l but was later subjected 
 to a scientific investigation with the following results: 
 Monosulphones, such as diethylsulphone, 
 
 are inactive. The same is true of disulphones when 
 the sulphone groups are attached to different carbon 
 atoms, as in the case of ethylene diethylsulphone, 
 
 CH2 - SO2 - C2H5 
 
 1 Baumann and Kast, Z. physiol. Chem., 14, 52 (1890). 
 
ALrPATHIC SERIES 61 
 
 But when the two sulphone groups are attached to the 
 same carbon atom there is a hypnotic effect, and this 
 effect is increased as ethyl groups are added. 
 Diinethylsulphonethylmethane, 
 
 H 
 shows a slight action, while diethylsulphonethylmethane, 
 
 W SO 2 C 2 H 5 
 
 has a powerful hypnotic action, but at the same time 
 a toxic effect. This latter effect disappears when the 
 hydrogen of the central carbon atom is replaced by an 
 alkyl group. 
 
 Dimethylsulphondimethylmethane, 
 
 s 
 
 ^S0 2 CH 3 
 
 has practically no hypnotic action, while dimethylsul- 
 phonethylmethylmethane, 
 
 has a slight effect. The two isomers, dimethylsulphon- 
 diethylmethane, 
 
 / c \ 
 
 C 2 H/ X SO 2 CH 3 
 
62 ORGANIC COMPOUNDS 
 
 and diethylsulphondimethylmethane (Sulphonal) , 
 
 CH 3 SO 2 C 2 H 5 
 
 act equally powerfully, while diethylsulphonethylmethyl- 
 methane (Trional), 
 
 SO 2 C 2 H 5 
 
 is more powerful and, of course, the strongest of all the 
 members of the series is diethylsulphondiethylmethane 
 (Tetronal), 
 
 N S0 2 C 2 H 5 
 
 Now, quite in accord with our observations in other series, 
 we find again that the replacement of the methyl group 
 of sulphonal by alkyl groups containing more carbon 
 atoms renders the body more powerfully active. We 
 find the n-butyl is more active than iso-butyl. On the 
 other hand, the action is arrested by the introduction 
 of hydroaromatic and of aromatic groups and when two 
 aromatic groups enter the same carbon atom, then, ac- 
 cording to Hildebrandt, 1 the compounds become strongly 
 toxic. The entrance of carboxyl or an amino group into 
 the molecule of sulphonal also checks the hypnotic 
 action of the compound, according to Th. Posner. 2 
 
 Particularly interesting is the law proposed by Baumann 
 for this series of compounds. He claims that the action 
 of the sulphones depends upon the ease with which they 
 
 1 Hildebrandt, Arch. exp. Path. Pharm., 53, 90 (1905). 
 2 Th. Posner, Chem. Ztg., 29, 1107 (1905). 
 
AROMATIC SERIES 63 
 
 can be decomposed in the organism. But he says that 
 this decomposability cannot be tested out in vitro. For 
 it has been found that those very members of the series 
 which are most easily attacked by chemical reagents 
 will pass entirely undecomposed through the organism, 
 while, on the other hand, those members of the series 
 which are most resistant to reagents in vitro are de- 
 composed in the body. 
 
 The Aromatic Series 
 
 In the aromatic hydrocarbons there is only a slight 
 indication of narcotic action. Their predominant effect 
 is cramp excitant and paralytic. They also cause, 
 according to Baglioni, 1 clonic spasms. These, however, 
 are not preceded, as in the case of the phenols, by a 
 stage of increased excitation, but on the contrary, by 
 a state of profound paralysis. 
 
 Chassevant and Gamier 2 established in the case of 
 guinea-pigs three predominating symptoms of effect 
 upon the nerves. These are cramps, muscle hypo- 
 tonism, and hypothermism. Of these, the lowering of 
 the heat production is a constant one observed from all 
 derivatives, while the two other symptoms are variable. 
 
 In the homologues of this series there is to be observed 
 a great variation of the toxic effect, depending upon the 
 kind and number of alkyl groups present. Methyl 
 benzol (toluol), and ethyl benzol are more poisonous 
 than benzol itself; but isopropyl benzol (cumol) is less 
 poisonous. Repeated alkylation diminishes the toxic 
 effect so that we find, for example, in benzol and its 
 methyl derivatives the following rising scale of toxicity: 
 
 1 Baglioni, Z. allgem. Physiol., 3, 312 (1904). 
 
 2 Chassevant and Garnier, Arch, intern. Pharmacodyn., 14, 93 
 (1905). 
 
64 ORGANIC COMPOUNDS 
 
 Trimethyl benzols (mesitylene, pseudocumol) >di- 
 methyl benzols (xylols) ^benzol >methylbenzol (toluol). 
 Among the xylols the toxic effect rises from the ortho 
 to the meta and para compounds. 
 
 Naphthalene causes a retardation of the respiration,- 
 a depression of the temperature in cases of fever (but not 
 normally), an increase of blood pressure in small doses, 
 but a reduction of blood pressure in large doses. 
 
 Contrary to the case of the aliphatic series, where 
 the substitution by halogens exerted a very powerful 
 influence, it is almost without significance in the aromatic 
 compounds. 
 
 The introduction of hydroxyl groups in these aro- 
 matic hydrocarbons increases the cramp-producing action. 
 In some cases, as for example, phenanthrene, it may 
 be almost entirely lacking in the hydrocarbon, but ap- 
 pear very distinctly in the hydroxyl derivative. At the 
 same time, however, there is a change in the point of 
 attack or action of the compound upon the organism. 
 Benzol affects principally the brain, with a secondary 
 action upon the cerebro spinal cord; but the phenols 
 have quite the reverse action, affecting principally the 
 cerebro spinal cord, while the action on the brain is 
 very slight or almost lacking. So the phenols, since 
 they increase the excitability of the motor mechanisms 
 of the spinal cord, produce clonic spasms. Very large 
 doses result further in paralyses (Baglioni). 
 
 Increasing the number of hydroxyl groups in this 
 series has the same effect upon this cramp-producing 
 activity that it had upon narcotic activity in the case 
 of the polyatomic alcohols of the aliphatic series. That 
 is, it gradually disappears as the number of hydroxyl 
 groups is increased. Thus, the three dioxy benzols still 
 cause cramps in frogs; but the trioxy benzols produce 
 
AROMATIC SERIES 65 
 
 only convulsions or spasmodic contractions. On the 
 other hand, the substances become much more toxic 
 in another direction, which is manifested in a lethargy 
 and in tremors. 
 
 Chassevant and Gamier, 1 however, state that the dioxy 
 benzols are more poisonous than the phenols, while the 
 trioxy benzols are less poisonous. According to Meyer, 2 
 Phloroglucide, 
 
 OH 
 
 OH 
 
 CH C CH 
 
 C/"tTT /"I OTT 
 
 On. U U-tl 
 
 OH OH 
 
 is without pharmacodynamic effect. 
 
 The degree of toxicity in the several series depends 
 very largely upon the position of the substituting groups. 
 In case of the dioxy benzols it rises from hydroquinone 
 to resorcine to pyrocatechine. 
 
 In the organism, phenol is converted by synthesis 
 into phenol sulphuric acid and phenyl-glucuronic acid, 
 and also it condenses with partial oxidation to form 
 dioxybenzols (pyrocatechin and hydroquinone sulphuric 
 and glucuronic acids). The same is true for the homo- 
 logues and substitution products. 
 
 The action of naphthols is entirely analagous to 
 that of the phenols. Of the oxyderivatives of the 
 higher hydrocarbons, those of phenanthrene are of im- 
 
 1 Chassevant and Gamier, Soc. biol., 55, 1584. 
 
 2 See Herzig and Cohn, Wien. Monatsch., 29, 677, 
 
66 ORGANIC COMPOUNDS 
 
 portance on account of their relationship to the alkaloids 
 of the morphine group. As has already been mentioned, 
 they cause cramp effects. 
 
 Similar to the behavior of the phenols is that of the 
 quinones, as we should perhaps expect from the close 
 chemical relationship. According to Brissemoret, 1 there 
 are caused very excitant effects in the alimentary canal 
 and on the outer skin by ordinary Quinone, 
 
 Thymoquinone, 
 
 ,O 
 
 >CeH2 
 iH^ 
 
 and Naphthoquinone, 
 
 O 
 
 The same is true in the case of the natural product 
 Juglon, which is oxynaphthoquinone, 
 
 C 10 H 5 (OH)/ 
 ^O 
 
 Somewhat the same properties are manifested in the 
 purgative effects of various anthra-quinone derivatives. 
 
 1 Brissemoret, Soc. biol., 59, 453 (1905); 60, 175 (1906). 
 
AROMATIC SERIES 
 
 67 
 
 CHRYSOPHANIC ACID 
 
 OH CH 3 
 I CO 
 
 OH 
 
 is found naturally in members of Rumex and Rheum 
 species, as well as in the Cascara Sagrada. 
 
 There is a closely related body which has found appli- 
 cation in various affections of the skin. This is Chrysa- 
 robin, 1 
 
 OH 
 
 OH 
 
 OH 
 
 which, being a reduction product of chrysophanic acid, 
 can easily be converted into that substance by oxidation. 
 A similar relation holds between the related bodies 
 
 ANTHRAROBIN 
 OH 
 
 and 
 
 1 Hess, Ann. Chem., 309, 32 (1899). 
 
68 ORGANIC COMPOUNDS 
 
 Related to chrysophanic acid are the various emo- 
 dines of rhubarb, the aloe species, cascara sagrada, etc. 
 Thus the emodine of the Chinese rhubarb has, according 
 to Hess 1 the following formula: 
 
 Brissemoret 2 is authority for the statement that the 
 essential condition for the action of these oxymethyl 
 anthraquinones is the presence of an oxygen atom in 
 the quinone binding. Ordinary benzoquinone has a 
 purgative effect as has also resorufine. 
 
 \C 6 H 3 (OH) 
 
 Accordingly, there does seem to be a necessity for at 
 least one hydroxyl or quinone oxygen. 
 
 PHENOLPHTHALEIN 
 
 CO 
 
 has, of course, been also found to be an effective pur- 
 gative. Even more strongly purgative than the natural 
 
 1 Hesse, 1. c. 2 Brissemoret, Soc. biol., 55, 48 (1903). 
 
AROMATIC SERIES 69 
 
 emodines are some of the synthetic polyoxyanthraqui- 
 nones. It was found necessary for practical application, 
 however, on account of the violent side-effects of these 
 substances, to convert them into compounds which are 
 only gradually decomposed in the intestinal tract. Thus, 
 Purgatine is the diacetyl ester of anthrapurpurine, 
 
 HO-/ V V X ,-OH 
 
 Exodine is a mixture of diacetyl-rufigallic-tetra-methyl 
 ether, which acts only slightly, vrith the acetylpehtamethyl 
 ether, which by itself would h^ve too violent an action. 
 
 EXODINE 
 
 OH 
 
 CO | 
 
 HO-/VN/VOH 
 
 HO AA/V- H 
 
 CO 
 OH 
 
 Two other substances whose action is so violent that 
 it must be moderated for practical application are the 
 diacetyl-rufigallic acid and the rufigallic acid tetra- 
 methyl ether. But if the hydroxyls are all completely 
 closed by alkyl radicles as in the hexamethyl ether the 
 compound is ineffective. 1 
 
 In this connection we may mention that it is a general 
 
 ^bstein, Deut. med. Wochschr., 31, 55 (1905). 
 
70 ORGANIC COMPOUNDS 
 
 phenomenon that a given effect of a compound is dimin- 
 ished by the alkylation or acylation of the hydroxyl 
 groups. The general effect is, of course, to make the 
 compound less active chemically as well as pharmaco- 
 logically. Thus we find that guaiacol, 
 
 has an effect similar to that of phenol and pyrocatechol, 
 but less poisonous; the maximum dose being for man 
 1 gm. in the case of guaiacol and about one-tenth as 
 great in the case of phenol. The toxicity, moreover, is 
 still further diminished when the second hydroxyl group 
 is also alkylated, as in the dimethyl ether Veratrol, 
 
 a 
 
 OCHg 
 
 The introduction of acid groups into the phenolic 
 hydroxyl does not essentially change the physiological 
 character of the compounds as much as one might at 
 first expect. The reason for this is that the derivatives 
 so obtained are saponified in the organism and the 
 hydroxyl group is again replaced. But the use of com- 
 pounds of this sort has the advantage that the active 
 substance comes into play gradually, that is, only as 
 fast as the saponification proceeds. Moreover, since 
 this saponification takes place for the most part in the 
 intestines, the stomach and upper digestive tract are 
 protected from any chance secondary effects. 
 
AROMATIC SERIES 71 
 
 In some cases, however, alkylation of the hydroxyl 
 group does have the opposite effect. For example, the 
 dimethyl ether of resorcine is much more toxic than 
 resorcine itself. Dimethyl sulphate is much more toxic 
 than sulphuric acid. Such rather exceptional phenomena 
 may perhaps be explained by saying that the introduc- 
 tion of the alkyl group favors the selection of the sub- 
 stance by the sensitive membranes. And in the cases 
 which we are now considering, such a selection must 
 depend very largely upon a change in the physical con- 
 ditions of the membranes themselves. In some other 
 cases, moreover, we may have to deal not only with an 
 increase in the main effect, but also with the removal of 
 a disturbing influence which a hydroxyl, or particularly 
 a carbonyl group, exerts upon the primary action of the 
 substance. 
 
 The influence of a carboxyl group quite generally 
 appears in a retardation or inhibition of the primary 
 effect of a compound. For example, when it enters 
 an aromatic hydrocarbon it suppresses the action up to 
 the point of causing a constant hypothermic effect, and 
 too, it diminishes the toxic effect. If several carboxyl 
 groups are attached to the nucleus, or if there are other 
 substituted groups on the nucleus with the carboxyl 
 group, then the strength of the carboxyl influence depends 
 upon the relative position of these groups. This has 
 already been shown in the case of -the oxybenzoic acids. 
 In the dibasic acids the toxicity diminishes from the 
 meta to the para, to the ortho compounds, while in the 
 toluic acids, according to Chassevant and Gamier it 
 diminishes from the meta to the ortho to the para com- 
 pounds. 
 
 The sulphonyl group possesses this inhibiting or retard- 
 ing influence to a still more marked degree than the car- 
 
72 ORGANIC COMPOUNDS 
 
 boxyl group. This is very largely and fundamentally 
 the reason for the failure of some compounds which have 
 been prepared by introducing the sulphonyl group, in 
 order to render easily soluble some effective but difficultly 
 soluble substances. 
 
 Hydroaromatic Compounds 
 
 The general effect of ring-formed ketones is a paralysis 
 of the central nerve system and the motor nerve terminals. 
 The latter are more affected as the size of the ring is 
 increased. Thus, the effect increases from pentanone 
 or ketopentamethylene (I) to Hexanone or ketohex- 
 amethylene (II) to Suberone or ketoheptamethylene 
 (III). 1 
 
 II 
 
 CH 2 
 
 H 2 C 
 
 H 2 C L JCH 2 
 
 CH 2 
 KETOPENTAMETHYLENE KETOHEXAMETHYLENE 
 
 IV 
 
 CH 2 CH 2 CH 2 CH 
 
 CuC/ \CH 2 
 
 TT f~* f*i /"^TT 
 
 1130 u 0.0.3 
 
 [2< M^ 
 
 KETOHEPTAMETHYLENE or C^CHs 
 
 CYCLOHEPTANONE CAMPHOR 
 
 1 Jacobi, Hayashi and Szubinski, Arch., exp. Path. Pharm., 50, 
 199 (1903). 
 
AROMATIC SERIES 73 
 
 Camphor (IV) , which is related to ketohexamethylene, has 
 a cramp-excitant effect. It also stimulates the muscles 
 of the heart to such an extent that it will neutralize the 
 stoppage of heart action by muscarine in the case of the 
 frog. In warm-blooded animals camphor also raises 
 the blood pressure, even when the vasomotor nerve 
 center is paralyzed by chloral hydrate. 
 
 CH 
 
 FBNCHONE (Wallach) 
 
 VII VIII 
 
 CH JCH 3 
 
 H 2 C/Kc(CH 3 ) 2 
 
 HaC^CH. 
 H 2 C k 
 
 FENCHONE (Semmler) CARVONE 
 
 The behavior of Thujone (V) is similar to that of 
 camphor, but Fenchone 1 (which according to Wallach 
 has the constitution VI but according to Semmler has 
 the constitution VII) and Carvone VIII 2 have a different 
 action. Carvone is a poison which has a violent cramp- 
 
 1 Matzel, Arch, intern, pharmacodyn., 15, 331 (1905). 
 
 2 Hildebrandt, Z. physiol. Chem., 36, 441 (1902). 
 
74 ORGANIC COMPOUNDS 
 
 producing action, which may perhaps be attributed to 
 the double bond in the ring. A reason for ascribing this 
 action to the double bond is that such an effect does 
 not occur, for Menthone (IX) which is keto-hexahydro- 
 p-eymene, nor for Pulegone X. 
 
 IX X XI 
 
 CH 3 CH 3 CH 3 CH 2 CH 3 
 
 I \S V 
 
 CH CH 3 C C 
 
 8 
 
 CH 
 OC/\CH 2 OC/\CH 2 
 
 H 2 Cv JCH 2 H 2 Cv JCH 2 
 
 CH CH C 
 
 CH 3 CH 3 CH 3 
 
 MENTHONE PULEGONE LIMONENE 
 
 Nevertheless we must admit that the carbonyl group 
 plays a very essential part in the physiological action, 
 for we find only a very slight toxicity in Limonene (XI) 
 which is quite similarly constituted except that the car- 
 bonyl group is missing. 
 
