74 (1955) RECUEIL 919
`
`Rec. Trav. Chim. 7 4 , 9 19 -936 (1955)
`
`547.577-233.I
`SYNTHESIS OF f,-PHENYL-ETHYLAMINE DERIVATIVES.
`III 1) BRONCHODILATORS.
`
`BY
`H. D. MOED, J. VAN DIJK. and H. NIEWIND
`(Contribution from the Central Research Laboratory -
`N.V. Philips·Roxane. Weesp) .
`
`The synthesis is described of a number of P-(m,p-dihydroxyphenyl)(cid:173)
`P-hydroxy-N-aralkyl-ethylamine derivat:ves,
`
`HO- o -CHOH- CH2- NH- R1- < :>-R2
`HO-/
`which were screened for their bronchodilator effect against acetykholine(cid:173)
`induced bronchoconstriction in the guinea pig, and for their cardiovascular
`action.
`The influence of the side-chain R1- < ::>- R2 on the pharmacological
`activity of the basic structure,
`
`HO-) >-CHOH-CH2-NH2 (arterenol).
`
`HO-·
`was investigated. For comparison. a number of N-alkylarterenols were
`prepared and examined.
`At the same time attention was paid to the bronchodilator activity of
`
`adrenalone, HO-Q
`
`-co-CH2-NHCH3• and some N-alkyl and
`.
`
`HO-/
`N-aralkyl derivatives of noradrenalone.
`The U.V. absorption spectra of these sympathomimetics, aminoakohols
`as well as aminoketones, were measured.
`The results are discussed.
`
`Introduction.
`The sympathomimetics epinephrine (adrenalin) and N-isopropyl(cid:173)
`arterenol are valuable compounds in the symptomatic treatment of
`bronchial asthma.
`
`1) II, H . D. Moed c.s., Rec. trav. chim. 71, 933 (1952).
`
`ADAMIS EXHIBIT 1017
`Page 1 of 10
`
`

`

`920
`
`H. D. Moed, ]. van Dijk, and H. Niewind,
`
`Synthesis of P-phenyl-cthylamine derivatives.
`
`74 ( 1955) RECUEIL 921
`
`Their therapeutic use covers a wide range of indications and their
`effect is obtained swiftly.
`However. their activity after oral administration as a rule is poor,
`and their effect on the circulatory system is undoubtedly a dis(cid:173)
`advantage.
`We therefore set out to find bronchodilators of the epinephrine type
`with relatively fewer side effects and greater oral activity.
`In this investigation we did not consider it worth while to synthesize
`new N -alkyl- and N-cycloalkylarterenols, because so many of these
`compounds have already been prepared 2 ) and examined 3 ).
`From the literature it appears that N-isopropylarterenol is the most
`active bronchodilator. In our opinion N-(phenyl-sec. butyl) arterenol.
`the strong bronchodilator effect of which has been published 4 ), can be
`chosen as a starting point.
`This derivative of epinephrine still has a pronounced effect on the
`circulatory system.
`We investigated whether, and to what extent, the chemical structure
`of this substance could be changed into compounds in which the
`bronchcdilator effect exceeds the effect on the cardiovascular system.
`At the same time attention was paid to the activity of such derivatives
`after oral administration.
`We started with the synthesis of a number of N-aralkylarterenol
`derivatives. By varying the length and the branching of the alkylene
`group and by introducing substituents (OH, CH3 ) into the benzene
`nucleus of the aralkyl group, the series of aralkylated sympatho(cid:173)
`mimetics developed by Kiilz 5) could be extended with a large number
`of new compounds. In order to have material available for comparison
`with regard to the pharmacological examination, a number of N-alkyl(cid:173)
`arterenols were also prepared (IV).
`On account of the publication by Schneider c.s. G) on the broncho(cid:173)
`dilator effect of adrenalone and its derivatives, a number of type III
`compounds were included in our investigations. These relate to the
`chemical synthesis, the determination of the U.V. absorption spectra.
`and the pharmacological properties of the above-mentioned compounds.
`The present paper describes the chemistry of the compounds
`2 ) ]. R. Corrigan c.s., J. Am. Chem. Sec. 71, 530-1 (1949).
`(1940-'41); 0. H.
`•) H. Konzett, Arch. exptl. Pathol. Fharmakol. 197, 41
`Siegmund c.s .. J. Pharmacol. Exptl. Therap. 97, 14 (1949); D. E. Marsh c.s.,
`J. Pharmacol. Exptl. T herap. 92, 108 (1948); P. Siderius, Acta Phys!ol. et Pharmacol.
`Neer!. 2, 546 (1951) .
`•) K. Wiemers, Arch. exptl. Pathol. Pharmakol. 213, 343 (1951).
