May, 1931
`
`AMINO ALCOI-IDLS. VI
`
`1875
`
`The ratio of cyclohexylcarbinoi to toluene produced in the hydrogena-
`tion of benzyl alcohol was increased by the presence of phenol or diphenyl—
`amine and especially of benzene or acetanilide in the reaction mixture.
`MADISON. WISCONSIN
`
`[(‘.‘oNTRIBUTIoN FROM THE RESEARCH LAnoRAToR1Es or SHARP 8.: Donna. INc.]
`
`AMINO ALCOHOLS. VT. THE PREPARATION AND
`
`PHARMACODYNAMIC ACTIVITY OF FOUR ISOMERIC
`
`PHENYLPROPYLAMINES
`
`BY WALTER H. I-IARTImc. AND JAMES C. MUNCH
`Racnrvim FEBRUARY 7, 1931
`Punusnnn MAY 6, 1931
`
`The commoner hypertensive amines are derivatives of B-phenylethy1—
`amine, that is, compounds containing the aromatic nucleus separated from
`the amino group by two carbon_s of an aliphatic side chain; e. g., tyrarnine
`HOCaHACH2CH2NH2.
`epinephrine,
`(HO)2C5H3CHOHCHgNHCH3,
`and
`ephedrine, C5H_=,CH0HCI-I(NI-ICH3) CH3, all have this common structure.
`Recorded pharmacological studies with compounds in which the relative
`position of these two functional groups is modified are rare.
`Barger and Dale,‘ in their classical study on the relationship between
`chemical structure and sympathomimetic action,
`included a series of
`compounds in which the relative position of the amino portion with respect
`to the phenyl group varied. They found that aniline has no specific action;
`benzylamine gives a trace of the desired activity, cu-phenylethylamine is
`feebly active, B-phenylethylamine highly active and most active of the
`series, while quphenylpropylamine, CeH5CHgCHgCHgNH2,
`is again much
`less eliective.
`‘While no allowance was made for any influence on the
`physiological activity that might be produced by the successive lengthening
`of the side chain, they nevertheless advanced the conclusion that “the
`optimum constitution of a fatty-aromatic amine for the production of
`sympathomimetic action is, therefore, that which is found in adrenaline
`itself, mIz., a benzene ring with a side chain of two carbon atoms, of which
`the second bears the amino group."
`Concerning the value of the two-carbon side chain these conclusions
`must, in the light of recent findings, be amended, for it has been amply
`demonstrated that amino alcohols of the ephedrine type, that is, com-
`pounds with three carbons in the side chain, are not only very active
`pharrnacologically but may even possess physiological and therapeutic
`virtues not resident in the corresponding compounds with but two carbons.”
`
`‘ Barger and Dale, J. Pkysioh, 41, 19 (1910). Cf. Pyrnan,
`1103 (1917).
`(b) Hartung and
`3 (9.) Chen. Wu and Henriksen. J. Pkormacol, 36, 363 (1929);
`Munch, ‘hits JOURNAL, 51, 2262 (1929);
`(c) Hartung, Munch. Deckert and Crossley,
`s'b:'d., 52. 3317 (1930); (d) Piness. Miller and Alles, J. Am. Med. As.m.. 94, 790 (1930).
`
`J’. Chem. 505.. 111,
`
`Amerigen Ex. 1058, p. 1
`Amerigen Ex. 1058, p. 1
`
`

`
`1876
`
`WALTER I-I. HARTUNG AND JAMES c. MUNCI-I
`
`Vol. 53
`
`Aside from this work of Barger and Dale, comparatively little has been
`done to substantiate the other part of their conclusion, namely, the neces-
`sity for having the aryl and amino groups on adjacent "carbons of an
`aliphatic side chain. Baehr and Pick3 observed that if in hordenine, gh-
`HOC5H;CH-;CH2N(CH3)g, the din-rethylarnino group is removed from the
`aromatic portion by three or four carbons,‘ the pressor potency becomes
`correspondingly less.
`I-Iasama, in comparing the isomeric phenylethanob
`amines, Ci-,HaCH(N'H2)CHgOH and C5H5CHOHCH2NH-.-,
`found the
`former to have no influence on the blood pressure,‘ whereas the activity
`of the latter is well established.
