The discovery that PhOCH2CO2H derivatives have a remarkable hyperthermic action (cf. C. A. 19, 1599) suggested that there might be other compounds as good or superior which would replace in therapy the toxic proteins and other indefinite substances to which resort must now be had.A systematic study was therefore made, by means of hypodermic injection into rabbits and dogs, of the action of numerous compounds of different types in the attempt to determine the influence of various groups and thus by induction to foresee the ideal non-toxic compoundA special apparatus was devised for recording graphically the external temperature at all times, which comprised enclosing the animal in a double-walled chamber so that changes in temperature caused changes of volume of the outer chamber, which were in turn transmitted to a Mosse plethysmograph (cf. Atti. accad sci. Torino 11(1875); Foa, C. A. 3, 852).The following substances were hyperthermic: tyramine, carbazole, methylene blue, pyroglutamic acid, PhCH2CH2NH2, β-imidazolylethylamine, PhCH(OH)CHMeNHMe, adrenaline, tetrahydro-β-naphthylamine and its N-Me derivative, PhEtNH, PhOH, o-, m- and p-cresol, PhOAc, thymol, guaiacol, α- and β-naphthol, AcOEt, CH2(OH)CO2H, salicylic acid (small doses), acetylsalicylic acid (small doses), creatine, allylthiourea, PhOCH2CO2H, PhOCH2CO2Na, PhOCH2CO2Et, o-, m- and p-MeC6H4OCH2CO2H, thymohydroxyacetic acid, α- and β-naphthoxyacetic acid, p-IC6H4OCH2CO2H, p-IC6H4OCH2CO2Et, iodoguaiacoxyacetic acid, iodothymoxyacetic acid, iodo-β-naphthoxyacetic acid, o-, m- and p-cresoxyacetic acids, 3-courmaranone, 7-methyl-3-coumaranone, 6-methyl-3-coumaranone, 5-methyl-3-coumaranone, 2-isonitroso-3-coumaranone, 2-isonitroso-5-methyl-7-isopropyl-3-coumaranone, Na o-benzidinemonosulfonobisazobinaphthylaminodisulfonate, Na o-tolidinobisazodiaminonaphtholdisulfonate, strychnine, coniceine, cocaine, morphine (in small doses), atropine (in small doses), caffeine, pilocarpine, acamin, inosin and phytin.The following substances were hypothermic: petr. ether, ligroin, CHCl3, CHBr3, CHI3, CCl4, PhNO2, o-O2NC6H4CHO, PhNH2, PhNMe2, Ph2NH, antipyrine, quinoline, choirin, analgen, thalline, formanilide, acetanilide, lactanilide, exalgin, urea, phenylurethane, (NHPh)2CS, p-BrC6H4NHAc, metacetin, hypnacetin, cosaprin, phenacetin, methylphenacetin, phenocoll, lactophenine, pyrantin, thermodine, cryofin, valeridine, saliphen, apolysin, citrophene, neurodine, pyramidone, pyrodine, maretin, cryogenin, monoformyltetrahydro-β-naphthylamine, monoacetyltetrahydro-β-naphthylamine.Et tetrahydro-β-naphthylaminecarbamate, 5-acetylaminocoumaranone, MeOH, EtOH, AmOH, C7H15OH, CH2:CHCH2OH, chloral hydrate, Me2CO, PhAc, Ph2CO, BzOH, salicylic acid (large doses), acetylsalicylic acid (large doses), salol, betol, dulcin, AcNH2, guaiacoxyacetic acid, 4-acetylamino-3-coumaranone, quinine, veratrine, protoveratrime, aconitine, hyoscyamine, hematin, muscarine, morphine (in large doses), atropine (in large doses), picrotoxin and santonin.The following substances were inactive: vaseline oil, tyrosine and numerous derivatives, e. g., esters and nitrotyrosine, nitrotyramine, aminotyramine, tetrahydro-β-naphthobenzylamine, α-hydrindamine and its N-Me derivative, N-di-Et and N-di-Me derivatives of tetrahydro-β-naphthylamine, diacetyltyramine, carbethoxytyramine, tyraminohydantoic acid, tetrahydro-β-naphthylethylthiourea, mannitol, maclurin, HCO2H, EtCO2H, PrCO2H, CH2(CO2H)2, (CH2CO2H)2, olive oil, cottonseed oil, sesame oil, almond oil, glycine, sarcosine, alanine, aspartic acid, EtCHNH2CO2H, valine, leucine, glutamic acid and its esters, carbethoxyglutamic acid and its di-Me ester.In general there are few mol. groups which impart a definite biothermal action to their mol., for most substances behave in a way which varies with the dose and with other conditions such as the solvent, the means of administration and the animal.The CO2H group in an aliphatic chain, including amino acids, is usually athermic, whereas the NHAc group is usually hypothermic and the HOCH2CO group hyperthermic.When OH and CO2H groups are both present, the action varies to such an extent that conclusions are unwarranted. Aromatic amines, including N-substituted amines, are hypothermic.The ROCH2CO group is one of the very few which consistently imparts a hyperthermic action in quite different types of compoundsGlycolic acid and PhOH were studied to determine to what part of the mol. of phenoxyacetic acid the hyperthermic action is due, for they may be considered to be related thus: PhOH + HOCH2CO2H → PhOCH2CO2H + H2O, and the effect of the phenoxyacetic acids may be a combined action of PhOH and HOCH2CO2H.Tests of PhOCH2CO2H and of PhOH + HOCH2CO2H under suitable conditions lent support to this possibility, for the same peculiar temperature-time craves were obtained in each case.The hyperthermic action of a group can be diminished or even nullified by the introduction of a hypothermic group into the mol., and as in the introduction of a NHAc group into a coumaranone, may convert a hyperthermic compound to a hypothermic one.Among the dyes, only those containing the PhOCH2CO-group are hyperthermic.The hyperthermic action of phenoxyacetic acids, glycolic acid, coumaranones and 3-chromenol derivatives is not preceded or followed by hypothermia, as with carbazole and numerous other compounds, and the animals maintain normal appetites and activity, so that these types of compounds offer a promising field for further investigation.The definite hypothermic action of the NO2 group in simple compounds becomes masked in more complex mols.With increase in Ph groups a mol. becomes more definitely hypothermic, but when NH forms part of a closed nucleus, e. g., in carbazole, pyroglutamic acid, etc., the compound is hyperthermic, even when hypothermic groups are also present.When in amines containing C6H6 or heterocyclic nuclei, the NH2 group is in an Et or Pr side chain, the compound is hyperthermic, but if the NH2 is in a Me side chain the compound is athermic.In all amines, substitution of H in NH2 by an acid group renders the compound hypothermic or increases it if already so.Among phenols, PhOH is the most hyperthermic, and the action decreases in its homologs to the almost inactive naphthols.A hyperthermic action caused by local congestion or by a toxic action, as with HOAc, (CO2H)2, is not considered in the present study.Amides and esters in general are athermic.Guaiacoöxyacetic acid behaves differently from other phenoxyacetic acids, but it causes general anesthesia and its peculiar action requires further study.The marked hyperthermic action of the 3 vitamins is of special interest.Many references to closely related work are included.