`•) F. Kiilz, Arch. exptl. Pathol. Pharmakol. 181, 136 ( 1936) ; F. Kiilz and K . W.
`Rosenmund, Arch. exptl. Pathol. Pharmakol. 181, 135 (1936); F. Kiilz and M.
`Schneider, Klin. Wochschr. 1950, 535.
`') M. S chneider c.s., Klin. Wochschr. 1950, 709.
`
`NC-CH2-NHR H3Co- 0
`I
`H3CO-)=/
`
`-co- CH2-NHR
`II
`
`HO-<-~>-CHOH-CH2-NHR
`HO-/
`IV
`
`Ho-( )- co- -CH2-NHR
`Ho-/
`·
`III
`R =alkyl or R1-C)>-R2
`R 1 = alkylene
`Rz = H. OH, CH3
`The amino-alcohols were obtained through catalytic. reduction (Pd
`on C) of the hydrochlorides of the aminoketones, dissolved in water
`or in a mixture of alcohol and water. The bases were isolated by
`ammoniation of the hydrogenated solution, concentrated in vacuo
`under nitrogen. The arterenols, which became solid in a short time,
`were purified by extraction with hot water or by crystallization from
`methanol or dioxane.
`Some N-alkylarterenols were isolated as salts. Hydrogenation in
`alcohol involved difficulties: ethoxylation of the CHOH-group in some
`of the arterenols took place, probably under the influence of the weak
`acid medium.
`The N-aralkylarterenols with two asymmetrical C-atoms (IV 12, 14,
`15, 16, 18. 19, 25. 27 in table II) may belong to two stereochemical
`series. As the compounds were prepared in a similar way and the
`melting points are close to each other, while there is little difference
`in the bronchodilator activity of the crude bases and those purified to
`a constant melting point, it is not unlikely that these amino-alcohols
`· will belong to the same stereochemical series.
`In order to be able to reduce the possible influence of this uncertain
`factor in the study and the comparison of the pharmacological activities,
`we prepared a number of N -aralkylarterenols without an asymmetrical
`C-atom in the side-chain (IV 20. 22, 23 .. 24 and 26 in table II).
`The yields, melting points. and analyses of
`the N-(ar)-alkyl(cid:173)
`arterenols have .been summarized in table II.
`The aminoketones (III) were obtained by demethylation 1) of the
`w-amino-m, p-dimethoxy-acetophenones (II), prepared by conden(cid:173)
`sation of veratrole with aminoacetonitriles (I) 1).
`Melting points and analyses of the hydrochlorides of I, II, and III.
`and the yields of the hydrochlorides of II and III have been listed in
`table I.
`The U.V. absorption spectra of the amino-alcohols (IV) and the
`aminoketones (Ill) were measured •) under the supervision of Dr.
`K. ]. Keuning and Drs. F. ]. Mulder of our Analytical Department.
`The data Umw Em0,) are summarized in tables II and I.
`
`•) Ca.3 mg In 100 ml of ethanol.
`
`ADAMIS EXHIBIT 1017
`Page 2 of 10
`
`

`

`922
`
`H. D. Moed, ]. van Dijk, and H. Niewind,
`
`Synthuis of P-phenyl-ethylamine derivatives.
`
`74 (1955) RECUEIL 923
`
`Yields, melting points, analysis, u.v. absorption spectra (lmu. and •).
`
`"""'"h0d;1a10• activity
`
`Ta hie I.
`
`l
`Hydrochlorides of I
`RHN-CHz-C=N I
`i
`-
`Analysis% I
`IYield M.P.
`Cl
`found calc.
`
`-
`
`II Hydrochlorides of
`RHN- cH-CO
`IP' ~
`~-OCH3
`- OCH,
`Analysis%
`Cl
`found Cale
`
`%
`
`oci)
`
`!
`i 2>
`2>
`*)67
`*)62
`2)
`2>
`2)
`')52
`•)73
`')82
`
`*)77
`')70
`I ·in
`2)69
`
`; *)57
`1
`
`190-192
`193-191
`
`13.18 13.66
`12.98 12.96
`
`208-211
`219-220
`209-211
`
`10.23 10.32
`10.56 10.;6
`10.63•) 9.70
`
`213- 215
`203-205
`
`10.31 10.(l
`9.28 9.31
`
`200-202
`216- 218
`
`9 81 9.75
`9.68 9.75
`
`210-212
`
`9.01 9.02
`
`l)71
`l)82
`l)
`l)
`')
`' )14
`')79
`
`' )i3
`')60
`
`' 175
`')67
`')88
`
`UI Hydrochlorides
`
`of
`
`RHN-CH2-CO-c~-OH
`_ /
`"--OH
`
`Yield
`°lo
`
`M.P.