 Of the camphor derivatives, we find that monobrom 
 camphor, as well as the oxidation products formed within 
 the organism, show a cramp effect. On the other hand 
 we do not find this effect in oxy-camphor. 
 
 /CO 
 
 !H(OH) 
 which is a reduction product of camphor-quinone 
 
 C 8 H 14 <; I 
 
 \CJ 
 
AROMATIC SERIES 75 
 
 nor do we find it in borneol 
 CH 
 
 OH 
 
 According to Pouchet and Chevalier 1 however, borneol 
 and its esters (especially the iso-valerianate, which is in 
 use under the name of Bornyval) have an effect upon the 
 circulatory system similar to that of camphor. We 
 find also that when the carboxyl group is introduced 
 into this otherwise unchanged molecule with the forma- 
 tion of camphor carboxylic acid 
 
 OH COOH 
 
 the specific cramp effect is inhibited. It is a very remark- 
 able fact that oxymethylene camphor 
 
 CCHOH 
 
 shows no cramp effect, but paralyzes the central nerve 
 system and heart; but oxyethylidene camphor and 
 oxypropylidene camphor again show the typical cramp 
 effect. This may be explicable by the fact that the acid 
 
 Pouchet and Chevalier, Bull. gen. de Therap., 149, 828 (1905). 
 
76 ORGANIC COMPOUNDS 
 
 character of the first compound is vanishing in the 
 high homologues. 1 
 
 According to Hildebrandt 2 Sabinol XII 
 
 HOH 
 
 SABINOL 
 
 in spite of its close relationship to Thujone (V) has an 
 effect different from all the other camphor-like bodies in 
 that it causes hsemoglobinuria and methsemoglobinuria. 
 
 In this connection a fact established in several cases by 
 Hildebrandt 3 is particularly interesting, because it is 
 in contradiction to the condition found in other groups. 
 This is the fact that chain-form isomers of cyclic camphors 
 are the more powerful. For example we may cite citral 
 as compared with cyclocitral, nerol and geraniol as com- 
 pared with cyclogeraniol. 
 
 Concerning the influence of stereoisomerism there are 
 somewhat divergent opinions. In the case of the stere- 
 oisomers of camphor the qualitative similarity of effect 
 is universally acknowledged. According to Langguard 
 
 1 Bruhl, Ber., 37, 2179 (1904). 
 
 2 Hildebrandt, Arch. exp. Path. Pharm., 45, 150 (1901). 
 
 3 Ibid., Neuere Arzneimittel, p. 145 if. 
 
AROMATIC SERIES 77 
 
 and Maass 1 the excitant action of Isevo camphor is 
 even greater than that of the natural dextro camphor, 
 and racemic camphor is intermediary; but we find a 
 more recent statement, and we must confess a more 
 improbable statement, by Hamalainen 2 that the racemic 
 and dextro forms have nearly the same activity while 
 the Isevo compound is considerably weaker in effect. 
 
 Inner Disinfection 
 
 As is very well known, the phenols derive a special 
 importance from the fact that they exert powerfully 
 toxic effects upon the lower life forms (bacteria), that 
 is, a so-called antiseptic action. In order to combat 
 infectious diseases, as well as for prophylactic use, 
 it would be highly desirable to be able to employ 
 powerful internal disinfectants. But the unfortunate 
 situation is that there is quite generally associated 
 with the destructive action upon unicellular organisms 
 a toxic effect upon the higher organisms also. And 
 changes in the compounds which decrease the toxicity 
 toward the higher form have the deplorable result of 
 lessening the antiseptic properties of the substances. 
 Thus, by the introduction of the carboxyl group into 
 the phenol the toxicity is greatly reduced, especially 
 if the introduction is in the meta or para position. But 
 the ortho hydroxy acid (salicylic acid) is still more toxic 
 than benzol and benzoic acid. Of the three isomers, 
 then, salicylic acid alone still retains a rather consid- 
 erable power for disinfection, and this is considerably 
 lowered in comparison with phenol. 
 
 1 Langguard and Maass, Therap. Monatsh., Nov., 1907. 
 
 2 Hamalainen, Chem. Zentr., 1908, II, 1451. 
 
78 
 
 ORGANIC COMPOUNDS 
 
 Change in compounds. 
 
 Disinfection power. 
 
 Toxic effect. 
 
 Introduction of 
 
 Increased, correspond- 
 
 At first diminished, 
 
 halogen (Cl, 
 
 ing to the number 
 
 then increased. For 
 
 Br). 
 
 of halogen atoms. 
 
 tri-halogen com- 
 
 
 Sixteen (16) mole- 
 
 pounds it is about 
 
 
 cules of tetrachlor- 
 
 the same as that of 
 
 
 phenol, or, 2 mole- 
 
 phenol. Rises 
 
 
 cules of pentabrom- 
 
 strongly for further 
 
 
 phenol are equiva- 
 
 substituted bodies. 
 
 
 lent to 1000 mole- 
 
 The cramp effect is 
 
 
 cules of phenol. 
 
 diminished with in- 
 
 
 
 creased halogen con- 
 
 
 
 tent and finally 
 
 
 
 stops. 
 
 Introduction of 
 
 Increased. 
 
 Compensates the toxic 
 
 alkyl groups in 
 
 Tri-brom-w-xylenol is 
 
 effect of the halo- 
 
 the presence of 
 
 twenty tunes as act- 
 
 gen. Tetra-brom-o- 
 
 halogen in the 
 
 ive as tri-brom- 
 
 cresol has very little 
 
 molecule. 
 
 phenol. Tetra-brom- 
 
 toxic action. 
 
 
 o-cresol is sixteen 
 
 
 
 times as active as 
 
 
 
 tetra-chlor-phenol . 
 
 
 Combination of 
 
 
 
 two phenols. 
 
 
 
 Direct (bi-phenols) . 
 
 Increased. 
 
 
 By CH 2 . 
 
 Increased. 
 
 
 By CHOH. 
 
 Increased. 
 
 
 By CHOR. 
 
 Increased. 
 
 
 By CO. 
 
 Diminished. 
 
 
 By SO 2 . 
 
 Diminished. 
 
 
 This relationship, however, does not hold universally 
 and without exception. Thus, after alkylation in the 
 benzol ring with the formation of cresol, we find the 
 antiseptic action greater than in the case of the simple 
 phenol, while the toxicity of the compound for higher 
 life forms is increased only slightly, if at all. In fact, 
 
AROMATIC SERIES 79 
 
 for a frog, all the cresols are less toxic than phenol. 
 For warm-blooded animals para-cresol is more poison- 
 ous than phenol, while the ortho compound is about 
 the same as phenol and meta-cresol is still less toxic, 
 according to Tollens. 1 
 
 The admirable investigations upon this subject by 
 Bechhold and Ehrlich 2 disclosed the most varied changes 
 in action by modifications of the compounds. These 
 results -are given in table on page 78 in so far as they 
 have not been already treated. 
 
 It was found, however, in attempting a practical 
 application of such compounds that the strong dis- 
 infectant power of the best disinfectants is very much 
 modified in the blood serum. The result is that with 
 these compounds, too, we must confess that inner dis- 
 infection has not been successful. 
 
 1 Tollens, Arch. exp. Path. Pharm., 52, 220 (1905). 
 
 2 Bechhold and Ehrlich, Z. physiol. Chem., 47, 173 (1906). 
 
NITROGEN COMPOUNDS 
 
 Ammonia and Its Simpler Derivatives 
 
 Disregarding the excitant and caustic action of the 
 free bases, the characteristic effect of ammonia is a cramp 
 effect which causes in mammals the excitation of various 
 functional tracts of the spinal cord and its branches. 
 There results a temporary inhibition of respiration, more 
 pronounced in the cramp intermissions. Larger doses 
 cause, subsequent to the excitation stage, a paralysis of 
 the nerve centers that ends fatally. Immediately after 
 the injection of ammonia, there is a direct stimulation 
 of the heart and a consequently large increase in blood 
 pressure. Then follows a period of smaller increase in 
 blood pressure, caused by vascular contraction, due to 
 a stimulation of the vasomotor nerve centers. At the 
 same time there is a diminution in the pulse frequency, 
 although during the first stage this is increased. 
 
 In frogs the characteristic effect is manifested by strong 
 excitation indicated by a reflex cry; then there follow 
 convulsions and tetanus, and finally general paralysis. 
 
 The replacement of hydrogen of ammonia by alkyl 
 radicles immediately reduces the toxic action in a quite 
 extraordinary manner. Moreover, the ammonia group, 
 or all that remains of it, arrests the hypnotic action of 
 the hydrocarbons. So we may consider the ammonia 
 and alkyl radicles as mutually interfering groups. 
 According to Hildebrandt l the toxic effect in secondary 
 amines increases with increasing molecular weight. 
 
 1 Hildebrandt, Arch. exp. Path. Pharm., 54, 125 (1905). 
 
 80 
 
NITROGEN COMPOUNDS 81 
 
 The physiological character of the compounds is, how- 
 ever, completely changed, as we shall see later in our 
 discussion, when the alkylation is completed with the 
 formation of quaternary ammonium bases. 
 
 When an acid group is introduced, the characteristic 
 ammonia effect is reduced to an even more marked degree 
 than is caused by alkylation. This is the case whether 
 the ammonia group is in combination with the oxygen 
 of the carboxyl or with carbon. Both the acid amides 
 and the amino acids of the aliphatic series are in general 
 physiologically inactive. The amino acids of the higher 
 series are to be regarded as albumin builders, and there- 
 fore as belonging to the group of nutritive substances. 
 An exception to the previous statement is found in car- 
 bamic acid, NH2 COOH, which is poisonous. This 
 acts as a cramp-producing poison in a manner similar 
 to ammonia, but somewhat modified. The cause of 
 this exception is perhaps to be found in the ease with which 
 the compound is broken down. For as soon as we make 
 it more resistant to decomposition by the esterification 
 of the carboxyl, we have formed urethanes, which are 
 scarcely poisonous bodies. Furthermore in these com- 
 pounds, the original ammonia effect has been so reduced 
 or neutralized that the hypnotic action of the alkyl 
 radicle is able to assert itself, and the intensity of its 
 effect depends upon the character of the alkyl group. 1 
 In other words the original action has been suppressed 
 sufficiently for the newly introduced action to characterize 
 the compounds. Thus, in methyl-propyl-carbinol ure- 
 thane (Hedonal), 
 
 - 
 
 /NH 2 
 C0< 
 
 X)CH 
 
 NJH 
 
 1 Binet, Rev. medic, de la Suisse rom., 1893. 
 
82 ORGANIC COMPOUNDS 
 
 on find a useful, mild sleep producer, which leaves all 
 the life functions unaffected. 
 
 A more recent compound which has been introduced 
 under the name of Aponal is ethyl-dimethyl-carbinol 
 urethane. This is probably still more powerful in action. 
 It remains to be seen whether it possesses a diuretic 
 action which has rendered the use of hedonal somewhat 
 objectionable. These urethanes have, however, been 
 claimed to possess a somewhat injurious action upon the 
 heart and respiration. These effects, seem to have been 
 satisfactorily overcome by a compound introduced as 
 Aleudrin. This substance has, like Hedonal, the skele- 
 ton of isopropylurethane; but the alkyl groups are 
 chlorinated, 
 
 CH 2 CL 
 
 >CH.O CO NH 2 
 GH 2 CK 
 
 The margin between the narcotic dose and the fatal dose 
 is less for warm-blooded than for cold-blooded animals; 
 but it is large enough for practical purposes. For man, 
 sleep is produced by 0.5 gm. The body temperature, 
 respiration, heart action and circulation are very little 
 affected. Aleudrin appears to be a harmless sleep-pro- 
 ducer of scientifically correct construction according to 
 theoretical conceptions. 
 
 The essential part played by the acid radicle residuum 
 in the neutralization of the primary toxic effect is very 
 clearly shown by a comparison of the amino acids and 
 urethanes with the closely related aminoacetals. Ordi- 
 nary aminoacetal, NH2CH2CH(OC2Hs)2, produces a 
 paralysis of the respiration in the same way that ammonia 
 does. 1 
 
 1 Maltevre, Pfluger's Arch., 49, 484 (1891). 
 
NITROGEN COMPOUNDS 83 
 
 This, of course, is quite in contrast to the action of 
 the methanes and amino acids. 
 
 Of peculiar interest is the action resulting from the 
 conjugation of the ammonia residual group and the aro- 
 matic hydrocarbons, which are themselves cramp excit- 
 ants. We observe then a change in the points of attack 
 as compared with the action of ammonia. Aniline 
 attacks not only the motor centers in the branches of 
 the spinal cord, but also and more particularly those of 
 the middle brain, where it causes first a passing excita- 
 tion that manifests itself in convulsions, and then paraly- 
 sis. The prominent symptoms are dizziness, drowsiness, 
 and finally well-developed collapse. Aniline has the 
 further effect of destroying the hemoglobin. There is 
 also with aniline another effect which is therapeutically 
 exceedingly important and that is the diminution of the 
 body temperature. 1 
 
 As we have already seen, this action is peculiar to the 
 aromatic ring; but it becomes pronounced only after 
 certain substitutions have taken place. 2 It is lacking in 
 naphthalene and phenanthrene derivatives. In fact, 
 there is even a marked rise in temperature after the 
 administration of tetra-hydro-/3-naphthylamine. 3 
 
 The other aromatic amines possess in a marked degree 
 the injurious effects of aniline. The antipyretic effects 
 are modified by the introduction of alkyl radicles into the 
 molecule, the action depending largely upon whether the 
 group enters in the ortho, meta, or para position. Thus, 
 meta toluidine acts almost like aniline; but the ortho 
 and para toluidines are very much weaker in action. 
 The direct attachment of the amino group to the ring 
 
 1 Cahn and Hepp, Zentr. klin. Med., 1886, No. 33. 
 8 Cf. Frankel, Arzneimittelsynthese, 2d ed., p. 241 ff. 
 3 Stern s. Bambergerand Filehne, Ber., 22, 777 (1889), 
 
84 ORGANIC COMPOUNDS 
 
 seems also to be of essential importance for the anti- 
 pyretic effect. For example there is such an action 
 in only a slight degree in the case of benzylamine, 
 C 6 H 5 CH 2 NH 2 . 
 
 In the basic triphenyl methane dyestuffs the poison 
 effect increases in a marked degree with the introduction 
 of alkyl groups, especially if this introduction takes place 
 on the nitrogen. This effect, however, is still weak 
 enough in pararosaniline to permit its use in the thera- 
 peutic treatment of trypanosome diseases. The intro- 
 duction of acid groups diminishes the poison action; 
 but at the same time it also stops the trypanocidal power, 
 as either the sulphonic or carboxyl group will entirely pre- 
 vent this effect. 1 
 
 Naturally the same substituting groups which weaken 
 the effects of ammonia have a like effect upon aniline. 
 The next logical step was to determine whether such a 
 diminution of action would be more in a desirable or in 
 an objectionable direction. If acid groups (carboxyl 
 or especially sulphonyl) are introduced into the ring the 
 action is weakened in both directions, but the poison 
 effect is strongest in the ortho derivatives, and it is still 
 further increased by introducing methyl in the amino 
 group. 2 
 
 The substitution of alkyl groups on the nitrogen has 
 little effect, while acid groups have a quite noticeable 
 effect. Thus, in the case of acetanilide (Antifebrin) the 
 poison effect is sufficiently diminished and the antipyretic 
 action sufficiently retained so that a practical applica- 
 tion of the substance is possible. Nevertheless there 
 remains enough of the ill effect to demand caution in 
 its administration. The poisonous action is still fur- 
 
 1 Ehrlich, Berl. klin. Wochschr., 44, 223 ff. (1907). 
 
 2 Hildebrandt, Hofmeister's Beitr., 7, 433 (1905). 
 
NITROGEN COMPOUNDS 85 
 
 ther diminished in phenyl urethane (Euphorine), 
 C6H 5 NHCOOC2H 5 ; but the antipyretic efficiency is 
 rather low. The aniline action is still further diminished 
 in both directions in such cases as acetanilido acetic acid, 
 
 /CH 2 COOH 
 C 6 H 5 N< 
 
 XX).CH 3 
 
 and acetyl sulphanilic acid and its salts (Cosaprine being 
 the sodium salt), 
 
 >NH-CO.CH 3 
 C 6 H 4 < 
 
 Methyl acetanilide (Exalgine), 
 C 6 H 5 -N 
 
 is less desirable than acetanilide, but the nearly related 
 diacetyldiphenylethylenediamine, 
 
 CH 3 .CO.N< >N.CO-CH 3 
 
 X CH 2 - CR 2 ' 
 
 is said to be less violent. 1 
 
 Now it has been shown by the investigations of 
 Schmiedeberg 2 that aniline and its derivatives are 
 rendered harmless by the organism by the introduction 
 of an hydroxyl group in a position para to the amino 
 group. Paraaminophenol is much less poisonous than 
 aniline, although it does cause the formation of methaemo- 
 
 1 Grassmann, Bull. soc. ind. Mulh., 1907, 4. 
 
 2 Schmiedeberg, Arch. exp. Path. Pharm., 8, 1 (1878). 
 
86 ORGANIC COMPOUNDS 
 
 globin. This effect is somewhat but not sufficiently 
 reduced by the introduction of an acetyl group. Only 
 when the hydroxyl is esterified do we attain a point 
 where the preparation is adapted for therapeutic use. 
 The type of this sort of a compound is acetyl-p-amido- 
 phenol ethyl ether or para-ethoxy acetanilide (Phena- 
 cetine) , 
 
 /NH-CO-CHs 
 C 6 H 4 < 
 
 X).C 2 H 5 
 
 Numerous derivatives have been prepared from phene- 
 tidine, the base of phenacetine, as well as from Anisidine, 
 which is the base of Methacetine, 
 
 ,NHCOCH 3 
 4Ns OCH 3 
 
 the lower homologue of phenacetine. Such bodies have 
 been subjected to careful physiological examination; 
 but we will mention here only some of the preparations 
 derived from phenacetine: 
 
 1. Compounds derived by replacing the acetyl with 
 other acid groups: 
 
 Propionyl derivative (Triphenin), 
 
 ,NH.CO-CH 2 .CH 3 
 \ 
 
 Lactyle derivative (Lactophenin) , 
 
 /NH-CO-CHOH-CHa 
 C 6 H 4 < 
 
 X OC 2 H 5 
 
NITROGEN COMPOUNDS 87 
 
 Mandelic acid derivative ( Amygdophenin) , 
 
 /NH-CO-CHOH-CeHs 
 C 6 H 4 < 
 
 N OC 2 H 5 
 
 Methylglycolic acid derivative (Kryofin), 
 
 Acetylglycolic acid derivative, 
 C 6 H 4 
 
 Succinic acid derivative (Pyrantin), 
 
 CO CH 2 
 N 
 C 6 H 4 
 
 /N | 
 
 < X CO CH 
 X OCH 
 
 Citric acid derivative (Apolysin), 
 
 /COOK 
 
 ,NH - CO CH 2 C CH 2 - COOH 
 C 6 H 4 < | 
 
 X)C 2 H 5 OH 
 
 The preparation which has been advertised under the 
 name of Citrophene as citric acid triphenetidide is accord- 
 ing to Hildebrandt 1 essentially a citric acid salt of phene- 
 tidine. 
 
