Patented Aug. 3, 1933
`UNITED STATES PATENT OFFICE
`
`
`1,921,424
`
`MEDICIINAIL REMEDY
`
`Fred P. lglahenhauer, Philadelphia. Pa., assignor
`to Smith. Kline
`.3». French Laboratories,
`Philadelphia, Pa... 3- Corporation of Pennsyl-
`vania
`
`No Drawing. Application lllareh 8. 1930
`Serial No. 434,452
`8 Claims.
`
`(Cl. 167—58)
`
`‘My invention relates to improvement in me-
`dicinal remedy and more particularly to one for
`use in connection with the treatment of common
`(30155. rose colds, hay fever, sinusitis, nasal ca-
`tarrh. and in conditions causing congestion of
`the nasal passages.
`In accordance with my invention, I provide a
`novel remedy for use in the treatment of alfec.
`tions. more particularly of the nasal passages. as
`indicated, which will be effective to shrink the
`mucosa and to reduce the size of turbinates.
`which under the conditions indicated become en-
`larged and congest the nasal passages.
`The novel remedy in accordance with my in-
`vention may be readily administered. for ex-
`ample. by the use of a dropper, by spraying, or by
`direct application. as with a cotton pledget and
`will be found to be especially advantageous in
`that it will effect a shrinkage of the mucosa of
`long duration, say of from two to three hours
`and further in that it possesses anasthetic prop-
`erties which enable its administration without
`discomfort. as stinging, especially in cases where
`the membrane is inflamed and sensitive.
`The novel remedy in accordance with my in-
`vention lends itself to administration in forms of
`varying activity in that, for example, it may be
`administered in solution in, for example, an
`oil. from which it will be relatively slowly released
`to the tissue and in that it may be administered
`in. for example, an aqueous solution from which
`it will be substantially directly released to the
`tissues- The remedy may be administered in va-
`rious other forms,
`though its administration
`either in solution in oil or in aqueous solution will
`be preferred.
`The medicinal remedy in accordance with my
`invention comprises a benzyl carhinamine, hav-
`ing the structure
`:1
`
`NH:
`
`l'l*x
`
`or equivalently a salt thereof. Preferably the
`benzyl carbinamine will be non-hydroxyiated.
`and may desirably be an alkyl or equivalently an
`alphyl benzyl carbinamine. or a polybenzyl car-
`binamine, as dibenzyl carbinamine. The remedy
`may, for example, comprise benzyl carbinamine.
`benzyl methyl carbinamine, benzyl ethyl car-
`binamine. benzyl pi-opyl or isopropyl carhinarn-
`Inc. dibenzyl carbinamine, etc.. or salts thereof
`as hydrochlorides. sulphates, acetates, etc.
`As illustrative of the remedy embodying my
`invention, for example, dibenzyl carbinamine
`may be graphically indicated as follows:
`E: H 11-:
`
`03;it‘*0
`
`10
`
`15
`
`20
`
`45
`
`60
`
`B0
`
`Dibenzyl carbinamine may be prepared by re-
`duction Of dibenzyl ketone oxime, as for ex-
`ample. with metallic sodium in alcoholic solu-
`tion. The oxime may be produced by dissolv-
`ing the ketone in alcohol. adding a slight excess
`of hydroxylamine hydrochloride. rendering the
`solution alkaline and boiling; dibenzyl
`ltetone
`oxime will be formed and will crystallize out of
`solution on the addition of water after cooling.
`When the dibenzyl ketone airline has been suf-
`ficiently reduced a portion of the alcohol is dis-
`tilled orf. water added and the solution acidified
`with acetic acid. Then unreduced dibenzyl ke-
`tone oxime is separated by filtration and dibenzyl
`carbinamine is freed from its salt (acetate) by
`the addition of alkali and extraction with hen-
`zene. Pure dlbenzyl carbinamine chlorideis then
`freed from the benzene solution with hydrochlo-
`ric acid and the dihenzylamine hydrochloride
`converted back to free dibenzyl carblnamine by
`dissolving the hydrochloride in water, using heat
`to obtain the desired concentration, and adding
`an alkali. as caustic soda. or the like to the solu-
`tion whlch causes the free dibenzyl carbinamine
`to separate in the form of an oil. which will so-
`lidify on cooling.