`oC')
`
`I Analysis % I
`I foun.fl calc. ,--l-m_:;"_µ- ,-
`
`U.V. Abs. Spectrum
`-1--1-mm-a:--,--1 -l:-m·-!-:- , -1
`
`Broncho(cid:173)
`dilator
`ActivityS)
`
`255- 257
`240-211
`
`15.15 15.31 I
`14."19 Ii.ii
`
`232 12100
`
`279 8500
`
`312 7300
`
`232 12900
`
`279 8900
`
`312 7800
`
`199.5- 201
`220- 222
`
`11.'IO 11.23
`10.92 11.536)
`
`202-·204
`208-211
`
`163-166
`176-180
`225-227
`
`10.95 10.96
`10.96 11.02
`
`I 0.50 I 0.5:>
`10.13 10.56
`JO.Si 10.56
`
`232 13600
`
`279 9200
`
`312 8100
`
`228 18700
`
`281 10600
`
`312 7900
`
`<O.o3 < 0.05
`< 005
`< 0.05
`< 0.05
`<0.1
`<0.1
`
`< 0,02
`I < 0.05
`
`I
`2
`3
`i
`5
`6
`7
`8
`9
`10
`II
`12
`13
`Ii
`15
`16
`
`17
`
`10
`
`19
`20
`21
`22
`23
`21
`25
`26
`27
`
`M.P.
`oc•)
`
`I
`
`141-li2 '1 29.16 29.i2
`*)91- 97 26.24 26.36
`
`*)198-201 1 17.10 17.33
`*)137-110 j 18.32 18.01
`*)158-159 I 15.70 15.65
`i
`*1170-171 16.85 16.81
`*1174-175 15.17 li.74
`
`15.91 15.79
`*)168-169
`2JJ39- l i0 15.85 15.79
`
`*)161-163 13.87 13.95
`
`R
`
`1 I H
`
`2 CH3-
`3 CH.-CH,-
`1 CH3-CB1-CH,-
`5
`(CH.),1;t1-
`6 CHs-CH..1-CH,-CH,-
`7 CH3-C(CH.),-
`8 CH,-C(CH,),-CH,-C(CH,),-
`9 c.H,- CH,-CH,-
`10 p.CH,-O-C,H,-CH,-CH,-
`11 p.HO-C.H,-CHi..-CH,-
`12 C,H,-CH,-CH(1;H,)-
`13 p.CH,-a-:-c.H,-CH,-CH (CH,)(cid:173)
`H p.HO-C.,H,- CH,- CH(CH,)-
`15 p.H,C-C.H,-CH,-CH(CH,)-
`16 C,H,-CH,-CH,-CH(CH,l-
`17 p.CH,-O-C.H,-CH,-CH,-
`-CH(CH,)-
`18 p.HO-C,H,-CH,- CH,(cid:173)
`-CH(CH.J-
`19 p.H.C-C,H,-CH,-CH,-
`-CH(CH.J-
`20 C.H,.- CH,-C(CH,),-
`21 p.CH,-O-C,H,-CH,-C(CH,),-
`22 p.HO-C,J:fJ-CH,-C(CH,),-
`23 , p.H,C-C,tt,-CH,-C(CH.J,-
`2i C,H,-CH,-CH,-C(CH,),-
`25 C,H,- CH,-C(CH,) (C,H.l -
`26 C,H0-CH,-CH,- CH,-C(CH.J,-
`27 C,H,-CH(CH.)-CH,-
`
`*)119-120 I li.80 H.88
`*)21i- 215.5'1 16.17')15.79
`*)208-209 14.60')13.95
`
`15.63•)14.86
`*'1217- 218
`*j202-203 15.18')14.86
`*')198-199 15.62')1'1.86
`*)187-190 11.15 11.01
`*)165-167 17.70 16.81
`
`*)63
`*)68
`I »50
`*)37
`*)'18
`*)3i
`*)68
`*)57
`
`193-196
`238- 240
`217-220
`
`223-224
`223-225
`218-220
`221-223
`188-190
`
`8.72•) 9.11
`9.85 9.75
`9.19 9.0i
`
`9.13 9.3~
`9.02 9.39
`9.53 9.39
`8.501) 9.Q?°
`10.14 10.11
`
`' )86
`
`')85
`')79
`
`231-235
`
`10.13 10.08
`10.17 10.17
`196 - 200
`227-230 I 10.5i 10.56
`
`II
`
`252-253
`')78
`23i-235
`')i7
`227 - 230
`')79
`206-208
`')15
`')i9 1 237-210
`')80
`195-199
`
`'
`
`10.18 10.08
`J0.21 JO. Ii
`10.07 10.11
`10.iO JO.Ii
`9.80 9.75
`J J.Oi 11.02
`
`*) New compound.