 1 Hildebrandt, Zentr, inn. Med., 16, 1089 (1895), 
 
88 ORGANIC COMPOUNDS 
 
 Salicylic acid derivatives: 
 (a) Salicylphenetidide, 
 
 C 6 H 4 
 
 NH.CO.C 6 H 4 OH 
 
 OC2H5 
 
 (6) Salicylic acetic acid derivative (Phenosal), 
 
 /NH - CO . CH 2 O - C 6 H 4 - COOH 
 C 6 H 4 < 
 
 X OC 2 H 5 
 
 (c) Acetyl salicylic acid derivative, 
 
 Acetyl-ethyl carbonic acid derivative (Thermodin), 
 
 /CO.CH 3 
 /N< 
 
 C 6 H 4 < >CO.OC 2 H 5 
 N OC 2 H 5 
 
 Amino carbonic acid derivative (Dulcin), 
 
 /NH.CO.NH 2 
 C 6 H 4 < 
 
 X OC 2 H 5 
 
 Amino acetic acid derivative (Phenocoll), 
 
 / 
 C 6 H 4 < 
 
 N OC 2 H 5 
 
 2. Compounds derived by introducing acid groups 
 in the ring (for the purpose of obtaining easily soluble 
 bodies) : 
 
 Phenacetine sulphonic acid. Phenacetine carbonic acid. 
 
NITROGEN COMPOUNDS 89 
 
 3. Compounds obtained by condensation with alde- 
 hyde and ketones: 
 
 with salicylic aldehyde (Malakin), 
 
 /N.CH.C 6 H 4 .OH 
 C 6 H 4 / 
 
 OC2ll5 
 
 with acetophenone (the citric acid salt is Malarine), 
 
 C 6 H 4 
 
 NH=C 
 / 
 OC2Hs, 
 
 N C 6 H 5 
 
 with vanillin ethyl carbonate (Eupyrine), 
 ,N : C 
 
 C 6 H 4 / 
 \ 
 
 From an examination of these substances and similar 
 preparations, and an observation of their physiological 
 action, it has been possible to generalize somewhat and 
 formulate some regularities in their action. In the first 
 place, considering the substitution of the amino group 
 of amino phenol by an acid radicle, this must be firmly 
 enough bound so that it is not split off by the acid of the 
 gastric juice (which amounts to two per cent hydrochloric 
 acid). For if this happens there appear at once the unde- 
 sirable and poisonous effects of para-phenetidine. On the 
 other hand the binding of such an acid radicle must not 
 be too firm. For it has been found that the only sub- 
 stances of this group which have a good antipyretic 
 action are those whose ingestion causes the appearance 
 of the indophenol reaction in the urine. This color 
 reaction which results from the action of a. or )8 naphthol 
 upon bodies with an amino group indicates that the sub- 
 
90 ORGANIC COMPOUNDS 
 
 stances ingested must be capable of being broken down in 
 the organism to compounds which have such a free amino 
 group (for example para-aminophenol from para-amido- 
 phenetol or para-phenetidine). 1 And observation has 
 justified the conclusion that the intensity of the anti- 
 pyretic effect is within certain limits proportional to the 
 amount of para-aminophenol which is split off in the qrgan- 
 ism. It is obvious, then, that too slow a process of splitting 
 up the compound will result in failure of the desired effect. 
 This was the result and its cause when the attempt was 
 made to use a combination with salicylic acid, a com- 
 pound which has its own antipyretic and antineuralgic 
 properties and therefore gave hope of forming particularly 
 active preparations. The mandelic acid derivative is an 
 example of another class of failures. The fundamental 
 reason is the same that is, there is too little splitting 
 down of the compound in the organism; but the reason 
 in this case is the slight solubility of the substance in the 
 stomach and intestinal tract and the consequent insuffi- 
 cient resorption. 
 
 So far as substitution of the hydroxyl group by alkyl 
 radicles is concerned it does not pay to go higher than the 
 ethyl group, as the antipyretic effect diminishes with the 
 higher alkyl radicles. In fact the ethyl ether is some- 
 what less active in this respect than the methyl compound ; 
 but the difference is so slight that it is more than offset 
 by the desirable and very considerable diminution of the 
 toxic effect. 
 
 If we start with a body such as acetyl-p-amino phenol, 
 which has a free hydroxyl group, and replace by an alkyl 
 radicle the hydrogen which is still attached to the nitro- 
 gen, the result is a series of inactive compounds. But 
 if at the same time we alkylate the hydroxyl also, then 
 
 1 Treupel and Hinsberg, Arch. exp. Path. Pharm., 61, 262 (1904). 
 
NITROGEN COMPOUNDS 91 
 
 there is observed a narcotic effect, which is barely sug- 
 gested in the parent body. In this respect the methyl 
 and ethyl derivatives behave about alike, and with a 
 further increase in the magnitude of the alkyl radicle 
 all the effects seem to diminish. 1 
 
 An antipyretic effect is also to be observed in the urea 
 derivatives of anisidine and phenetidine. The phene- 
 tidine compound, which is para-ethoxy-phenyl carbamide, 
 is particularly distinguished by an intensely sweet taste 
 and has therefore been called Dulcin. This sweet taste 
 is found in neither the lower compound (the methoxy 
 body) nor in the higher homologues. 2 
 
 An effect similar to that of phenacetine, but weaker, 
 is found with the isomeric compound acetyl-ortho- 
 phenetidine. 
 
 Of the diamines the aliphatic bodies such as tetrameth- 
 ylenediamine (Putrescine), NH2 (CE^U NH2, and pen- 
 tamethylenediamine (Cadaverine) , NH2 (CHys NH2 
 are physiologically entirely inactive. In some derivatives 
 in which one or both of the amino groups have been 
 converted into imino groups by means of negative sub- 
 stituents there appear strong toxic effects. 
 
 Thus, for example, in the formaldehyde derivative of 
 Cadaverine and in Sepsirie prepared by Faust 3 this effect 
 appears. 
 
 The aromatic diamines, on the contrary, possess a rather 
 strong toxicity, their peculiar action being a destruction 
 of the coloring matter of the blood. According to Dubois 
 and Vignon 4 meta-phenylene-diamine causes vomiting, 
 cough, coma and death. Nevertheless its hydrochloride 
 
 ir Treupel and Hinsberg, Arch. exp. Path. Pharm., 33, 216 (1894). 
 
 2 Spiegel and Sabbath, Ber., 34, 1936 (1901). 
 
 8 Faust, Arch. exp. Path. Pharm., 51, 262 (1904). 
 
 4 Dubois and Vignon, Compt. rend., 107, 533 (1888), 
 
92 ORGANIC COMPOUNDS 
 
 under the trade name of Lenthin is recommended as an 
 antidiarrheal even for children. 1 There is a still stronger 
 action observed for the para compound, which causes 
 violent inflammations of the internal mucous membranes 
 and cramp paroxyms. The former effect, however, is 
 attributed by Erdmann and Vahlen 2 to quinonediimine, 
 
 which is a first product of oxidation. Quinone imides, 
 according to Brissemoret, 3 also have a purgative effect 
 consequent upon the stimulation of intestinal secretion. 
 The ortho compound has also a remarkably great toxicity. 
 
 Toluylenediamines (or diamido toluenes) have a still 
 more powerful action on the blood, producing icterus 
 and hsematuria. 4 
 
 The blood corpuscles are also peculiarly affected by 
 benzidine, NH2 CeEU CeEU NH2. In vitro .this sub- 
 stance causes the formation of methsemoglobin, although 
 in the organism it is somewhat less active in this direc- 
 tion. In the dog, but not in the rabbit, it causes nausea, 
 vomiting and motor unrest, and in all animals it causes 
 the appearance of considerable sugar in the urine. 5 
 
 An interesting consideration is the influence of hydro- 
 genization upon the physiological activity of the aromatic 
 amines. 6 Thus the two naphthyl-amines produce a 
 paralysis of the central nervous system in animals, the 
 
 1 Boye, Zentr. inn. Med., 1905, 113. 
 
 2 Erdmann and Vahlen, Arch. exp. Path. Pharm., 53, 401 (1905). 
 
 3 Brissemoret, Soc. biol., 62, 657 (1907). 
 
 4 Stadelmann, Arch. exp. Path. Pharm., 14, 231 (1881); 16, 
 118 (1883); 23, 427 (1887). 
 
 6 Adler, Arch. exp. Path. Pharm., 58, 167 (1908). 
 6 Stern, Virchow's Arch., 115, 14; 117, 418 (1889). 
 
NITROGEN COMPOUNDS 
 
 93 
 
 a compound acting more strongly than the /3 compound. 
 The latter body causes also a slight contraction of the 
 pupil of the eye. Of the two tetrahydro-j(3-naphthyla- 
 mines, 
 
 I II 
 
 CH 2 CH CH CH 2 
 
 NH 2 HC/\/NcH . NH 2 
 
 HC 
 
 CH 2 CH 
 
 CH CH 2 
 
 the body (I) which is hydrogenized on the non-substi- 
 tuted ring is inactive, and the other compound (II) which 
 is hydrogenized in the ring which bears the amino group 
 is quite active, causing strong rise in temperature, cramp 
 phenomena, and dilatation of the pupil (mydriasis). 
 The effect of the compound is considerably increased by 
 the introduction of an ethyl group in the amino group, 
 but a methyl group in this position is without appreciable 
 influence. 
 
 If a second amino group is introduced into the non- 
 hydrogenized ring of the first compound (I), we have the 
 aromatic alicyclic tetrahydro naphthalene diamine, a 
 strongly toxic compound which, however, does not dilate 
 the pupil. 
 
 The influence of hydrogenization upon physiological 
 action which we see here, may be also observed in a marked 
 degree in the cyclic bases. 
 
 II 
 
 CH 2 
 
 HC 
 
 CH 
 
 H 2 C 
 
 Ill 
 
 HC CH 
 
 ne CH 
 
 CH- 
 
 NH 
 
94 ORGANIC COMPOUNDS 
 
 Pyridine (I) shows, to be sure, some effect upon the sen- 
 sory apparatus, the respiration and heart action; but it 
 may be considered as being comparatively non-poison- 
 ous. 1 Piperidine (II), however, has a very essentially 
 stronger action. This acts in warm-blooded animals 
 as a cramp-producing poison, which considerably increases 
 the blood pressure through contraction of the blood 
 vessels, and finally causes paralysis of both central and 
 peripheral nerves. Pyrrole (III) is itself a poison, caus- 
 ing a central nervous paralysis. 2 The greater action of 
 this compound compared with pyridine is probably due 
 to the reactive imino group. But the effect increases in 
 pyrroline (IV) and is still greater in pyrrolidine (V). 
 This latter compound, 
 
 IV V VI 
 
 HfciCH I 
 
 HP r*w "PT r< r<tr TI r* r*i 
 
 2^> \jtt.2 Il2U \jLi<2, 112^ OJ 
 
 V V II 
 
 NH NH H 2 C CH 2 
 
 v 
 
 NH 
 
 is qualitatively like piperidine, as is also the higher ring 
 homologue cyclohexamethylenamine (VI). Quantita- 
 tively, however, the effect is not the same. It increases 
 from pyrrolidine to piperidine to hexamethylenamine. 
 That is, it increases with the size of the ring, as we have 
 already noted in the case of the cyclic ketones. As 
 further example of this general principle, we may also 
 cite the isoximes pyrrolidone (VII), piperidone (VIII), 
 
 1 Brunton and Tunicliffe, J. Fhysiol., 17, 292. 
 
 2 Ginzberg, Dissertation, Konigsberg, 1880; cf. Pighini, Arch, 
 fisiol., 3, Vol. I (1906). 
 
NITROGEN COMPOUNDS 
 
 95 
 
 cyclohexanoneisoxime (IX) where the order of activity 
 is the same as the order of the compounds given. 
 
 VII 
 H 2 C CH 2 
 
 H 2 C CO 
 
 V 
 
 NH 
 
 VIII 
 CH 2 
 
 H.cl^JGO 
 NH 
 
 IX 
 
 [ 2 C-CH 
 
 H 2 CH2 
 
 i i 
 
 H 2 C CO 
 
 v 
 
 NH 
 
 Likewise the toxicity increases from quinoline (X) to 
 tetrahydroquinoline (XI) to decahydroquinoline (XII). 1 
 
 CH 
 
 XI 
 CH CH 2 
 
 HC 
 
 HC 
 
 CH N 
 
 H 2 C/\* 
 
 H 2 C 
 
 C 
 
 NX 
 
 CH NH 
 
 XIII 
 CH CH 
 
 CH 2 
 
 CH 2 NH 
 
 CH CH 
 
 The same statement holds also in the case of isoquinoline 
 XIII and its hydrogenized bodies as well as with their 
 homologues and derivatives, among which we shall find 
 some of the alkaloids which will receive a special considera- 
 tion later. 
 
 Heinz, Virchow's Arch., 122, 116 (1890). 
 
96 ORGANIC COMPOUNDS 
 
 As one further example we may mention that the toxic 
 effect of dihydroindole (Indoline) is greater than that of 
 Indole. 1 
 
 Ammonium Bases 
 
 There is a fundamental difference between the com- 
 pounds of trivalent nitrogen and those of pentavalent 
 nitrogen, in other words between those with free valences 
 and those with saturated valences. 2 In the case of the 
 latter (with pentavalent nitrogen) there is observed quite 
 generally a physiological phenomenon consisting of a 
 paralysis of the motor end-plates. 
 
 This action is called the curare effect, from the name of 
 the poison whose administration was observed to be 
 followed by this action. The intensity of this effect 
 diminishes with increasing molecular weight of the com- 
 pound. It depends also, of course, upon the structure 
 of the compound and the spacial grouping of the radicles 
 combined with the nitrogen. 3 
 
 Accordingly we find in ammonium bases which result 
 from the alkylation of tertiary bases the same special 
 physiological properties which belong to these tertiary 
 bases; but they are very much weakened in the derived 
 bodies. Now then, if this weakening of action takes 
 place upon the undesirable effects more than upon the 
 desirable therapeutic effects, then we can proceed with 
 alkylation. The result is that from alkaloids, for example, 
 which though powerful and effective, are of doubtful 
 value, because of injurious side-effects, we may thus 
 obtain valuable and useful derivatives. A case in point 
 
 1 Cuttitta, Bioch. Zentr., 7, 349 (1908). 
 
 2 C.f. Spiegel, Z. anorg. Chem., 19, 365 (1902). 
 
 3 Hildebrandt, Arch. exp. Path. Pharm., 53, 76 (1905). 
 
NITROGEN COMPOUNDS 97 
 
 is that of the methyl atropinium salts. Frequently, 
 also, it is a fact that the addition products possess new 
 properties. 
 
 The curare effect has been observed for the platinum, 
 cobalt, rhodium and chromium ammonia compounds, 1 
 which argues that in these compounds the ammonia 
 is held, as we have assumed, by means of neutral valences. 
 Furthermore this same effect occurs in the analogues of 
 the ammonium bases, that is in the phosphonium, arso- 
 nium and stibonium bases. 
 
 We must admit, it is true, that this curare effect is not 
 unconditionally dependent upon the ammonium consti- 
 tution. To a lesser degree it is also found in some 
 secondary bases (piperidine, coniine, methyl aniline, 
 guanidine) 2 and also in nitrogen-free substances of the 
 camphor group in fact in camphor itself. The extent 
 to which this effect is favored by the ammonium consti- 
 tution, however, has been shown by the investigation of 
 Boehm 3 on the curare alkaloids. 
 
 He found in this arrow poison, besides the quaternary 
 base Curarine, a tertiary base Curine. Each of these 
 alkaloids is capable of producing the characteristic effect; 
 but the ammonium base Curarine is 226 times as power- 
 ful as Curine. This latter alkaloid can be converted by 
 methylation into the former. 
 
 Besides the curare effect, there is observed in a series 
 of ammonium bases, another action which was first 
 observed for natural Muscarine (I), and is therefore 
 called the muscarine effect. This consists of the arrest 
 
 iHofmeister, Arch. exp. Path. Pharm., 16, 393 (1883) and 
 Bock, ibid., 52, 1, 30 (1905). 
 'Fiihner, Ibid., 50, 1 (1903). 
 3 Boehm, ibid., 35, 20 (1895), also Arch. Pharm., 235, 660 
 
 (1897). 
 