`
`Matsuo and Mizuno“ report that on-phenylethylamine, C5H5CH(NHg)-
`CH3, increased the contraction amplitude of the frog heart and the blood
`pressure of a rabbit, while the 5-compound, CaH5CH2CH2NHg, showed the
`opposite effect.
`if possible,
`The present investigation was undertaken to determine,
`whether in the series of amino alcohols being studied in these Laboratories
`maximum activity is obtained when the aryl and amino groups are sepa-
`rated by two aliphatic carbon atoms. And in order to confine as nearly as
`possible any modification in physiological behavior to a corresponding
`change in the relative positions of these two functional groups, four isomeric
`phenylpropylamines were prepared and their behavior observed. These
`four compounds are given in Table I along with a summary of their pharma-
`cological and toxicological behavior.
`:9-Phenylethylarnine and phenyl-
`propanolamine are included for comparison.
`
`Base
`
`I
`
`C5H5CHgcHgNH2
`
`C51-I5CI-I(NHg)CH2CHs
`II
`III CaH5CH2CH(NH2)CHa
`
`I1-" CaH5CHzCH3CHzNH3
`
`V
`
`CeH5CH(CHs)CH2NH2
`
`TABLE I
`
`DATA on Comounns
`M. L. D. of
`hydrochloride, mg./kg.
`Rats, sob-
`Rabbits.
`cutaneous
`intravenous
`
`Presser activity of hydrochloride
`(Intravenous to dogs)
`
`.
`
`.
`
`1000
`25
`
`100
`
`500
`
`BO
`
`50
`25
`
`50
`
`50
`
`1 Mg./kg. gave good rise that
`persisted about 20 min.
`1 Mg./kg., very slight rise
`1 Mg./kg. gave rise equal to that
`of I. Effect persisted longer.
`Orally active“
`1 Mg./kg. gave medium transi-
`tory rise
`also active after
`Good pressor;
`oral administration.
`
`VI C3H5CHOHCH(NH2)CHa
`
`.
`
`.
`
`75-90
`
`Equals ephedrine
`
`3 Baehr and Pick, Arch. exptl. Path. Pharmakal, 80, 161 (1912).
`4 V. Braun, Ber., 47, -192 (1914).
`-" Hasarna, Arch. e.'cpt£. Path. Pkarmakok, I53, 165 (1930).
`‘"‘ Matsuo and Mizuno, Aria Sakai. Mlzd. Univ. Imp. Kiota, [1] 7, 11 (1924); Chem.
`Absh, 19, 2705 (1925).
`
`Amerigen Ex. 1058, p. 2
`Amerigen Ex. 1058, p. 2
`
`

`
`May, 1931
`
`AMINO ALCOHOLS. VI
`
`1877
`
`The data on comparative pressor potencies are not yet satisfactorily
`quantitative, but the information thus far obtained is very illuminating.
`For instance, it is readily seen that Barger and Dale are substantially
`correct in ascribing the optimum constitution for producing a rise in blood
`pressure to compounds containing at least a 45‘-phenylethylamine skeleton.
`If any deviation is made from this elementary structure either by moving
`the amino closer to the phenyl (II) or by removing it farther away (IV),
`the degree of physiological response is very greatly diminished. But if
`this minimum skeleton is left unchanged (III, V and VI), substitutions in
`the other portions of the molecule may modify the nature of the pharmaco-
`dynamic behavior, but the ability to produce a rise in blood pressure is not
`diminished.
`
`Chen, Wu and Henriksen” attribute the oral efficacy of ephedrine to the
`presence of the third carbon in the side chain;
`thus, for instance, phenyl-
`propanolamine (VI) is active when taken by mouth whereas phenyl-
`ethanolaznine, C5H5CHOHCH2NH2, is not.