`The reaction involved in the production of di-
`benayl carbinamine may. for example, be graph-
`ically illustrated as follows:
`
`i:i_i‘0 3 0
`
`Dibencyl lretone
`+
`HaN-OH-HC1+Ne0H
`Hydroxyiamine hydrochloride
`
`1
`
`OLE— +H:0+NaGl
`
`ts
`Dibunayl ketone crime
`+
`+No+ U2Hs0H
`
`1
`H2111}:
`
`ode
`
`Dibenzyl carblnsmino
`
`65
`
`70
`
`75
`
`85
`
`90
`
`95
`
`100
`
`105
`
`l1D
`
`11-5
`
`The dihenzylcarbinamine will be found to be a
`solid having a melting point at about 5E1“ C. and
`
`120
`
`Amerigen Ex. 1063, p. 1
`Amerigen Ex. 1063, p. 1
`
`

`
`2 m
`
`ay be prepared for use by dissolving it, for ex-
`ample, in a hydrocarbon oil, as liquid petrolatum,
`in a vegetable oil, as olive oil. almond oil, or the
`like. or it may be prepared for use by dissolving
`one of its salts in water. Solutions of dibenzyl
`carbinarnlne may be. if desired, flavored, as with
`lavender, oil of geranium, oil of ncroli, menthol,
`or other suitable flavoring and if desired may be
`colored with any suitable coloring matter which
`will be soluble in the solution to be colored.
`As illustrative of the preparation of dibenzyl
`carbinamlne for use in solution in, for example,
`an oil, hydrocarbon or vegetable. solutions may,
`for example, be prepared within the ranges given
`in the following table:
`
`Percent
`Dibenzyl carbinamlne______________ _- 9.5- 3.0
`oil __________________ __'........... -- 995-9’?
`
`Illustrative of a desirable solution for use as
`indicated, for example,
`the following formula
`may be used:
`
`Percent
`Dihenzyl carbinamlne ___________________-_ 1.0
`Oil ___________________________________ __ 99.0
`
`As has been indicated and as it will be appre-
`ciated is contemplated by me, I may use a salt of
`dibenzyl carbinamine equivalently for the free
`compound and in general when using a salt, in
`place of the compound, such will be used in aque-
`ous solution- Thus. I may, for example, utilize
`dibenzyl carbinamine hydrochloride, which may
`be graphically indicated as follows:
`
`OELEO‘$13:
`
`or I may, for example, use dibenzyl carbinamlne
`sulphate, which may be graphically indicated as
`follows’
`
`it i‘
`H:
`
`lN
`
`ct
`é=o.
`AI
`NH:
`
`J
`
`—d—cH.
`I
`I It
`
`It will be understood that the salts of dibenzyl
`carblnamine may be readily prepared from the
`free compound by addition to the compound of
`desired acid radical which, in the case of the
`sulphate, for example, may be accomplished by
`suspending dibenzyl oarbinamine in warm water
`and neutralizing with sulphuric acid. The solid
`dibenzyl carbinamine sulphate will crystallize
`out on concentration and cooling. The hydro-
`chloride, acetate, and the like, may be similarly
`prepared by neutralizing with acetic acid, hydro-
`chloric acid, or the like.
`For the purpose of illustrating the use of a
`salt of dibenzyi carbinamine in aqueous solution.
`for example, a. solution within the ranges shown
`in the following table may be used:
`
`_ Percent
`Salt ................................- 0.5- 5.0
`Water ____________________________ __ 99.5-95.0
`
`By way of illustrating a desirable solution, for
`
`20
`
`26
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`G5
`
`70
`
`76
`
`1,921,694
`
`example, a solution prepared in accordance with
`the following formula may be used:
`
`Percent
`
`2.0
`Salt................................... --
`Water_________________________________ -.. 98.0
`
`88
`
`It will be appreciated that solutions of a salt
`of dibenzyl carbinarnine may be flavored as de-
`sired and likewise may, if desired. be colored.
`The various benzyl carbinamines indicated as
`included within the scope of my invention may
`be produced in a manner similar to that de-
`scribed above for the production of dibenzyl car-
`binamine, it being appreciated that in the for-
`mule.