98 ORGANIC COMPOUNDS 
 
 of the heart in diastole in consequence of the excitation 
 of the inhibitory nervous apparatus. 
 
 I 
 H 2 CH(OH) 2 
 
 H 
 
 This effect is already exhibited by tetramethyl ammonium 
 chloride and still more by tetramethylammoniumtri- 
 iodide l further by iso-amyltrimethyl ammonium chloride 
 (II) and by valeryltrimethyl ammonium chloride (III). 2 
 
 II III 
 
 /CH2 CH2 CH(CH 3 )2 yCsHgO 
 
 f< (CH 3 ) 3 =N< 
 
 xa x ci. 
 
 According to Waller and Sowton the effect upon the 
 heart is to be observed in the action of the other bases, 
 which are closely related to Muscarine such as Choline 
 (IV), Neurine (V) and Betaine (VI). Choline and betaine 
 are much less poisonous than Neurine and muscarine. 
 
 IV V 
 
 /CH 2 CH 2 OH 
 
 (CH 3 )3^N< (CH 3 ) 3 =N 
 
 N OH 
 
 VI 
 
 i - 
 CO 
 
 It is presumable that stereo conditions in muscarine also 
 have important bearing upon its action, because the 
 
 1 Jacob! and Hagenberg, Arch. exp. Path. Pharm., 48, 48 (1902). 
 
 2 Schmiedeberg and Harnack, Arch. exp. Path. Pharm., 6, 110 
 
 (1877). 
 
NITROGEN COMPOUNDS 99 
 
 choline muscarine obtained by Schmiedeberg from 
 choline by oxidation 1 is physiologically different from 
 the natural muscarine. 2 Both are toxic; but the mus- 
 carine from choline causes paralysis of the intermuscular 
 nerve terminations and myosis in the pupils of the eyes 
 of birds, while the natural Muscarine produces neither 
 of these effects. Honda states that the muscarine of 
 toadstools has the same action as the muscarine from 
 choline. 3 Likewise anhydromuscarine (VII), obtained 
 by Berlinerblau 4 and isomuscarine (VIII) 5 differ from 
 muscarine in having no action on the frog's heart or on 
 the pupil of the eye. 
 
 VII VIII 
 
 /CH 2 CHO /CHOH CH 2 OH 
 
 (CH 3 ) 3 =N< (CH 3 ) 3 =N< 
 
 N OH X)H 
 
 A lengthening of the side chain in the derivatives of 
 neurine and muscarine diminishes their toxicity. In 
 the same way we find in comparing tetraethylammonium 
 iodide with the tetramethyl compound that the higher 
 homologue possesses the curare effect of the lower body 
 but not its muscarine effect. 6 The corresponding tri- 
 iodide is lacking in both effects. 7 But in the case of 
 choline, we find that the introduction of the ethyl group 
 
 Schmiedeberg and Harnack, Arch. exp. Path. Pharm., 6, 110 
 (1877). 
 
 2 Waller and Sowton, Proc. Roy. Soc., 72, 320 (1903). 
 
 3 Honda, Arch. exp. Path. Pharm., 65, 444 (1911). 
 
 4 Berlinerblau, Ber., 17, 1139 (1884); E. Fischer, ibid., 26, 
 464 (1893); Nothnagel, ibid., 26, 801 (1893). 
 
 5 H. Meyer s. Schmidt, Ann. Chem., 337, 37 (1904). 
 
 6 Jordan, Arch. exp. Path. Pharm., 8, 15 (1877). 
 
 7 Jacobi and Hagenberg, I.e. 
 
100 ORGANIC COMPOUNDS 
 
 into the hydroxyl causes a strong increase in the toxic 
 effect. 1 
 
 Cyclic Bases and Alkaloids 
 
 Pyridine, as we have already mentioned, has only 
 slight effects upon the sensory nerves or upon the respira- 
 tion and heart action. It undergoes a special treatment 
 in the organism, due probably to the fact that it does not 
 combine with either glucuronic acid or sulphuric acid 
 after oxidation. It is converted into the methyl ammo- 
 nium base, HO-CHaNCoHo. 2 Its activity is increased 
 by the addition of aliphatic side chains, especially alkyl 
 groups, and its effect upon the sensory nerves particularly 
 is thus augmented. 3 In the series pyridine, picoline, 
 lutidine, collidine and parvoline there is an increasing 
 degree of action which is manifested by an intoxicant 
 effect and an increase in the respiration and pulse fre- 
 quency. 
 
 The same condition holds true for the derivatives of 
 piperidine C5HnN. Piperidine itself causes a strong 
 increase in blood pressure, has a noticeable action on the 
 motor end-plates, that is, an incipient curare effect, and 
 also has an effect upon the heart action. Pipecoline 
 (a-methyl piperidine) has a complete curare effect with- 
 out arresting the heart action. The same thing is true of 
 a-ethyl piperidine and a-propylpiperidine but in a decreas- 
 ing degree. But the real toxic effect of the compounds 
 which results in a paralysis of the central nervous system 
 and subsequent paralysis of the motor nerve terminals 
 rises from piperidine to pipecoline to ethyl piperidine to 
 
 1 H. Meyer s. Schmidt, I.e. 
 
 2 His, Arch. exp. Path. Pharm., 22, 253 (1887); Cohn, Z. 
 physiol. Chem., 18. 
 
 3 Kendrick and Dewar, Proc. Roy. Soc., 22, 432. 
 
NITROGEN COMPpUNDS 101. 
 
 coniine in a geometrical progression 1:2:4:8. If the 
 alkylation is continued very far the ratio is increased. 
 If we replace by successive alkyl radicals the hydrogen 
 of the 7 carbon atom in Lupetidine, 
 
 H H 
 
 C 
 H 2 C/\CH 2 
 
 -Hcl JcHCH 3 
 
 N 
 H 
 
 we find that the toxic effect of the resulting compounds 
 increases in a geometric progression for an arithmetic 
 progression of the molecular weight. But this is true 
 only up as far as the propyl derivative. The isobutyl 
 derivative shows a decrease again and the hexyl deriva- 
 tive a still further decrease. 1 Moreover, the position 
 which the radicle occupies upon the nucleus is not with- 
 out material effect. Thus the lethal dose of /3-propyl 
 piperidine is nearly twice as great as that of the a-propyl 
 piperidine (Coniine). But the lethal dose of 0-ethyl 
 piperidine is twice as great as that of the a-propyl com- 
 pound. 2 We should note here, that alkylation on the 
 nitrogen is very important and generally results in an 
 increase in the physiological activity of the compound. 
 This increase, also, is greater than that caused by alkyla- 
 tion on a carbon atom. Here again, there is a rise in 
 the effect up as far as the propyl body and then a decrease 
 in the higher homologues. Considering the compounds 
 where the alkyl radicles are attached to the nitrogen 
 
 1 Giirber, Arch. Physiol., 1890, 401. 
 
 2 Ehrlich and Granger, Ber., 30, 1060 (1897) and Giinther, Ber., 
 31, 2141 (1898). 
 
192 ORGANIC COMPOUNDS 
 
 of piperidine we have the following series of lethal doses 
 per kilogram of body weight in the case of a rabbit: 
 
 N-methyl : ethyl : propyl : amyl as 
 0.4 : 0.1 : 0.01 : 0.04 
 
 Derivatives formed by acylation on the nitrogen cause 
 cramps that can reach a condition of perfect tetanus, 
 as in the case of the formyl derivative. 1 The presence 
 of an hydroxyl group in the side chain seems to weaken 
 the physiological effect of the compound. For an ex- 
 ample, Conhydrine, 
 
 CH 2 
 
 NH 
 
 is qualitatively like coniine, but its action is milder. 2 
 If the hydroxyl is in the ring, the substances seem to 
 be enabled to act upon the brain; but if such hydroxyls 
 are covered by ether formation the compounds will then 
 further the excitation of cramps. 
 
 The derivatives of quinoline have in general a less 
 toxic effect than the corresponding substituted pyridine 
 derivatives. In other words the condensation of a benzol 
 ring with the pyridine weakens its action. On the other 
 hand the inherent antiseptic action of the benzol which 
 we may assume it to have, judging from its oxy deriva- 
 tives, is considerably increased by this condensation 
 with pyridine. 
 
 Let us now take up a discussion of the individual 
 alkaloid groups from the standpoint of constitutional 
 
 1 R. and E. Wolffenstein, Ber., 34, 2408 (1901). 
 
 2 Wertheim, Ann. Chem., 100, 337 (1856). 
 
NITROGEN COMPOUNDS 103 
 
 relationships which seem to be responsible for similarities 
 in physiological activities. 
 
 Group of Atropine and Cocaine 
 
 These two alkaloids are closely related in chemical 
 constitution. Atropine (III) is derived from tropine (I) 
 and Cocaine (IV) is derived from Ecgonine (II), which 
 is the orthocarboxylic acid of Tropine. 
 
 I TROPINE 
 
 H 2 
 P 
 
 H 
 P 
 
 PR 
 
 i 
 
 N CH 3 
 p 
 
 CHOH 
 
 PR~ 
 
 H 2 H 
 
 II ECGONINE 
 
 H 2 H 
 
 C C : CHCOOH 
 
 H 2 C- 
 
 N CH 3 GHOH 
 
 In L 
 
 -Ul L1 2 
 
 III. ATROPINE 
 
 H 2 
 
 H 
 
 
 
 ^ 
 
 
 -CH 2 
 
 
 ^ 
 
 
 
 N CH 3 
 
 CH-O-CO CH< 
 
 /CHsOH 
 
 , 
 
 PR 
 
 -PR^ 
 
 X C 6 H 5 
 
104 ORGANIC COMPOUNDS 
 
 IV. COCAINE 
 
 H 2 
 p 
 
 pu 
 
 prr POOPTT 
 
 i 
 
 N CH 3 
 
 \jn ^L/v7Oll 3 
 
 CH.O.CO.C 6 H 5 
 
 In both of these compounds the alcoholic hydroxyl is 
 esterified by an aromatic acid, tropic acid, 
 
 /CH 2 OH 
 C 6 H 5 .CH< 
 
 N COOH 
 
 in the case of atropine and benzoic acid in the case of 
 cocaine. In the latter, the hydrogen of the carboxyl 
 group of ecgonine is further replaced by the methyl 
 group. 
 
 There is a definite physiological relationship which 
 corresponds to this chemical relation. Both alkaloids 
 act in the same way upon the central nervous system, 
 the action being first excitant and then paralyzing. 
 They both have from the start a paralytic effect upon the 
 endings of certain peripheral nerves. But there is one 
 essential difference in this action. While cocaine exercises 
 this effect essentially upon the ends of the sensory nerves 
 (the result being a local anaesthesia) atropine extends its 
 sphere of action to all the organs and nerves upon which 
 muscarine has an excitant effect. These are the inhibi- 
 tory apparatus of the heart, all glands proper, the motor 
 elements in the organs with plain or unstriped muscle 
 fibers (intestine) and particularly the organs of adapta- 
 tion and accommodation of the eye. 
 
 The pupil of the eye is enlarged (mydriasis) on account 
 of the paralysis of the nervus occulomotorius and con- 
 
NITROGEN COMPOUNDS 105 
 
 sequent lack of nerve control of the ciliary muscle. 
 The result is the impossibility of accommodation for near 
 objects. This effect of atropine is a local one, just like 
 the effect of cocaine upon the sensory nerve ends. 
 
 When cocaine is applied to mucous membrane, it causes 
 a pallor due to a contraction of the blood vessels. Other 
 effects that may be mentioned are a foamy degeneration 
 of the liver, 1 a strong rise in temperature, 2 and the prop- 
 erty of increasing the capacity for work, which is the 
 reason for the extensive use of cocaine in its native land. 3 
 
 According to some observers 4 atropine has a feeble 
 but appreciable effect on the sensory nerve endings, 
 and cocaine causes a weak but long-continued mydriasis. 
 
 Now then, if we are led to believe that the combined 
 ring system which is the foundation of these two alkaloids 
 is the secret of their action upon peripheral nerve ends, 
 we shall at least have to modify our view to include 
 the fact that a suitable substitution in these rings is 
 essential to the action. For tropine has no mydriatic 
 action, but does have an effect upon the heart. Of the 
 tropeines (the organic acid esters of tropine according to 
 Ladenburg) those of the aliphatic acids act essentially 
 like tropine. 5 But when an aromatic acid radicle is 
 introduced, the heart effect becomes more or less ob- 
 scured, and the nerve effect becomes apparent. 6 In this 
 substitution, however, the character of the acid radicle 
 is the factor which determines whether this effect shall 
 be manifested as mydriatic or anaesthetic. The tro_ 
 
 1 Ehrlich, Deut. med. Wochschr., 17, 717 (1891). 
 
 2 Reichert, Zentr. med. Wissensch., 1889, 444. 
 
 3 Mosso, Pfliiger's Arch., 47, 553 (1890). 
 
 4 Filehne, Berl. klin. Wochschr., 24, 107 (1887). 
 
 5 Gottlieb, Arch. exp. Path. Pharm., 37, 128 (1896). 
 
 6 Buchheim, Arch. exp. Path. Pharm., 5, 463 (1876). 
 
106 ORGANIC COMPOUNDS 
 
 peines of benzole acid, CeHsCOOH, of cinnamic acid, 
 C 6 H 5 -CH=CH-COOH, of atropic acid, 
 
 and of salicylic acid, 
 
 / 
 C 6 H 4 < 
 
 N COOH 
 
 cause anaesthesia but no, or only slight, mydriasis. The 
 benzoyl tropeine has a strong anaesthetic action and the 
 benzoic acid ester of pseudotropeine (which is a stereo 
 isomer of tropeine) is the tropacocaine which is found in 
 Java coca leaves. This substance has no mydriatic 
 effect, and is less toxic and a more powerful anaesthetic 
 than cocaine. 1 Only when the tropine is esterified with 
 an organic acid with a side chain which contains an 
 hydroxyl group do we observe the presence of the charac- 
 teristic atropine effect. For example, as the tropeine of 
 mandelic acid is still nearer to benzoic acid than is tropic 
 acid, so the anaesthetic power of homatropine is stronger 
 than that of atropine. We have already noted that stereo 
 arrangement has a considerable influence in these con- 
 siderations. According to the investigations of Cushny 2 
 the optical components of atropine (dextro and laevo 
 hyoscyamine) are each selectively preferred by certain 
 organs, and together they seem to be responsible for the 
 total effect of the racemic isomer. It was found that in 
 mydriatic effect the laevo hyoscyamine is almost twice as 
 effective as atropine and is 12 to 18 times as strong as 
 dextro hyoscyamine. 
 
 1 Chadbourne, Brit. Med. J., 1892, 402. 
 8 Cushny, J, Physiol., Oct., 1903. 
 
NITROGEN COMPOUNDS 107 
 
 Conversion of atropine into alkyl atropinium salts 
 such as Eumydrin results in an equal but more evanescent 
 mydriatic effect. It also results in a diminution of the 
 other poisonous effects, and is therefore advantageous 
 for therapeutic use. 
 
 The atropine action remains practically unchanged 
 when the alcoholic hydroxyl of the tropic acid is replaced 
 by chlorine; but the same substitution by bromine di- 
 minishes the effect much more. 1 
 
 Ecgonine has no anaesthetic effect and benzoyl ecgo- 
 nine and ecgonine methylester show only slight indica- 
 tions of a cocaine effect. 2 
 
 Now one might be led to believe that the effect is 
 dependent upon simply the closing up of both the car- 
 boxyl and the hydroxyl groups at the same time. But 
 this is not a tenable theory, for the esters of anhydro- 
 ecgonine (V) are also without effect. 3 
 
 V. ANHYDROECGONINE ESTER 
 H 
 
 H 2 C C CHCOOR 
 
 N CH 3 CH 
 H 2 C- -CH- -CH 
 
 So we must conclude that this closing up of the carboxyl 
 and alcoholic hydroxyl must be accomplished by certain 
 groups. For the carboxyl, in general any alkyl radicle 
 will suffice. Whether methyl, ethyl, propyl, isopropyl 
 
 1 Lewin and Guillery, Die Wirkungen von Arzneimitteln und 
 Giften auf das Auge, Berlin, 1905, p. 204 S. 
 
 2 Stockmann, Pharm. J. Trans., 16, 897 (1888). 
 
 3 Einhorn and Konek de Norwall, Ann. Chem., 280, 96 (1894). 
 
108 ORGANIC COMPOUNDS 
 
 or isobutyl is used the effect is the same. 1 In the case of 
 the hydroxyl group, however, the benzoyl radicle seems 
 to be rather essential and unique in its influence. With 
 all other acids, the esters obtained have at most only a 
 weak anaesthetic effect. 2 The mandelic acid ester is 
 essentially mydriatic like that of tropine. Therefore 
 we may say that alkylation removes the disturbing 
 influence of the carboxyl group when it is on the carbon 
 atom next to the benzoylated hydroxyl group; but it 
 does not do so when it takes place on the same carbon 
 atom that carries the hydroxyl. For example, a-ecgo- 
 nme (VII) was prepared by Willstatter 3 from tropinone 
 (VI). 
 
 VI. TROPINONE 
 CH2 CM CH 2 
 
 X CH 3 CO 
 HoC - CH- CH 2 
 
 VII. CX-ECGONINE 
 
 CH 2 CH CH 2 
 
 | I OH 
 
 N-CH 3 C< 
 | | \COOH 
 
 -CH CH 2 
 
 Now if the carboxyl of this compound is methylated 
 and the hydroxyl is benzoylated the resulting com- 
 
 !Falck s. Merck, Ber., 18, 2955 (1885); Novy, Am. Chem. 
 J., 10, 147 (1888). 
 