`Piness, Miller and Alles,2d who are interested clinically in pi1enylethano1-
`amine, were desirous of determining what it lacked structurally to make it
`active when administered orally. Since phenylethanolamine differs from
`ephedrine by two methyl groups, one in the side chain and the other on the
`
`C51-I;CI-IOI-IC‘lI-I;
`NH;
`
`CaHgCI-IOH(‘1HCH;
`NHCI-I5
`
`Phenylethanolamine
`
`Ephedrine
`
`amino group, they investigated two methyl substituted derivatives of B-
`phenylethylamine, one in which the methyl was substituted on the nitrogen
`and the other in the side chain. They found the for-1ner'inefi'ective when
`
`CoH5CH2CH:
`I|\lHCHa
`
`C5H5CH2C1:HCH3
`NH;
`
`given by mouth and the latter, with three carbons in the side chain, very
`active when so administered. Hence, they also conclude that it is the
`three-carbon side chain that makes for oral activity.
`Our results show that in extending the side chain of ,8-phenylethylamine,
`the entering methyl may be substituted on either of the two aliphatic
`carbons and in either case (III and V) oral activity is conferred. While
`quantitative values for pressor activity of these two isomers have not yet
`been determined, the wide diflerences in toxicity are very well defined and
`very striking indeed.
`Phenylpropanolamine (VI) is included in the table in order to emphasize
`the importance of the alcoholic hydro:-ryl.
`Its elimination, which gives
`III, increases the intravenous toxicity to rabbits by 300% or more, a very
`significant extent.
`
`Amerigen Ex. 1058, p. 3
`Amerigen Ex. 1058, p. 3
`
`

`
`1878
`
`warzraa H. HARTUNG AND muss c. MUNC1-I
`
`Vol. 53
`
`Procedure
`
`the amines were prepared by the catalytic hydrogenation of an
`All
`appropriate intermediate by the process already described.’
`
`Experimental
`
`Pheny1-1-amino-1-propa.ne.—~Propiophenone oxime' was dissolved in absolute
`alcohol containing three equivalents of hydrogen chloride and smoothly reduced to the
`corresponding amine, isolated as the hydrochloride. The salt melted at 189.5” (con'.)
`and the base distilled at 100—105° at 35 mm; a benzoyl derivative melted at 115-1 16°
`(corr.).'
`Phenyl—1-amino-2-propane was obtained by reducing phenyl-l—chloro-1-arnino~2—
`propane. Sixteen grams of phenylpropanolarnine was heated in a bomb tube with 130
`ml. of concentrated hydrochloric acid at 110-115“ for four hours. No pressure de-
`veloped. The solution was then chilled in an ice-salt bath and the hydrochloride of
`phenyl-1-cl1loro-1-amino-2-propane which settled out was filtered off, dried and recrys-
`tallized from absolute alcohol. The crystals melted at 201° (con-.): 8.5 g., a yield of
`48%. Calcd. for Cal-I1;NClHCl: CI, 34.4. Found: CI, 33.3. The organic chlorine
`seems to be very labile and further recrystallization gives a product with even less
`chlorine.
`
`By shaking the chloro compound, dissolved in absolute alcohol, with palladium
`catalyst in an atmosphere of hydrogen. the chlorine was completely replaced by hydro-
`gen;
`the resuiting amine was isolated as hydrochloride, the salt melting at 144-147”
`and the base distilling at 200-201 ‘‘ (u.ncorr.).1°
`Pheuyl-1-amino-3-propane.——An impure cinnamaldoxirne“ was reduced in an
`absolute alcoholic solution containing three equivalents of hydrogen chloride. Reduc-
`tion ceased when 90% of the hydrogen calculated as required by the pure oxime had been
`taken up. The catalyst was removed and the filtrate evaporated to dryness on a steam-
`hath; the residue was taken up in water and an insoluble dark oily impurity removed by
`extraction with ether. The aqueous solution was treated with excess alkali, the liberated
`base extracted with ether, dried over sodium sulfate and distilled, boiling at 2l6—220°
`(uncorr.). For CgHuCH3CH:CH2NHg the following boiling points are recorded: 215°,"
`215-216 °.” 221.5°.“ The hydrochloride was precipitated from an ethereal solution of
`the base by addition of an absolute alcoholic solution of hydrogen chloride. The salt
`melted at 218° (con-.). From 11.6 g. of cinnamaldoxime 8.1 g. of the salt was obtained,
`a yield of 60%.