`_
`H NB:
`
`85
`
`90
`
`l‘i'x
`
`105
`
`110
`
`"115
`
`“X” will indicate an alkyl or an alphyl group,
`as, for example, CE; for bensyl methyl carbin-
`amine, C2Hs for benzvl ethyl carbinamine, CaH1
`for the benzyl propyl amines, and that the "X”
`will include an additional benzene ring or rings
`for polybenzyl carbinarnines.
`In the prepara-
`tion of the various carbinamines the correspond-
`ing ketone may be used. as benzyl methyl ke-
`tone, benzyl ethyl ketone, benzyl propyl ketone.
`etc. The salts of
`the various benzyl carbin-
`ainines, as the hydrochloride, sulphate. acetate,
`etc., may be prepared as described above in con-
`nection with preparation of the salts of dibenzyl
`carbinamine.
`It will now be understood that my invention
`contemplates the use of a benzyl carbinamlne
`or equivalently of a salt of a benzyl carbin.
`amine, as the hydrochloride, sulphate, acetate, or
`the like, for the treatment of the mucosa in con-
`ditions such as exist in cases of ordinary cold,
`hay fever, sinusitis, nasal catarrh, and other
`conditions of congestion of nasal passages.
`Further, I contemplate the use of a benZy'1car-
`binamine or equivalently a salt thereof, in solu-
`tion in a suitable solvent and more particularly
`in solution in a suitable hydrocarbon or vege-
`table oil, or in water, depending upon the activity
`or rapidity of action desired of the compound. or
`equivalently of the salt.
`It will be understood that a bensyl carbin-
`amine and equivalently a salt thereof, will be
`high eifective to shrink the mucosa and to reduce
`turbinates, that it will be of special advantage
`due to its capacity to enact shrinkage of long
`duration and due to the fact that more particu-
`larly in the case of dibenzyl carbinamine arias-
`thetic properties are possessed which will tend to
`negative unpleasant effect in administration.
`As has been indicated, it will be appreciated
`that in accordance with my invention, I contem-
`plate a benzyl oarbinarnine or a salt thereof, as
`for example, the hydrochloride, sulphate, acetate,
`etc., to be equivalents and it will be understood
`that where in the claims appended hereto I men-
`tion benzyl carbinamine, or a specific benzyl car.
`binarnine, I intend to include as equivalent there-
`of the salts of the benzyl carbinamlne.
`What I claim and desire to protect by Letters
`Patent is:
`1. As a medicinal remedy for local treatment 145
`of the mucosa, dibenzyl carbinamlne.
`2. As a medicinal remedy for local treatment
`of the mucosa, dibenzyhcarbinamine in solution
`in a solvent therefor to a concentration within
`about the range 0.5%-5.0%.
`
`125
`
`130
`
`135
`
`140
`
`150
`
`Amerigen Ex. 1063, p. 2
`Amerigen Ex. 1063, p. 2
`
`

`
`1,921,434
`
`3
`
`the mucosa. 2. substituted benzyl carbinnmine
`3. As amedlclnsl remedy for local treatment or
`the mucosa, dlbenzyl carbinnmine in solution in having the formula
`3'1 011-
`CoHa.CH2.CHX.NE-I,
`...:~.*:*......“”?1:.°‘”‘....,1°“°“’......‘..°“.°°..“*..“:.?:;*:;:E:3 um-mus an mm «W mu».
`8. As a medicinslremedy tor local treatment or
`an oil to a concentration within about the range
`the mucosa. a substituted benzyl carbinmnine
`0.5%—3.0%.
`having the formula,
`5. As a.medlcina.lremedyfor1oca.1treatmentod!_
`CaHa.CIE['z.CIEII.NH:.
`the mucosa. 9} saltot dibenzyl csrbinamlne.
`8. Asa.med1c1nalreInedytor1oca.ltreat1:nentof' inwh1chxlsa.na1kylora1phy1g'mup.inm1utlon 85
`the mucosa, dibemyl can-blnanune hydrochloride.
`in an on.
`'
`FREDP. UER.
`'7. Asamedicina1remedyforIocaltrea.tmento1'_
`'
`
`..
`
`10
`
`100
`
`105
`
`110
`
`115
`
`125
`
`130
`
`135
`
`140
`
`145
`
`Amerigen Ex. 1063, p. 3
`Amerigen Ex..10UB, p. 3
`
`45
`
`7|]
`
`9