 2 Liebrich and Liebermann, Ber., 21, 2344 (1888); Ehrlicb, 
 Deut. med, Wochschr., 17, 717 (1891). 
 
 s Willstatter, Ber., 29, 2216 (1896). 
 
NITROGEN COMPOUNDS 109 
 
 pound has no anaesthetic effect. But we shall see that 
 when the nucleus has a somewhat different structure 
 this combination may also be active. 
 
 Dextro cocaine has a more intense but more evanescent 
 action than the natural laevorotary base. 1 
 
 The methyl group of the nitrogen bridge seems to be 
 without significance for the anaesthetic action, since 
 Norcocaine (the methyl ester of benzoyl Norecgonine, 
 (VIII) possesses this action to the same degree as cocaine 
 but has a stronger toxic effect. 2 
 
 NORCOCAINE 
 
 VIII 
 CH 2 -CH- -CHCOOH 
 
 N H CHOH 
 CHo CH CH* 
 
 A further attachment of methyl iodide causes a loss of 
 the anaesthetic effect. The effect upon the liver which is 
 constantly observed in the cocaine derivatives is also 
 absent. 3 
 
 The same result is accomplished if an amino group is 
 introduced in the meta position in the benzoyl group of 
 cocaine. Also, the benzol-sulpho derivatives of this 
 amine and of the urea are without effect upon the liver. 
 But as soon as the amino group is substituted by acid 
 radicles the liver effect is again observed. The acetyl- 
 
 iPoullson, Arch. exp. Path. Pharm., 27, 301 (1890); Ehrlich, 
 loc. cit. 
 
 2 Poullson. loc. cit. 
 
 3 Ehrlich, loc. cit. 
 
110 .ORGANIC COMPOUNDS 
 
 amino and benzoylamino cocaine possess no anaesthetic 
 effect; but the corresponding urethane has a greater 
 action in this respect than cocaine itself. Considering 
 for a moment the effect of the other substitutions in the 
 cocaine molecule we find that halogen and nitro groups 
 decrease the anaesthetic action without altering the liver 
 effect. 
 
 The oxy-cocaines are intermediate in physiological 
 action between the nitro and the amino compounds. The 
 hydrochloride of dextro-cocaine azodimethylaniline causes 
 at most faint traces of anaesthesia, while the hydrochloride 
 of dextro cocaine-azo-a-naphthylamine causes a distinct 
 even if only slight anaesthesia. Neither of these com- 
 pounds have the characteristic liver effect. 1 
 
 We may say, then, that there is a special significance 
 in the henzoyl group. As this was also observed in a 
 whole series of benzoyl derivatives of other alkaloids, 
 Filehne 2 was led to consider this group as directly respon- 
 sible for the anesthesia action. But we have seen 
 instances whera this action is entirely lacking either in 
 consequence of a disturbing group (as the carboxyl group 
 in benzoyl ecgonine) or in consequence of an unfavorable 
 structure, even though that structure differs only slightly 
 from that of cocaine (as in the methyl ester of benzoyl 
 norecgonine) . Further experiences show that although 
 the benzoyl group favors this anaesthetic activity, it is 
 not absolutely essential. 3 We may say then, that the 
 benzoyl group in itself is not directly responsible for this 
 action; but that rather the effect is brought about by a 
 structure of the nucleus which makes the power of the 
 benzoyl group available. A comparison with the sub- 
 
 1 Ehrlich and Einhorn, Ber., 27, 1870 (1894). 
 
 2 Filehne, Berl. klin. Wochschr., 24, 107 (1887). 
 
 3 Ehrlich and Einhorn, loc. cit. 
 
NITROGEN COMPOUNDS 111 
 
 stances which are mydriatically active forces us to believe 
 that the capacity for paralyzing the peripheral nerve 
 endings is inherent in the nitrogen-containing nucleus, 
 and that the acid radicle acts, we may say as a selective 
 anchor which attaches the action to definite nerve end- 
 ings. Thus, in the case of the benzoyl group, the sensory 
 nerves are the seat of the attachment. In other words, 
 in this specific case, the benzoyl group will furnish the 
 hold upon the nerves, and whether anaesthesia will result 
 or not, must depend upon the nitrogen-bearing nucleus 
 that is attached to the benzoyl group. 
 
 The fact that the benzoyl group seems to have this 
 selective action is responsible for the interest that was 
 aroused in the benzoyl derivatives whose structure is 
 somewhat near that of tropine. These compounds were 
 experimented upon to the neglect of other derivatives of 
 ecgonine and tropine. Two bodies which received such 
 attention are triacetone alkamine and vinyl-diacetone 
 alkamine. Two derivatives of these substances have 
 proved to have an anaesthetic action very similar to that 
 of cocaine. These are Eucaine (benzoyl triacetone alka- 
 mine carboxylic acid methyl ester) (I) and Eucaine B 
 (benzoyl vinyl diacetone alkamine or 2-6-6 trim ethyl 
 4-benzoxypiperidine) (II). In this case, as in the cocaine 
 series, it appears that the elimination of the methylated 
 carboxyl group is of little importance. That the removal 
 of the methyl group attached to the nitrogen does not 
 impair the effect is most certainly established by the fact 
 that the norcocaines are as active as the cocaines. Other 
 relationships between the two series were established by 
 Vinci. 1 Among other points it was found that in this 
 case also only one of the stereometric isomers is active. 
 
 1 Vinci, Virchow's Arch., 145, 78 (1896); 149, 217 (1897); 154, 
 549 (1898). 
 
112 ORGANIC COMPOUNDS 
 
 I. EUCAINE 
 
 CH 3 
 I 
 
 -CH 2 
 
 | /COOCH 3 
 X H C< 
 | | X O.CO.C 6 H 5 
 
 -CH 2 
 
 CH 3 
 
 II. EUCAINE (B) 
 CH 3 
 
 CH; 
 
 \^ 
 
 N H 
 
 CHOCOC 6 H 5 
 
 nu 
 
 L 
 
 CH : 
 
 The work of Einhorn and Heinz l resulted in a great 
 simplification in the complex to be benzoylated. For 
 they discovered that it was not necessary, as formerly 
 supposed, and as in the case in the cocaines, that the 
 nitrogen atom shall belong to a ring system. 
 
 In fact they found that nearly all amino-oxy-benzoic 
 acid esters have a local anaesthetic action. Representa- 
 tives of this group are Orthoform (I), which is the methyl 
 ester of para-amino-meta-oxybenzoic acid, and Ortho- 
 form new (II) , which is meta-amino-para-oxybenzoic acid 
 methyl ester. These compounds are difficultly soluble 
 powders and are useful only for reacting on exposed nerve 
 ends. Such a use is found in cases of burns. The soluble 
 salts react too strongly acid and consequently cause an 
 excessive irritation of the tissues. It was expected that 
 
 1 Einhorn and Heinz, Munch, med. Wochschr., 44, 931 (1897). 
 
NITROGEN COMPOUNDS 113 
 
 this disadvantage could be overcome by using glycocoll 
 derivatives. Nirvanin (III), for example, is the methyl 
 ester of di-ethyl-amino-acetyl-para-amino-ortho-oxy-ben- 
 zoic acid, and this substance has found practical applica- 
 tion. 1 
 
 I. ORTHOFORM II. ORTHOFORM NEW 
 
 NH 2 OH 
 
 v-NH 2 
 
 OOCH 3 COOCH 3 
 
 III. NIRVANIN IV. AN^ESTHESIN 
 
 NH.CO.CH 2 .N(C 2 H 5 ) 2 NH 2 
 
 COOC 2 H 5 
 
 It was afterwards determined, however, that the 
 hydroxyl group is not a necessary requisite for the 
 anaesthetic action of such compounds. Rissert recom- 
 mended the use of the ethyl ester of para-amino-benzoic 
 acid (IV), which was marketed under the name Anses- 
 thesin. 2 A more recent member of this group is Cyclo- 
 form, which is the isobutyl ester of para-amino-benzoic 
 acid, NH 2 C 6 H 4 COOC4H 9 , investigated by Impens. 3 
 
 1 Einhorn and Heinz, Munch, med. Wochschr., 45, 1554 (1898). 
 
 2 Pharm. Ztg., 47, 356 (1902). 
 
 3 Therap. Gegenw., 51, 348. 
 
114 ORGANIC COMPOUNDS 
 
 This investigator states that the amyl and the benzoyl 
 esters have an even greater effect. This is a good ex- 
 ample of increase of action with increase of carbon con- 
 tent of the esterifying alkyl group. 
 
 The trouble with these last-named compounds, however, 
 is their slight solubility, which renders their practical 
 application as analgesics very slight. Even cycloform is 
 rather difficultly soluble in water, being only .014 to .022 
 per cent at 10 to 22 C. But these solutions have an 
 action about as strong as saturated solutions of the propyl 
 or ethyl esters, although these contain .03 to .04 per cent 
 and .08 per cent respectively. We may in fact find an 
 advantage in cycloform over the lower homologues in 
 that its solubility results in a correspondingly lower 
 resorption capacity. This is an advantage because the 
 amino-benzoic acids, just like aniline, cause methsemo- 
 globinuria. These compounds in contradistinction to 
 the amino-oxy benzoic acid esters, do not in vitro convert 
 the blood-coloring matter to methaemoglobin. These 
 amino-benzoic acid esters are, as a consequence of their 
 slight solubility, used almost exclusively externally. 
 Subcutine 1 is a similar body and is capable of steriliza- 
 tion without decomposition; but has not met with a 
 very favorable reception. This is a para-phenolsulphonic 
 acid salt. The propyl ester of this compound is better 
 still, and is used under the name of Propsesine. 2 
 
 We must remark, however, that none of these 
 compounds containing the nitrogen atom on the benzol 
 ring has been generally recognized as a wholly satis- 
 factory substitute for cocaine. Besides other special 
 disadvantages they seem to lack the power of deep pene- 
 tration which that substance has. Much better results 
 
 i Pharm. Ztg., 48, 405 (1903). 
 
 2 Stiirmer and Luders, Deut. med. Wochschr., 34, 2310 (1908). 
 
NITROGEN COMPOUNDS 115 
 
 were obtained when the position of the nitrogen atom 
 was shifted to the alcoholic group. A series of such com- 
 pounds which possessed a strong anaesthetic effect, was 
 prepared by Fourneau.. 1 Of this series the member which 
 has proved to be most useful in practice is Stovaine. This 
 is the benzoic acid ester of di-methyl-amino-dimethyl- 
 ethyl-carbinol (V). The Farbenfabriken vorm. Friedr. 
 Bayer u. Co. prepared and introduced another compound 
 which they called Alypin (VI) by the introduction of a 
 dimethyl-amino group on the second methyl group of 
 stovaine. 2 
 
 This naturally acts very much like stovaine; but it 
 has the advantage that its salts have a neutral reaction. 
 A third body in this group was introduced by the Farb- 
 werke Meister, Lucius u. Bruening, Hochst a. Main, under 
 the name of Novocaine. This is a diethyl-amino deriva- 
 tive of their ansesthesin, and consequently is para-amino- 
 benzoic acid diethyl-amino-ethyl ester or para-amino- 
 benzoyl-diethyl-amino ethanol (VII). 3 
 
 V. STOVAINE 
 
 (CH 3 ) 2 N H 2 C C O CO - C 6 H 5 
 
 LH 
 
 ^2*1 
 
 VI. ALYPINE 
 (CH 3 ) 2 N.H 2 C X 
 
 >C 0-CO.C 6 H 5 
 (CH3) 2 N-H^X | 
 
 2 Hs 
 
 VII. NOVOCAINE 
 
 (C 2 H 5 ) 2 N - CH 2 - CH 2 O - COC 6 H 4 NH 2 
 
 1 Fourneau, Compt. rend., 138, 766 (1904). 
 
 2 Impens, Deut. med. Wochschr., 31, 1154 (1905). 
 
 3 Braun, Deut. med. Wochschr., 31, 1667 (1905). 
 
116 ORGANIC COMPOUNDS 
 
 Although the investigations upon these three sub- 
 stances, particularly on their comparative value, cannot 
 be said to be concluded, nevertheless we can say that they 
 all stand very near cocaine and the eucaines as far as the 
 manner of their anaesthetic action is concerned, and 
 moreover they have the advantage of being less toxic. 
 On the other hand they lack one of the advantages of 
 cocaine, which is often desirable, and that is the power 
 of contracting the blood vessels. In fact stovaine and 
 alypine have the opposite effect, causing a dilation of the 
 blood vessels. 
 
 This brings us to a substance which comes to the rescue 
 in this condition, a substance which is also related in 
 constitution and has in itself a slight anaesthetic action, 
 although its pre-eminent powerful effect is vasocontrac- 
 tile. This substance is Adrenaline. 1 
 
 ADRENALINE 
 
 j CH(OH) CH 2 NH (CH 3 ) 
 H( 
 
 According to Fourneau 2 the simplest analogue of 
 cocaine is obtained from chloroxyisobutyric acid, 
 
 \C-OH 
 C1H 2 (X | 
 
 COOH 
 
 and has the formula 
 
 (CH 3 ) 2 NH 2 C / X COOCH 3 
 
 1 Zeigan, Therap. Monatsh., April, 1904. 
 
 2 Fourneau, J. pharm. chim., (6) 27, 513 (1908). 
 
NITROGEN COMPOUNDS 117 
 
 It differs from stovaine by having a carboxyl group 
 instead of an ethyl group. As a matter of fact it is really 
 more comparable with methyl-benzoyl-a-ecgonine than 
 with cocaine. Nevertheless it possesses a strong anaes- 
 thetic power (compare also eucaine). It cannot be used 
 in practice because the fundamental basic character of 
 the substance is so weak that its salts have an acid 
 reaction. Fourneau also says that for a practically use- 
 ful cocaine substitute the compound must have at least 
 two carbon atoms between the two ester groups. 
 
 A very decided anaesthetic effect is shown by the alka- 
 loid. Yohimbine l although it contains no benzoyl group. 
 Yohimbine does not have a mydriatic action, but does 
 dilate the blood vessels. An anaesthetic effect is found, 
 also, in the glucosides of the digitalis group. These 
 substances cause at the same time a contraction of the 
 pupil and more or less hyperaemia. 2 Anilides have to a 
 slight degree an anaesthetic action as also have the 
 ordinary phenetidine derivatives. The action is, however, 
 increased, by the addition of a second basic complex to 
 the amino group, as for example in Holocaine, which is 
 para-diethoxy-diphenyl-ethanyl-amidine, 3 
 
 ,N.C 6 H 4 .OC 2 H 5 
 
 or in the alkyl-oxyphenyl guanidines, 
 
 N NH.C 6 H 4 OR 
 
 1 Arnold and Behrens, Chem. Ztg., 25, 1083 (1901). Magnani, 
 Munch, med. Wochschr., 50, No. 28 (1903); Loewy and Miiller, 
 Munch, med. Wochschr., 50, No. 15 (1903). 
 
 2 Korizki, Dissertation, Petersburg, 1906. 
 
 3 Timber, Therap. Monatsh., April, 1897. 
 
 4 Trolldenier, Therap, Monatsh., 1899, 36. 
 
118 
 
 ORGANIC COMPOUNDS 
 
 Finally we may mention that this anaesthetic action is 
 also found in phenols and phenol ethers with at least 
 one free hydroxyl, in a-aminopyridine, tri-methyl- 
 ethylene, etc. 1 
 
 Opium Alkaloids and Relatives. 
 
 The most important substance in opium is morphine 
 (I). This is a phenanthrene derivative, as are also 
 codeine (II) and thebaine (III). 
 
 I. MORPHINE 
 HO X 
 
 >Ci 7 H 17 ON 
 HCK 
 
 H 2 
 
 CH 2 
 
 II. CODEINE 
 
 CH 3 <\ 
 
 >C 17 H 17 ON 
 HCK 
 
 III. THEBAINE 
 
 CH 3 (X 
 
 >C 17 H 15 ON 
 CH 3 CK 
 
 1 Frankel, Arzneimittelsynthese, 2d Ed., p. 380. 
 
NITROGEN COMPOUNDS 119 
 
 Morphine and of course codeine, which is methyl 
 morphine, are derived from hexahydrophenanthrene, 
 while thebaine is derived from tetrahydrophenanthrene. 
 The physiological effect of morphine is somewhat compli- 
 cated. In the first place it diminishes and finally stops 
 the functioning of the cerebrum, particularly the power of 
 sensation. This is the cause of the most potent and 
 important results of the administration of morphine, 
 which are a deadening of pain, hypnosis, euphoria and 
 narcosis. After larger doses the paralysis extends to 
 the voluntary movements and to the reflex movements 
 which depend upon pain production for excitation and 
 which are also finally completely suppressed. In some 
 kinds of animals morphine acts like strychnine in causing 
 an increase in the sensitiveness of reflex actions, which are 
 controlled by sense excitation. This effect is much more 
 pronounced in the case of codeine, and is entirely pre- 
 eminent in thebaine, which should be placed, as far as 
 physiological action is concerned, in the strychnine group. 
 
 Morphine is attracted to the brain and is here largely 
 destroyed. The extent of the attraction and destruction 
 by the brain substance is, moreover, commensurate with 
 the habituation or tolerance which results from continued 
 
 use. 1 
 
 First of all, it is of interest to investigate the extent of 
 the role of the phenanthrene nucleus in this effect. It 
 is true that Overton has stated that phenanthrene itself 
 acts as a narcotic on tadpoles; but with warm-blooded 
 animals it has no such action. On the other hand, it 
 undoubtedly does have a tetanic effect. This is also 
 true of the phenanthrols, the carboxylic acid, and 
 even of the sulphoacid. 4-methoxy-phenanthrene-9-car- 
 boxylic acid acts like phenanthrene carboxylic acid. A 
 1 Cloetta, Arch. exp. Path. Pharm., 50, 453 (1903). 
 