`Phenyl-2-amino-1-propane was obtained from a-phenylpropionitrile. This in-
`termediate nitrile was prepared from the sodium derivative of phenylacetonitrile and
`methyl iodide according to the directions of Victor Meyer” and Freund and Ktinig.“
`
`7 Hartung, Ims J DURNAL, 50, 3370 (1928).
`5 “Beilstein,” 4th ed., Vol. VII, 11. 301.
`" Busch and Leefhelm, I. prakt. Ch.em., [2] 7?, 7 (1908). describe CgHgCH(C2I-I.)-
`NH:-HCI as melting at 194'’, the free base as distilling at 99-100” at 16 mm., and the
`benzoyl derivative as melting at 1 15-116 °.
`1° Hey, J. Chem. 306., 18 (1930).
`H Ref. 3. p. 351.
`-
`1‘ Lasch, .Monutsh., 34, 1658 (1913).
`" Tafel. B891, 19, 1924 (1886).
`H Tafel, £bz'd., 22, 1354 (1339).
`*5 Meyer, Aflfh. 250, 118 (1889).
`1' Freund and Kdnig, Beta. 26, 2874 (1893).
`
`Amerigen Ex. 1058, p. 4
`Amerigen Ex. 1058, p. 4
`
`

`
`May, 1931
`
`THE PREPARATION or ALIPHATIC AMIDES
`
`1879
`
`However. the good yields they report. as high as 79%, have not been duplicated; our
`yields were 10-14%.
`The reduction of a-phenylpropionitrile dissolved in absolute alcohol containing
`three equivalents of hydrogen chloride proceeded smoothly and completely, although
`about a third as rapidly as for the oximes, and the product was isolated as its hydro-
`chloride salt, melting at 123-124° (corn). Freund and Ktinig, by reducing the nitriie
`with sodium and absolute alcohol, obtained the base CgI‘I§CH(CHa)cHgNHg, whose hy-
`drochloride melted at 124 °.
`
`Summary
`
`Four isomeric phenylpropylamines were prepared by catalytic hydi-ogcn—
`ation of an appropriate intermediate. A preliminary pharmacological
`examination of these compounds indicates that:
`(1) The optimum skeleton for pressor compounds is dphenylethylamine.
`(2) A shift in the relative positions of the phenyl and amino groups very
`greatly decreases pressor potency.
`(3) Substitution of a methyl on either of the two carbons in the side
`chain of this skeleton confers oral activity.
`(4) The presence of the secondary alcoholic hydroxyl in pheny1propano1-
`amine serves to decrease the toxicity to a degree that becomes significant
`therapeutically.
`BALTIMORE, MARYLAND
`
`[CONTRIBUTION anon THE Cnzemcar. LABORATORY or TEE JOHNS HOPKINS UNIVERSITY]
`
`THE PREPARATION OF ALIPHATIC AMIDES
`
`BY James A. MITCHELL AND E. Enmrr REID
`
`Rncarvun FEIBR.L:'AR‘li' 9, 1931
`
`Punusunn Mm: 6, 193].
`
`The most satisfactory methods of preparing amides have involved de-
`hydration of the ammonium salt of the corresponding acid. Hofmannl
`prepared various amides by heating ammonium salts of aliphatic acids for
`five or six hours at 230° under pressure. Kundig* prepared acetamide by
`the rapid distillation of ammonium acetate and by heating an alcoholic
`solution of acetic acid and ammonia in a sealed tube for a long time at 100°.
`He also obtained a yield of amide greater than 25% by passing dry ammonia
`through acetic acid and then heating to boiling. Grant and James“ have
`prepared amides by saturating the acid With dry ammonia and boiling.
`Dunlap,‘ Keller‘ and Ver1ey° have modified the procedure by heating so-
`dium acetate and ammonium chloride at 240°.
`
`1 Hofmann, Ben. 15, 977 (1882).
`I Kundig, Am, 105, 277 (1853).
`' Grant and James, THIS JOURNAL, 39, 933 (1917).
`‘ Dunlap. £523., 24, 762 (1902).
`6 Keller, 1. prakt. cam, 12] 31, 354 (1335).
`‘ Verley, Bull. soc. ch£m.,
`[31 9, 691 (1893).
`
`Amerigen Ex. 1058, p. 5
`Amerigen Ex. 1058, p. 5