120 ORGANIC COMPOUNDS 
 
 further addition of alkyl and acid groups upon the 
 hydroxyl diminishes very considerably the cramp produc- 
 ing action and the general toxic effect. None of these 
 preparations, however, possesses any narcotic action. 1 
 
 The action of phenanthrene quinone derivatives, is 
 somewhat different. Phenanthrene quinone-3-sulphonic 
 acid has no cramp effect, but does cause pronounced 
 methaemoglobinuria, 2 2-brom-phenanthrene quinone sul- 
 pho acid causes strong poison phenomena and degenera- 
 tion of the organs, and is said to act, when introduced 
 directly into the veins, in a manner similar to morphine, 
 in so far as it retards and diminishes the respiration. 3 
 According to Pschorr 4 we must also consider as belong- 
 ing here the Epiosin of Vahlen 5 which is methyl- 
 diphenylene-imidazol (IV). This substance dulls the 
 sensibility for pain, has a slight hypnotic effect, and a 
 strong cramp, producing action. Like Schmidt's com- 
 pound, it causes an increase in blood pressure. 
 
 IV. EPIOSIN 
 
 1 Bergell and Pschorr, Z. physiol. Chem., 38, 17 (1903). 
 
 2 Ibid. 
 
 3 Schmidt, Ber., 37, 3565 (1904). 
 
 4 Pschorr, Ber., 35, 2729 (1902). 
 
 5 Arch. exp. Path. Pharm., 47, 368 (1902). 
 
NITROGEN COMPOUNDS 121 
 
 According to Pschorr the morphine-like effects are not 
 caused by action upon the nerves, as in the case of mor- 
 phine itself, but by a poisoning of the blood. 
 
 Therefore it seems as if the narcotic effects of morphine 
 were dependent upon the addition of a nitrogen-contain- 
 ing ring. In order to cause a stronger action the phenolic 
 hydroxyl of the morphine must be free, for it is evident 
 that this group functions as a binder of the alkaloid to 
 the nerve substance. To be sure, codeine, in which this 
 hydroxyl is methylated, does produce in small doses a 
 narcotic effect, but it is of much shorter duration and less 
 deep than that of morphine. Upon the administration 
 of larger doses of codeine, this narcosis is hardly per- 
 ceptible, because the tetanic effect becomes of paramount 
 importance. 1 
 
 The same is true of the action of ethyl morphine 
 (Dionine), amyl morphine and benzyl morphine (Pero- 
 nine) . Similar changes in effect are caused by the intro- 
 duction of acid radicles such as acetyl, benzoyl, etc., into 
 the phenolic hydroxyl. 2 Such compounds, however, 
 stand nearer to morphine than do codeine and its homo- 
 logues, because in the former compounds the radicles 
 which hinder or retard the morphine effect are more 
 easily split off. Diacetyl morphine (Heroine) finds a 
 considerable practical application. The inorganic acid 
 radicles act in a manner similar to the organic acid 
 radicles. The more easily the acid radicle can be split 
 off, the more nearly the effect approaches that of mor- 
 phine. For example, the carbonic esters and the car- 
 bonic acid alkyl esters of morphine act very much like 
 morphine, according to von Mering. Winternitz 3 states 
 
 1 Stockmann and Dott, Brit. Med. J., 1890, II, 189. 
 
 2 Ibid.; v. Mering, Merck's Jahresber., 1898, 5. 
 
 3 Winternitz, Therap. Monatsh., Sept., 1899. 
 
122 ORGANIC COMPOUNDS 
 
 that alkylation of morphine weakens the effect upon 
 the respiration, but acylation strengthens it very 
 materially. 
 
 These derivatives of morphine furnish remarkable 
 examples of the fact that it is exceedingly dangerous and 
 uncertain to assume that a chemical compound will have 
 the same effect upon man that has been observed with 
 other warm-blooded animals. For example, codeine is 
 much more poisonous for rabbits than is morphine. For 
 man, on the contrary, codeine is much less poisonous. 1 
 For experiments which affect the nervous system it 
 appears that the cat is most suitable if the results are to 
 be compared to those in man. 
 
 Of the products which result from tearing down the 
 morphine molecule, apomorphine is only a mild narcotic, 
 but it has a powerful emetic action, which is to be attrib- 
 uted to the free phenolic hydroxyls. The reason for 
 attributing it to these groups is that a half alkylation 
 leaves only a suggestion of the emetic action, and complete 
 alkylation or acylation removes it entirely. 2 
 
 On the other hand this specific emetic effect is not de- 
 stroyed by conversion into quaternary compounds. 
 For example, the effect is retained in apomorphine brom- 
 methylate (Euporphine) , but the undesirable"side effects, 
 such as action upon the heart, are said to be eliminated. 3 
 
 The methylated derivative, apocodeine, acts as a 
 sedative and purgative. 4 Dixon 5 states that it has a 
 
 1 Mayor, Therap. Monatsh., May- June, 1903; Vinci, Arch, 
 ital. di Biol., 47, Vol. Ill (1907). 
 
 2 Michaelis, Klin.-therap. Wochschr., 1904, 660; Kaminer, 
 Festschr. f. Salkowski, p. 205. 
 
 3 Schutze, Berl. klin. Wochschr., 43, 349 (1906). 
 
 4 Gurnard, Contribution a 1'etude physiologique de 1'apocodeine, 
 Lyon, 1893. Toy and Combemale, Merck's Jahresber., 1900, 62. 
 
 5 Dixon, J. Physiol., 30, 98 (1904). 
 
NITROGEN COMPOUNDS 
 
 123 
 
 paralytic action upon the nerve cells, thus causing dila- 
 tion of the blood vessels, that it depresses the blood 
 pressure, accelerates the heart frequency, and excites 
 the automatic movements of the smooth muscles. More- 
 over, it increases the reflex action even to convulsions, 
 like those caused by strychnine, and finally it has a 
 curare effect. 
 The methyl-morphimethines 
 
 CH(OH 
 CH 3 O.CioH 5 
 
 act neither as relievers of pain, nor as sleep producers. 
 They do, however, like morphine, paralyze the respiratory 
 center, and unlike it lower the blood pressure. 
 
 Intermediate in effect between morphine and codeine 
 stands papavcrine (I) 1 
 
 1 Schroeder, Arch. exp. Path. Pharm., 17, 96; Leubuscher, Deut. 
 med. Wochschr., 18, 179 (1902). 
 
124 
 
 ORGANIC COMPOUNDS 
 
 Laudanosine, which is the tetrahydro derivative of 
 papaverine, but is methylated on the nitrogen 1 has no 
 appreciable narcotic effect, and is in both its action and 
 toxicity similar to thebaine. 2 
 
 Narcotine (II) is nearer to morphine both chemically 
 and physiologically. It has, however, a much weaker 
 narcotic effect, which is preceded by a tetanic effect of 
 short duration. Hydrastine (III) is very closely related 
 chemically to narcotine; but it has no narcotic effect, 
 and we must attribute this lack to the presence of a 
 methoxyl group. Hydrastine has a toxic effect which is 
 manifested by general paralysis and tetanus. 
 
 S^~ 
 
 H 2 G< 
 
 ^O 
 
 II. NARCOTINE 
 CH CH 2 
 
 O C| C |CH 
 II 
 
 c (N. 
 
 \y 
 
 C CH 
 H 3 CO CH 
 
 GH 3 
 
 OCH; 
 
 The strychnine-like excitant action of hydrastine upon 
 the central nervous system is manifested first through the 
 
 1 Pictet and Athanasescu, Ber., 33, 2346 (1900). 
 
 2 Babel, Rev. me'd. de la.Suisse rom., 1899, 657. 
 
NITROGEN COMPOUNDS 
 
 125 
 
 H 2 C 
 
 III. HYDRASTINE 
 CH CH 2 
 
 C ]CH 2 
 
 II 
 
 C N-CH 3 
 
 v\/ 
 
 CH CH 
 
 vasomotor nerves, so that small doses cause a contrac- 
 tion of the blood vessels and thus an increase in blood 
 pressure. Considering for a moment the action of some 
 of the decomposition products of these two alkaloids, 
 we find that opianic acid is narcotic through a paralysis 
 of the central nervous system in cold-blooded animals, 
 but in warm-blooded animals it is without effect. Hydras- 
 tinine (IV) is distinguished from the parent body by an 
 absence of the tetanic stage and by a detrimental effect 
 upon the heart. 
 
 IV. HYDRASTININE 
 CH CH 2 
 
126 ORGANIC COMPOUNDS 
 
 It causes vaso-constriction and thereby a rise in blood 
 pressure, and a lowering of the pulse frequency by action 
 upon the vessels themselves. Cotarnine (V) has been 
 known longer, and its chemical similarity to hydrastinine 
 induced the belief that it also, like hydrastinine, might 
 possess astringent and styptic properties. 
 
 V. COTARNINE 
 CH CH 2 
 
 >CH 3 
 
 The hydrochloride (Stypticine) and later the phthalic 
 acid salt (Styptol) were in fact found to have a styptic 
 action. But, strange to say, the cause of this action was 
 quite different from the cause of the similar action of 
 hydrastinine salts. For the stypticine and styptol 
 cause neither a vaso-contraction nor blood coagulation. 1 
 Their styptic effect probably depends upon a slowing of 
 the respiration and consequent reduction of arterial blood 
 pressure. The action of cotarnine is similar to that of 
 the parent substance, narcotine. It causes first an exci- 
 tation of the central nervous system, and then a general 
 paralysis. 2 It is claimed by Williams 3 that an intrave- 
 nous injection of hydrastis causes a lowering of the blood 
 pressure by a reduction of the action of the heart muscles. 
 
 Hydrocotarnine has the typical effect of the codeine 
 group. 4 
 
 1 Marfori, Arch. ital. di Biol., 1897, Vol. II. 
 
 2 Falk, Therap. Monatsh., 1895, 646 and 1896, 28. 
 
 3 Williams, J. Am. med. assoc., 50, 26 (1908). 
 
 Stockmann and Dott, Brit, med, J., 1891, 24 Jan. 
 
NITROGEN COMPOUNDS 
 
 127 
 
 Berberine (I) acts like hydrastine, but is more powerful. 1 
 
 (I) BERBERINE. 
 CH 
 
 HsCOCl C 
 
 V 
 C CH C 
 
 OCH 3 
 
 C O- 
 
 The corydalis alkaloids, with the exception of the very 
 weakly basic corytuberine, produce in cold-blooded ani- 
 mals a morphine-like narcosis. These alkaloids stand 
 very near, chemically, to those we have just been discuss- 
 ing, as will be seen from the structural formula proposed 
 for corydaline (II) by Dobbie and Lauder. 2 
 
 II. CORYDALINE 
 
 -OCH 3 
 
 -OCH 3 
 
 1 Williams, loc. cit. 
 
 2 Dobbie and Lauder, Journ. Chem. Soc., 81, 145, 157 (1901). 
 
128 ORGANIC COMPOUNDS 
 
 These corydalis alkaloids can be chemically and also 
 pharmacologically divided into three groups: First, 
 the corydaline group (corydaline, corybulbine, iso- 
 corybulbine) ; second, the corycavine group (corycavine 
 and corycavamine) ; third, the bulbocapnine group (bul- 
 bocapnine, corydine and cory tuberine) . Common to 
 all three groups is a narcotic effect, an action on the 
 heart, consisting of a weakening of its general capacity 
 for reaction and injury to the muscle motor apparatus. 
 Besides these common effects the alkaloids of the first 
 group cause paralysis of the spinal cord, the second 
 stimulate the motor centers and the third group resemble 
 codeine in action and cause increased reflex excitability. 1 
 
 Veronal Group 
 
 The investigations of E. Fischer and v. Mering on di- 
 alkylated acids and their derivatives 2 are very instruc- 
 tive concerning the influence of an accumulation of 
 alkyl groups upon a compound, the effect of the size of 
 the radicle and the effect of the constitution of the ring 
 in the production of narcotic effect. We produce, there- 
 fore, an exhaustive table of experiments which were 
 made upon dogs. From this table one can observe that 
 there is no sleep-producing effect until we come to the 
 urea group, and it is decidedly stronger in a cyclical 
 arrangement of this group. Furthermore, it is essential 
 that there be in the combination a group that contains 
 several alkyl radicles rich in carbon. 
 
 These alkyl radicles cause an increase in effect with 
 rising carbon content of the radicle up as far as propyl, 
 and after that the effect again diminishes. A very strik- 
 
 1 Peters, Arch. exp. Pathol. u. Pharmakol., 51, 130 (1904). 
 
 2 Therapie der Gegenwart, 5, 97 (1903). 
 
NITROGEN COMPOUNDS 
 
 129 
 
 ^ S.s^i 
 K.ss-g^ 
 
 s iffll 
 Id**III 
 
 iJg.ali'S 
 
 ^Jj'gol 
 
 P-, 02 ^Jfe 
 
 *0 
 
 
 
 I 
 
 Pij 1 
 
 .Sto <D 
 
 02 03 
 
 bCbC 
 iO 10 
 
 .Sfc 
 <^.5 
 
 10 
 
 10 
 
 100 
 
 
 UV 
 
 
 
 w 
 
 I 
 
 Q 
 
 s 
 
 .S *'5 1 02 "3 a e 
 
 2 O S O^ H S _2 
 
 a *s^a * S^o^ 
 
 JSlgl S 81J- 
 
 SiSiSS ^ 
 
 RIVE 
 tylui 
 
 s 
 
 ^ .2 
 
 CJ os 
 
 ! 
 
 a 
 
 lhy 
 
 a 
 
130 
 
 OKGANIC COMPOUNDS 
 
 ~ QJ i faf"~i <*"i 
 
 **.H e "S K 
 
 ms.fr-ii 
 
 o 
 
 bC 
 CO 
 
 1 
 
 ^H 
 
 CO 
 
 O 
 
 O 
 
 I I 
 
 I 1 
 
 S 43 
 
 5 ^ 
 
 ^ ?,. 
 
 a 
 
 CO 
 
NITROGEN COMPOUNDS 
 
 131 
 
 s 
 
 S II 
 
 . 00 
 
 5 'Sn^ *-> blO 2 bC .S -2 c3c o t2 
 
 S || .g .S.o gJ-S^-gg 
 
 Pell |i" ||l'|11|l| 
 
 ^,-1^730 I- w Cl<a2-C3CHT3CC.^c5^3 
 
 O^ 
 
 
 
 
 feS 
 
 18 
 
 
 fi 
 
 10 
 
 00 
 
 CO NH X 
 
 \ 
 
 CO NH/ 
 
 W 
 
 O -3 
 
 O 1 
 
 AX 
 
 W W B W 
 
 s g i 
 
 i i ll 
 
 1 1 
 
 o o 
 o o 
 
 o 
 
 X X 
 
 y ** ^J& ** 
 
 o c5 u Q 
 
 i 1 
 
 
 
 \? V ^ 
 
 o R S 
 
 tC ffi tC ffi ffi ffl S 
 
 c5 o d o o o s 3 
 
 hy 
 ure 
 
 
 c3 63 X5 
 
 .IS I 
 
 5 S 
 
 ! 
 
132 
 
 ORGANIC COMPOUNDS 
 
 JD D- 5 
 
 : $* 
 
 i+2 '02 
 
 III 
 
 MO 
 
 i 
 
 
 o u 
 
 g 
 
 CC 
 
 X 
 
 W B W W 
 
 1^1 111 
 
 D O O O O O 
 
 17 S? V 
 
 A A A 
 
 *o o t^. t o >o 
 
 5 d c5 o c5 o 
 
 >> 
 
 Ic5 
 
 s.s 
 
 Q 
 
NITROGEN COMPOUNDS 133 
 
 ing phenomenon is the increase in toxicity upon methyla- 
 tion on the nitrogen (23) and upon the introduction of 
 sulphur in place of oxygen (26). Contrary to this is the 
 replacement of the same oxygen by NH (25) which nulli- 
 fies the action. It is easier to understand removal of 
 the effect caused by a free carboxyl group (24 as com- 
 pared with 9). It would be interesting to determine 
 whether esterification of this group would reestablish the 
 effect. 
 
 A slight chemical modification of Veronal which has 
 given rather surprising physiological results is the so- 
 called Luminal of the Farbenfabriken of Elberfeld. One 
 of the ethyl groups of veronal is replaced by phenyl, 
 giving phenyl-ethyl-barbituric acid: 
 
 CeHs^ /CO NH 
 
 /^\ /CO 
 
 Although in general the aliphatic radicles are more effect- 
 ive in sleep-producing action than aromatic radicles, 
 the reverse seems to be true in this case since, 0.2 gm. of 
 Luminal is equivalent to 0.5 gm. of Veronal. According 
 to Impens, however, this hypnotic action of the aromatic 
 radicle can take effect only when there is attached to the 
 same carbon atom with it one or two other alkyl groups. 
 
 Quinine and Fever Remedies Deduced from Quinine 
 
 According to Schmiedeberg 1 the general character of 
 the physiological action of quinine is probably to be inter- 
 preted as being a sort of mortification effect for all the 
 organs concerned. The functions or the functional 
 capacity of the organs, and their nutrition processes are 
 at first increased, then lowered, and finally entirely 
 1 Schmiedeberg, Grundriss der Pharmakologie, 1902, p. 179. 
 
134 OKGANIC COMPOUNDS 
 
 destroyed, as in the case of mortification from other 
 causes. 
 
 A .5 per cent to 1 per cent solution of quinine imme- 
 diately suppresses the movements of all kinds of infusoria. 
 A solution of this concentration also stops the amoeboid 
 movements of the white blood corpuscles of mammals. 
 
 For man and other mammals small doses lessen the 
 pulse frequency and increase the blood pressure, while 
 larger doses (upward from 1 gm. in the case of man) 
 cause a decrease in pulse frequency and also a decrease 
 in blood pressure. At the same time there appears a 
 weak morphine effect on the sensory brain sphere, which 
 is called quinine intoxication. Smaller doses cause also 
 at first a rise in the body temperature; but larger doses, 
 not sufficient for poisoning effect, of course, have an 
 insignificant effect on temperature in a normal invididual, 
 but cause a considerable drop in temperature of a fever 
 patient. This action is stronger in antipyrine and the 
 salicylic acid group than it is in quinine. But quinine 
 is much preferable to these compounds or in fact any 
 other substance known at present, as a specific against 
 malaria. 
 
 Metabolism as measured by the nitrogen excretion is at 
 first increased by quinine and then often considerably 
 diminished. In fact it is always largely diminished after 
 large doses. Quinine is for the greater part destroyed in 
 the organism if ingested in moderately small quantities. 
 Gijemsa and Schaumann 1 state that the power of the 
 organism in destroying quinine is increased with repeated 
 dosage with the substance. Schmitz, 2 however, was 
 unable to confirm this statement. 
 
 1 Giemsa and Schaumann, Arch. Schiffs. Tropen hyg., 11, 
 Vol. Ill (1907). 
 
 2 Schmitz, Arch. exp. Path. Pharm., 56, 301 (1907). 
 
NITROGEN COMPOUNDS 135 
 
 The constitution of quinine can be to-day regarded 
 with a considerable degree of certainty as being formula 
 (I). 1 The side chain of the para-methoxy-quinoline that 
 contains a piperidine ring is designated as the loipone or 
 meroquinine part of the formula. Of the accompanying 
 alkaloids cinchonine (III) stands very near to quinine, 
 since it lacks only the methoxy group in the para position. 
 But this very slight chemical difference reduces the effec- 
 tiveness of the physiological action tremendously. Cin- 
 chonine is more detrimental to the heart, and possesses a 
 cramp-excitant effect that is only very slightly apparent 
 in quinine. Moreover cinchonine is a much less efficient 
 febrifuge, and its specific action against malaria is only 
 vaguely apparent, and only after large doses. But it 
 seems to be clear that the secret of the action of the 
 methoxyl group lies in the covered hydroxyl group, 
 because the higher alkyl derivatives obtained from cupre- 
 ine (II) such as quinethyline, quinpropyline, quinamyline 
 have an action still more powerful than that of quinine. 
 In other words, the more readily oxidizable is the alkyl 
 group which covers the hydroxyl, the more powerful is 
 
 I QUININE 
 
 CH^CH^ CH-CH=CH2 
 
 CH (OH)-CH CH 2 CHa. 
 HaCO-f Y S ^ 
 
 'N 
 
 i Compare Rabe, Her., 40, 3655 (1907); 41, 62 (1908). 
 
136 
 
 ORGANIC COMPOUNDS 
 
 the action of the compound l on account of the greater 
 ease with which it is split down to cupreine. 
 
 II CUPREINE 
 
 H 
 
 OH 
 
 CH(OH)-CH CH 2 CH 2 
 
 N 
 
 III ClNCHONINE 
 
 (OH)-CH CH 2 CH 2 
 
 It seems, then, very probable that the slight febrifuge 
 effect of cinchonine may not belong to that substance 
 itself, but is due to cupreine, which is formed within the 
 organism by the hydroxylation of the cinchonine in para 
 position. In fact we have many cases analogous to this. 
 
 iQrimaux and Arnaud, Compt. rend., 112, 766, 1364 (1891); 
 114, 548, 672 (1892); 118, 1803 (1894). 
 
NITROGEN COMPOUNDS 137 
 
 The earliest and most numerous investigations as to 
 the connection between the effect of quinine and its con- 
 stitution started from the quinoline part which was 
 demonstrated to be present. At first there was assumed 
 to be a tetra-hydroquinoline ring. Quinoline itself 
 proved to be antiseptic, antizymotic and antipyretic 
 in its effect. It was found to be weaker against fever 
 than quinine and to be entirely useless against malaria. 
 Moreover it caused some detrimental effects such as 
 collapse and difficulty in respiration, even with the admin- 
 istration of small quantities. 1 
 
 A recent quinoline derivative which deserves particular 
 mention is Atophan, which is 2-phenyl-quinoline T 4-car- 
 boxylic acid. 
 
 COOH 
 
 This substance has found practical application in acute 
 attacks of gout because it causes an extraordinary increase 
 in the elimination of uric acid. On account of the 
 relation of quinine to quinoline, the derivatives of this 
 latter body have been subjected to considerable physi- 
 ological examination. Nicolaier and Dohrn 2 examined 
 a series of the quinoline carboxylic acids, particularly in 
 regard to their effect on uric acid excretion. From their 
 results we may say that the 4 position for the carboxylic 
 
 iDonath, Ber., 14, 178 (1881); Biach and Loimann, Virchow's 
 Arch., 86, 456 (1881); Brieger, Z. klin. Med., 4, 296 (1882); v. 
 Jacksch, Prager med. Wochschr., 1881, No. 28. 
 
 2 Nicolaier and Dohrn, D. Arch. f. klin. Med., 93, 331 (1908). 
 
138 ORGANIC COMPOUNDS 
 
 group is favorable; but the unsubstituted 4 carboxylic 
 acid is without effect, as is also the 2-4 dicarboxylic acid. 
 But if an aliphatic or aromatic radicle is introduced in 
 the 2 position then the increased uric acid excretion is 
 caused. This action is slight for the methyl-substituted 
 body, but strong for the phenyl. Given this compound 
 (atophan) the effect remains unchanged upon introduc- 
 tion of a second phenyl group (in 3 position) , of a second 
 carboxyl group (in 3 or 8 position) , or of a methyl in 6 po- 
 sition, and hydroxyl weakens the effect. The exact 
 behavior of atophan in the organism is as yet not fully 
 understood. Very little of it is excreted unchanged. 
 Moreover the increase in uric acid excretion cannot be 
 ascribed to an increased nucleine destruction because the 
 excretion of total nitrogen, phosphoric acid and sulphur 
 is not increased. In fact the action would almost seem 
 to indicate that the atophan releases an amount of uric 
 acid which has been stored up in the organism, for after 
 the discontinuance of the atophan treatment the uric acid 
 excretion falls below the normal. The only other com- 
 pound of those examined by Nicolaier and Dohrn which 
 showed a similar action was 2-phenyl-3-oxyquinoline-4- 
 carboxylic acid. 
 
 Isoquinoline is similar in every respect to quinoline. 1 
 When hydrogen of the quinoline is substituted by methyl 
 groups the effect is weakened, but is qualitatively the 
 same. 2 The introduction of methoxyl in the para posi- 
 tion in quinoline weakens the antipyretic effect which is 
 just the opposite of the action of the same group in the 
 relation between cinchonine and quinine. 2 A con- 
 siderably stronger antipyretic body is para-methoxy- 
 tetra-hydroquinoline (Thalline) (I) whose effect, however, 
 
 1 Stockmann, J. Physiol, 15, 245 (1894). 
 
 2 Ibid. 
 
NITROGEN COMPOUNDS 
 
 139 
 
 is of short duration. This substance is also injurious to 
 the blood and kidneys. 
 
 I. THALLINE 
 CH 2 
 
 This effect is not altered either by the introduction of 
 alkyl radicles, nor by the introduction of acid radicles 
 in the imino group. A similar condition holds also with 
 kairine (II) and kairoline (III) which are both prepara- 
 tions which are without a methoxyl group, and are alky- 
 lated on the nitrogen. 
 
 III. KAIROLINE 
 CH 2 
 
 N C 2 H 5 
 
 OH N R(CH 3 or C 2 H 5 ) 
 
 None of these quinoline derivatives approaches the specific 
 effect of quinine. 
 
 In the meroquinine residue of the quinine molecule 
 the binding of the piperidine nitrogen by the bridge 
 containing hydroxyl is of prime importance. If this is 
 split off, as in the change from quinine to quinotoxine 
 (IV), or in the same way if cinchonine is converted to 
 cinchotoxine, these new substances do not behave as 
 febrifuges at all, but as a digitoxine-like poison. 1 We 
 
 1 v. Miller and Rohde, Ber., 33, 3214 (1900). 
 
140 
 
 ORGANIC COMPOUNDS 
 
 are, however, hardly surprised by this toxic effect, when 
 we note the presence of two groups of particularly great 
 capacity for reaction the CO and the NH groups. 
 
 The unsaturated side chain of the quinine seems to 
 have a definite significance. If hydrogen is added at the 
 double binding, the poison effect is hardly changed for 
 mammals and infusoria. Hydrochlor-quinine, which is 
 formed by addition of HC1, is said to be less poisonous 
 for mammals than quinine, although it is more poisonous 
 for certain infusoria. 1 
 
 IV. QUINOTOXINE 
 
 CH 
 H, 
 
 :-CH=GH 2 
 
 H 3 CO 
 
 In order to have a sort of standard test body that 
 might stand as near as possible to the object of attack 
 of the specific quinine effect, the malaria parasites, 
 Tappeiner 2 selected the paramecium, and undertook 
 experiments upon it. It was found that the order of 
 strength in quinine effect is first para-methoxylepidine 
 (V), then lepidine (VI), and finally quinoline; but that 
 meroquinine (VII) is entirely without such effect. 
 
 1 Hunt, Arch, intern, pharmacodyn, 12, 497 (1904). 
 2 v. Tappeiner and Grethe, Deut. Arch. klin. Med., 56, 189, 369 
 (1896). 
 
NITROGEN COMPOUNDS 141 
 
 V. PARAMETHOXYLEPIDINE VI. LEPIDINE 
 
 CH 3 CH 3 
 
 HaCO-/" 
 
 VII. MEROQUININE 
 CH CH 2 .COOH 
 
 2 c 
 
 CH 2 
 NH 
 
 On the other hand y-phenylquinoline (VIII) is con 
 siderably stronger in action than quinine. 
 
 VIII. y-PHENYLQUINOLINE 
 
 We may conclude, then, that the action of quinine upon 
 infusoria proceeds from the quinoline ring, and can be 
 materially increased by the complex attached to it in the 
 y position, even though this complex be in itself inactive. 
 Since the substitution of the benzol ring proved to give 
 such an effective compound it was natural that the 
 phosphines, the beautifully colored compounds obtained 
 from acridine, such as chrysaniline (IX), should be 
 tested out. This was done, and they were found ex- 
 traordinarily effective. But these substances, as well as 
 
142 
 
 ORGANIC COMPOUNDS 
 
 phenyl-quinoline, do not seem to destroy the malarial 
 parasites, but only to paralyze them in a manner similar 
 to the constitutionally related methylene blue (X). 1 
 
 IX. CHRYSANILINE 
 
 X. METHYLENE BLUE 
 
 (CH 3 ) 2 X-/ 
 
 The constitution which Knorr first 2 ascribed to a 
 tetra-hydroquinoline derivative was the cause for test- 
 ing out the so-called dimethyl-oxy-quinizine (I) with a 
 view to finding antipyretic effects, and such an effect 
 was found to be very pronounced 3 and led to the name 
 of this compound, Antipyrine. 
 
 I. ANTIPYRINE 
 
 H 
 
 CO 
 
 It was only later 4 that this compound was recognized 
 
 Mannaberg, Arch. klin. Med., 59, 185 (1897). 
 
 2 Knorr, Ber., 17, 546, 2032 (1884). 
 
 3 Filehne, Z. klin. Med., 7, vol. 6 (1884). 
 * Knorr, Ann. Chem., 238, 137 (1887). 
 
NITROGEN COMPOUNDS 143 
 
 as dimethyl-phenyl-pyrazolon (II). Michaelis 1 affirms 
 that the formula (III) can also be ascribed to this body. 
 
 II. ANTIPYRINE III. ANTIPYRINE 
 
 CH 3 CH 3 
 
 N C ( 
 
 /2 
 
 CO CH C CH 
 
 Antipyrine does not act against malaria, but aside from 
 this it is to be preferred over quinine, as it has less undesir- 
 able side effects, and it has a specific anti-neuralgic action. 
 
 The alkylation of the nitrogen is of importance. 
 Phenyl-monomethylpyrazolon has no particular anti- 
 pyretic action. The presence of the aromatic substituting 
 group is, according to Curtius 2 not essential for the 
 physiological action, but Filehne 3 finds that it is impor- 
 tant for the degree of effect. The introduction of the tolyl 
 group in place of the phenyl, giving us tolyl-pyrine, does 
 not cause any essential change. A compound which is 
 better than antipyrine in regard to strength and duration 
 of effect is the 4-dimethyl-amino-antipyrine, which is 
 called Pyramidon (IV). 
 
 IV. PYRAMIDON 
 CH 3 
 
 N(CH 3 ) 2 
 
 1 Michaelis, Ann. Chem., 320, 1 (1902). 
 
 2 Curtius, Ber., 26, 408 (1893). 
 
 8 Filehne, Z. klin. Med., 32, 568 (1907). 
 
144 ORGANIC COMPOUNDS 
 
 [3] Antipyrine (V) is considerably more poisonous than 
 the ordinary antipyrine; but when we go to the dimethyl- 
 amino derivatives we find the situation reversed. 
 
 V. [3] ANTIPYRINE 
 CH 3 
 
 GH 
 
 Iso-antipyrine (VI) is, so far as toxicity is concerned, 
 about like ordinary antipyrine. 1 
 
 VI. ISO-ANTIPYRINE 
 CH 3 
 
 C 6 H 5 -N 
 
 X CO 
 
 The Purine Group 
 
 This group is important on account of the diuretic 
 effect that is found in most of its members. The member 
 of the group that was formerly of greatest therapeutic 
 importance is caffeine (I). Associated with its diuretic 
 action there is a stimulating effect upon the nervous 
 system. 
 
 I. CAFFEINE 
 H 3 C N - CO 
 
 CO C N-CH 3 
 
 H 3 C N - C N 
 1 Robert, Z. klin. Med., 62, 57 (1907). 
 
NITROGEN COMPOUNDS 
 
 145 
 
 Xanthine (II) has practically no diuretic effect. Of 
 its monomethyl derivatives the 3-methyl xanthine (III) 
 is more distinctly diuretic, and the 7-methyl-xanthine 
 (heteroxanthine) (IV) is only insignificantly diuretic in 
 action. 
 
 II. XANTHINE 
 HN CO 
 
 CO 
 HN- 
 
 C NH 
 
 CH 
 
 -C N 
 
 III. S-METHYL XANTHINE 
 HN CO 
 
 H 3 C N 
 
 IV. HETEROXANTHINE 
 HN - CO 
 
 CO C N- 
 
 CH 
 
 HN 
 
 C N 
 
 The dimethyl xanthines are more strongly diuretic than 
 caffeine. Of these theobromine (V) is the least active, 
 while theophylline (VI) and para-xanthine (VII) act more 
 strongly. 1 
 
 V. THEOBROMINE 
 HN - CO 
 
 CO C N CH 3 
 
 II > CH 
 
 H 3 C N - C N 
 
 Theophylline (Theocine) is the most rapidly powerful 
 of all in its action, but its effect diminishes very quickly. 
 
 1 Arch. exp. Path. Pharm., 44, 319 (1900). 
 
146 ORGANIC COMPOUNDS 
 
 VI. THEOPHYLLINE (THEOCINE) 
 H 3 C-N CO 
 
 CO C NH 
 
 i ii > 
 
 H 3 C-N C N 
 
 VII. PARAXANTHINE 
 H 3 C-N CO 
 
 CO G-N. 
 
 HN- 
 
 C N-CH 3 
 
 L\/~1TT 
 ^CH 
 N 
 
 It has been determined that the effect of theocine is 
 due only to the closing of the imide-azol ring. 1 Ethyl- 
 methyl-xanthine is similar in action to theobromine. 2 
 Other members of the group which also act as diuretics 
 are ethyl-theobromine, ethyl-para-xanthine and ethyl- 
 theophylline. Ethyl-theophylline is weaker than ethyl- 
 theobromine. 3 
 
 8-dimethyl-amino-para-xanthine (Paraxine) (VIII) acts 
 very energetically and persistently but not instantly like 
 theophylline. 
 
 VIII. PARAXINE 
 H 3 CN CO 
 
 CO C N CH 3 
 
 \C.N(CH 3 ) 2 
 HN CN 
 
 *Dreser, Pfliiger's Arch., 102, 1 (1904). 
 
 8 Birk, Dissertation, Halle- Wittenburg, 1905. 
 
 Bergall and Richter, Z. exp. Path., 1, 655 (1905). 
 
NITROGEN COMPOUNDS 
 
 147 
 
 8-dimethyl-amino-heteroxanthine, on the other hand, 
 like theophylline, acts intensely but only for a short time. 1 
 Uric acid (IX) is a diuretic according to Starkenstein, 2 
 but in large doses it injures the kidneys. 
 
 IX. URIC ACID 
 HN CO 
 
 HN 
 
 NH 
 
 3- and 7-methyl uric acid (X), (XI), cause at first anuria, 
 then a strong flow of urine. 
 
 X. 3-METHYL URIC ACID 
 HN - CO 
 
 C NH 
 
 H 3 CN 
 
 XI. T-METHYL URIC ACID 
 HN - CO 
 
 CO 
 
 HN- 
 
 C N-CH 3 
 
 ii > 
 
 C NH 
 
 1-3 dimethyl uric acid (XII) has a slight diuretic action 
 and is non-injurious. 1-3-7 trimethyl uric acid (hydroxy- 
 caffeine) (XIII) is a strong diuretic and is also non- 
 injurious at least in the case of rabbits. 
 
 ^orschback and Weber, Arch. exp. Path. Pharm., 56, 186 
 (1907). 
 
 2 Starkenstein, Arch. exp. Path. Pharm., 57, 27 (1907). 
 
148 ORGANIC COMPOUNDS 
 
 XII. 1-3 DIMETHYL URIC ACID 
 H 3 C-N CO 
 
 H 3 CN 
 
 XIII. HYDROXY CAFFEINE 
 H 3 C N - CO 
 
 O 
 
 CO C N CH 3 
 
 H 3 C N- 
 
 The derivatives of the closely related azinpurine (XIV) 
 act as diuretics similarly to the purine derivatives; but 
 they are distinguished from the latter in having a stronger 
 cramp-excitant effect. 1 
 
 XIV. AZINPURINE 
 N CH 
 
 HC C N=CH 
 
 N C Ni=CH 
 
 According to Levene 2 even thymine (XV) acts like 
 the dimethyl and trimethyl xanthines. 
 
 1 Sachs and Meyerheim, Ber., 41, 3959 (1908). 
 
 2 Levene, Biochem. Zeitschr., 4, 816 (1907). 
 
NITROGEN COMPOUNDS 149 
 
 Hydrazine, Its Derivatives, and Hydroxylamine 
 
 Hydrazine or diamide, H^N NH2, is much more 
 poisonous than ammonia. 1 Subcutaneous injection of the 
 sulphate in quantities of 0.1 gin. per kg. of body-weight 
 causes in the case of a dog, an excitation, then depression 
 and finally coma. There occur irregularity of the pulse, 
 vomiting, salivation and evacuation of the bowels. The 
 quantity of allantoin in the urine, and possibly in the 
 saliva is increased. 
 
 The entry of acid radicles into the molecule weakens 
 both the chemical reactivity and the physiological ac- 
 tivity. Dibenzoyl-diamide has, according to Borissow, a 
 weaker action than diamide. Morevoer the action is 
 manifested by somewhat different phenomena. The phys- 
 iological action is also less in the case of semi-carbazide, 
 
 H 2 N CO NH NH 2 , 
 
 and amino-guanidine, 
 
 H 2 N C(NH) NH NH 2 ; 
 but pyrocatechin-mono-carbonic acid-hydrazide, 
 HO C 6 H 4 CO NH NH 2 
 
 is said to act about like free hydrazine. 2 
 
 The derivatives of phenyl hydrazine were subjected to 
 a great deal of investigation, because it was expected that 
 among these compounds there might be found substitutes 
 for antipyrine. The reason for this expectation was the 
 constitutional formula which was originally ascribed to 
 
 1 Loew, Ber., 23, 3203 (1890); Borissow, Z. physiol. Chem., 
 19, 499 (1894). 
 
 2 Loew, Chem. Ztg., 22, 349 (1898). 
 
152 HESUME 
 
 acid, or its ortho-dichlor compound with two molecules of 
 2-amino-naphthaline-3-6-disulphonic acid (Trypan red) or 
 with other naphthaline 3-6-disulphonic acids. According 
 to Ehrlich 1 other radicles can be introduced into these 
 bodies, preferably in the 7 position. Combinations with 
 l-8-amino-naphthol-3-6 disulphonic acid are also effective 
 against certain trypanosomes. 2 
 
 Azoimide is less poisonous for plants than either hydra- 
 zine or hydroxylamine. But for mammals it causes 
 lightning-like cramps and sometimes immediate death, 
 with a dark coloring of the blood. 3 Loew attributes the 
 effect to a reaction of the sudden breaking down of the 
 protoplasm. 
 
 A brief review of our discussion of the organic com- 
 pounds may n*w be profitable. We have studied cer- 
 tain groupings! which furnish the preliminary basis for 
 certain effects. Then we have observed that, given these 
 fundamental nuclei, the physiological action of the com- 
 pounds may be varied either weakened or strengthened 
 or modified by the action of individual side chains. 
 Among those side chains which seem to release the latent 
 action of the nucleus we find those groups which also 
 favor an increased chemical activity. The strikingly 
 noticeable groups of this sort are the amino, hydroxyl 
 and carbonyl groups. In fact these groups are so power- 
 ful in this manner that it is frequently necessary to intro- 
 duce other groups with a weakening effect before the 
 compound is suitable for safe and reliable therapeutic 
 
 Ehrlich, Berl. klin. Wochschr., 44, No. 9-12 (1907). 
 
 2 Nicolle and Mesnil, Ann. inst. Pasteur, 20, 417, 513 (1906). 
 
 3 Loew, Ber., 24, 2947 (1891). 
 
RESUME 153 
 
 use. Such a weakening of action may naturally be pro- 
 duced upon amino bodies by introducing acid constituents. 
 A possibility which is to be guarded against is the carrying 
 of this weakening effect so far as to destroy the action 
 entirely. Such is often the case with carboxylic acids 
 and even more frequently with sulphonic acids. This is 
 easily understood from a chemical standpoint, because 
 we have strongly acid groups introduced into basic com- 
 pounds and we should expect this to wholly change the 
 character of the compound. But this same phenomenon 
 is also observed in' the case of compounds which are 
 already of an acid nature such as phenols. In such cases 
 we should expect an increase rather than a decrease of 
 effect upon introducing an acid radicle. We are, however, 
 reasonably certain in saying that in this case there is 
 another factor which plays a very large part. This 
 factor is the distribution coefficient. The carboxylic 
 acids and sulphonic acids must of course enter the body 
 fluids in the form of their alkali salts, and these substances 
 are not nearly so easily taken up by the tissue cells as are 
 the free phenols. 
 
 The alkyls we found to play an important role in several 
 ways. In the first place, we repeatedly observed that 
 their accumulation about certain groups is a condition 
 for sleep-producing effects. The alkyl groups also have 
 a specific action when combined to the ring by means of 
 oxygen, thus acting as closures for hydroxyl or carboxyl 
 groups. In the case of hydroxyl groups their function is 
 frequently a softening of the otherwise violent reaction. 
 In the case of carboxyl groups their effect is generally in 
 the nature of a neutralization of the disturbing effect of 
 violent action. The alkoxyl group occasionally also 
 strengthens an effect; but such action is probably explica- 
 ble in most cases by a change in the distribution coefficient. 
 
154 RESUME 
 
 Although in general the alkyl groups are about the same 
 in effect, yet in some cases there are decided differences. 
 This is particularly noticeable in the case of the sleep- 
 producing compounds. In fact in this respect special 
 action was for some time assigned to the ethyl group. 
 But more recent observations have shown that the propyl 
 groups are at least the equal if not superior to the ethyl. 
 This seems to be the case with some series where equi- 
 valence of all alkyl radicles was assumed merely from an 
 observation and comparison of the methyl and ethyl 
 compounds. Thus, according to Sturmer and Liiders l the 
 propyl ester of para-amino benzoic acid (Propsesin) is 
 essentially more active than the corresponding ethyl 
 ester (Ansesthesin) . 
 
 An a priori opinion, that is only too readily conceived, 
 is that the combination of several substances which act 
 in a similar direction will result in an especially desirable 
 action. But this has often led to disillusionment and 
 failure. Examples of such failures we noted in the com- 
 binations of salicylic acid with other febrifuges. More 
 recently Sttirnier and Ltiders 2 report a fact which 
 appeared, to them at least, to be very striking namely 
 that the esters of para-amino benzoic acid with phenols 
 and hydroaromatic alcohols (as guaiacol, thymol, men- 
 thol), which in themselves have an anaesthetic action, are 
 really weaker in effect than the corresponding com- 
 pounds of aliphatic alcohols. There may be several 
 reasons for this. In the first place it is likely that 
 such compounds can act only in the form of their 
 decomposition products. This splitting up proceeds 
 only with difficulty, as is generally the case for these sali- 
 cylic acid compounds. Then, too, it may be that in 
 
 1 Stunner and Luders, Deut. med. Wochschr., 34, 231^(1908). 
 
 2 Ibid. 
 
RESUME 155 
 
 order to be effective, both components must find anchor- 
 age at the same point. If such were the case it is quite 
 possible that the physiologically less active component 
 may hold off or stand in the way of the more active one. 
 Even in cases where the effects of the components do 
 seem to be additive in a positive manner, there still 
 remains to be decided by experimentation in each individ- 
 ual case, whether the proportion of the two which holds in 
 a chemical combination is that proportion which gives 
 the best physiological results. Therefore we must con- 
 fess that work which looks toward a synthesis of such 
 compounds is in general not a promising field. 
 
 It will of course be understood that this treatise has 
 not attempted to refer to all the observations which 
 are relevant to the subject. Only the most important 
 and most thoroughly investigated groups have been 
 considered. We have not touched upon the interesting 
 subject of the effect of constitution upon the odor and 
 taste of chemical compounds. Those who are inter- 
 ested in this subject we would refer to the writings of 
 Zwaardemaker, "Die Physiologie des Geruchs," trans- 
 lated by Junker von Landegg. 
 
 Unfortunately, experimentation in this field must 
 suffer, among other things, from the considerable influence 
 of the subjectivity of the observer. For example, opin- 
 ions are wholly contradictory whether ^-anisol-carbamide 
 has a sweet taste like the corresponding phenetol deriva- 
 tive or not. We must also remind our readers of the 
 complete work of Frankel, "Die Artzneimittelsynthese 
 auf Grundlage der Beziehungen zwischen Chemischem 
 Aufbau und Wirkung, 2. AufL, Berlin, 1906, a work which 
 has served largely as a guide for the older literature. 
 
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 Edition, revised. i2mo. cloth. 185 pp. net, $1.00 
 
 HALL, CLARE H. Chemistry of Paints and Paint Ve- 
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 HILDITCH, T. P. A Concise History of Chemistry. 
 16 diagrams. I2mo. cloth. 273 pp. net, $1.25 
 
 HOPKINS, N. M. Experimental Electrochemistry : Theo- 
 retically and Practically Treated. New Edition. 
 
 In Press. 
 
 HOULLEVIGUE, L. The Evolution of the Sciences. 
 8vo. cloth. 377 pp. net, $2.00 
 
 HiJBJCTER, JULIUS. Bleaching and Dyeing- f Vegetable 
 Fibrous Materials. 95 illus. (many in two colors). 
 Svo. cloth. 457 pp. net, $5.00 
 
 HUDSON, 0. F. Iron and Steel. An introductory text- 
 book for engineers and metallurgists. With a section 
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 cloth. 184 pp. net, $2.00 
 
 HURST, GEO. H. Lubricating Oils, Fats and Greases. 
 Their origin, preparation, properties, uses, and analy- 
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LIST OF CHEMICAL BOOKS 
 
 Oils. Second Edition, revised and partly rewritten. 
 ii illustrations. 5^x8^. 204 pp. net, $3.00 
 
 HYDE, FREDERIC S. Solvents, Oils, Gums, Waxes and 
 Allied Substances. 5^x8^2. cloth. 182 pp. 
 
 net, $2.00 
 
 INGLE, HERBERT. Manual of Agricultural Chemistry. 
 Illustrated. 8vo. cloth. 388 pp. net, $3.00 
 
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 istry. Revised and icwritten by Charles A. Cameron 
 and C. M. Aikman. Nineteenth Edition. Illustrated. 
 121110. cloth. 502 pp. $2.60 
 
 JONES, HARRY C. A New Era in Chemistry. Some of 
 the more important developments in general chemis- 
 try during the last quarter of a century. Illustrated. 
 121110. cloth. 336 pp. net, $2.00 
 
 XEMBLE, W. F., and UNDERBILL, C. R. The Periodic 
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 KERSHAW, J. B. C. Fuel, Water, and Gas Analysis, for 
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 Electro-Thermal Methods of Iron and Steel Produc- 
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 F.R.S. 50 tables, 92 illustrations. 5^2 x 8^. cloth. 
 262 pp. net, $3.00 
 
 KNOX, JOSEPH. Physico-chemical Calculations. I2mo. 
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 The Fixation of Atmospheric Nitrogen. Illustrated. 
 
 5x7^/2. cloth. 120 pp. (Van Nostrand's Chemical 
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 Utilization of Waste Products. A treatise on the 
 
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 rational utilization, recovery and treatment of waste 
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 tions. $ I Ax7 I /2- 260 pp. $2.50 
 
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 Methods. Authorized translation by Harold E. Potts, 
 M.Sc. 35 diagrams. 8vo. cloth. 21 5 pp. net, $2.50 
 
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 LASSAR-COHN. Introduction to Modern Scientific 
 
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 University Extension students and general readers. 
 
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 Pattison Muir. Illus. I2mo. cloth. 356 pp. $2.00 
 
 LETTS, E. A. Some Fundamental Problems in Chemis- 
 try : Old and New. 44 illustrations. 8vo. cloth. 236 
 pp. net. $2.00 
 
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 LTJNGE, GEORGE. Technical Methods of Chemical 
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LIST OF CHEMICAL BOOKS 9 
 
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 cloth. 1174 pp. net, $18.00 
 
 Technical Chemists' Handbook. Tables and meth- 
 
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 Coal, Tar and Ammonia. Fifth and Enlarged Edi- 
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 cloth. 1600 pp. net, $1 ; 8.00 
 
 The Manufacture of Sulphuric Acid and Alkali. 
 
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 In three parts, not sold separately. 543 illustrations. 
 8vo. cloth. 1665 pp. net, $18.00 
 
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 1044 PP- ne V $15.00 
 
 Vol. III. Ammonia Soda. Various Processes of Al- 
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 Vol. IV. Electrolytical Methods. In Press. 
 
 Technical Gas Analysis. 143 illustrations. 6x9. 
 cloth. 422 pp. net, $4.00 
 
 McINTOSH, JOHN G. The Technology of Sugar. Third 
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 6x8^4. 540pp. $5.00 
 
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 HAQUET, A. Legal Chemistry. A guide to the detec- 
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LIST OF CHEMICAL BOOKS u 
 
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 PLATTNER'S Manual of Qualitative and Quantitative 
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 POPE, F. G. Modern Research in Organic Chemistry. 
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 PORRITT, B. D. The Chemistry of Rubber. 5x7^. 
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 PRESCOTT, A. B., and JOHNSON, 0. C. Qualitative 
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LIST OE CHEMICAL BOOKS 13 
 
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 PYNCHON, T. R. Introduction to Chemical Physics. 
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 RICHARDS, W. A., and NORTH, H. B. A Manual of 
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 RIDEAL, S. Glue and Glue Testing. Second Edition, 
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 ROGERS, ALLEN. Elements of Industrial Chemistry. 
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 ROHLAND, PAUL. The Colloidal and Crystalloidal State 
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 ROTH, W. A. Exercises in Physical Chemistry. Author- 
 ized translation by A. T. Cameron. 49 illustrations. 
 Svo. cloth. 208 pp. net, $2.00 
 
 SCHERER, R. Casein: Its Preparation and Technical 
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 Salter. Second Edition, revised and enlarged. Il- 
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 SCHIDROWITZ, P. Rubber. Its Production and Indus- 
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 SCHWEIZER, V. Distillation of Resins, Resinate Lakes 
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 SCOTT, W. W. Qualitative Chemical Analysis. A labo- 
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 SCOTT, W. W. (Editor). Technical Methods of Analysis. 
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 SCUDDER, HEYWARD. Electrical Conductivity and 
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 SEARLE, ALFRED B. Modern Brickmaking. 260 illus- 
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 Cement, Concrete and Bricks. 113 illustrations. 
 
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 SEIDELL, A. Solubilities of Inorganic and Organic Sub- 
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 SENTER, G. Outlines of Physical Chemistry. Second 
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 A Text-book of Inorganic Chemistry. 90 illustra- 
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 SINDALL, R. W. The Manufacture of Paper. 58 illus. 
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LIST OF CHEMICAL BOOKS 15 
 
 SINDALL, R. W., and BACON, W. N. The Testing of 
 
 Wood Pulp. A practical handbook for the pulp and 
 
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 SMITH, J. C. The Manufacture of Paint. A manual for 
 
 paint manufacturers, merchants and painters. Second 
 
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 8^4. cloth. 286 pp. net, $3.50 
 
 SMITH, W. The Chemistry of Hat Manufacturing. 
 
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 SOUTHCOMBE, J. E. Chemistry of the Oil Industries. 
 
 Illus. 8vo. cloth. 209 pp. net, $3.00 
 
 SPEYERS, C. L. Text-book of Physical Chemistry. 20 
 
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 SPIEGEL, L. Chemical Constitution and Physiological 
 
 Action. Translated by C. Luedeking and A. C. 
 
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 STEVENS, H. P. Paper Mill Chemist. 67 illustrations. 
 
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 SUDBOROTJGH, J. J., and JAMES, J. C. Practical Or- 
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 TERRY, H. L. India Rubber and Its Manufacture. 
 
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 TITHERLEY, A. W. Laboratory Course of Organic 
 
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 TOCH, M. Chemistry and Technology of Paints. Second 
 
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 VINCENT, C. Ammonia and Its Compounds. Their 
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 Chemistry of Dyestuffs. Translated from the Sec- 
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 412 pp. net, $4.50 
 
 VOSMAER, A. Ozone, Its Manufacture and Uses. 
 
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 WADMORE, J. M. Elementary Chemical Theory. Illus. 
 
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 WALKER, JAMES. Organic Chemistry for Students of 
 
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 WHITE, C. H. Methods in Metallurgical Analysis. 106 
 
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LIST OF CHEMICAL BOOKS 17 
 
 WHITE, G. F. A Laboratory and Class-room Guide for a 
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