`1) AU the compounds melted with decomposition; m. points are uncorrected.
`') H. D. Moed c.s .. Rec. trav. chim. 71, 939 (1952).
`•) ]. R. Corrigan c.s .. J. Am. Chem. Soc. 71, 530-1 (1919).
`
`' ) Impure compound (see experimental).
`') N-isopropylarterenol = 100.
`') Product contains 1 aq.
`
`ADAMIS EXHIBIT 1017
`Page 3 of 10
`
`

`

`;s
`~ r
`:0 8
`
`Vl
`
`~
`:0
`
`;;!
`
`l ;· ..
`l
`f
`" ! i;;·
`
`.!a.
`
`~
`
`~
`;:;·
`[
`ll
`<>.
`
`!>-
`~
`~
`:x:
`" 5.
`?<"
`~
`~
`<:
`-:-
`
`~
`
`~
`:x:
`
`'° N ...
`
`'O
`
`~ ~
`
`~
`
`-
`
`vt'O
`
`0
`
`-
`
`,.._
`0
`
`<I> -·
`
`
`
`01
`
`-
`
`f"'f" 1-1
`
`0
`
`N
`
`0.... ~
`~
`::s g
`"' •.
`5· q-
`I» .....
`s8 2.ir
`g:
`An g,...
`'°'°
`t:J"".._
`£.
`0.. Er
`'O 0
`lf ::s
`"'
`0
`-<
`(,/')
`rt-
`'"1
`-o·
`'O ...
`c: n
`"' 0..
`gig 3]
`<Q en
`~ ~ "'"'
`"' "'
`;;~ Q";.
`~
`-o-d
`*"'"' Q ...
`:0
`I *~~ !3°g
`::c
`"' "' -·
`!3
`Z 5.."' ...
`;ro
`IC:~~ nn
`:X ~-·,.,
`o,..O
`N
`np-o (0,...
`tv
`< I gt\n
`[i>' 5»
`,,;;-"' ~e:?-
`::c
`0
`...... "' "'
`-· <; 0
`...-'< <
`..., -·""
`....
`...
`...
`"'
`.
`C'l"'"'<s
`p-P-1»-
`"'O
`..
`f""f"
`I
`'<..,o
`..... ..,c:-
`o 6 ca· -
`,... o f"'f"
`"' « ......
`...... p-"'
`o.g-
`.,, ... ::s<
`... p..-<n
`.,.o
`'.;!...,"' P-~oO
`c:::r<:r
`,..ci>;:s::S
`n n ° · ~. 0.: lf ~
`::StoC""t'-~(./t'O~
`o
`en
`ts
`,....
`....
`~-.ton=nga>
`::soa~c
`::!:"'o"'o"'!3P(cid:173)
`$l-o<;"'>-l
`><::S
`.,.5·5" ... !3~"'
`... <:r ~~ ~g OJ
`
`tot
`
`-
`
`(9
`
`"' !3 ~ g--· 8 -
`
`0
`::r--0... 0 0
`
`::r--
`
`I
`
`0
`:X:
`
`(9
`
`I
`~ I
`
`I +
`~gg 1· +
`800 I +
`I +
`SC +
`
`100
`10
`800
`100
`75
`
`50
`
`100
`
`5
`0,2
`
`3000
`3120
`3090
`3050
`3080
`4~90
`3180
`3180
`1820
`3190
`3190
`1780
`3190
`4700
`3090
`3250 I
`
`282
`282
`282
`282
`282
`280
`282
`282
`280
`282
`282
`280
`282
`280
`282
`282
`
`i--1--dilator
`
`Oral
`
`U.V. Abs. Bron-
`
`··---· -
`
`', ~~
`I 2 I
`
`-
`
`150
`5
`100
`5
`
`1
`
`----~ound calc. found calc. r~.und calc. __ :;,~1_•_l_~~~. I __ 200 y
`at
`°C
`cho· activity
`
`H
`
`C
`
`%
`
`I
`·1Yield M.P.1) -----i---·-i · Spectrum
`
`---.).,-1.
`
`I
`:
`I N
`
`··--·--·----•k--
`
`·------••
`
`Analyslsi), %
`
`""--OH
`RHN-CH2-CHOH-(~)-OH
`
`IV
`
`(l ...... and e.}, bronchodilator activity.
`
`Yields, melting points. analysis, u.v. absorption spectra
`
`Tab I e 11.
`
`0
`------· -· "' ,.,
`
`·-)
`
`M
`
`C>
`
`g
`
`~I
`~I
`..,,
`
`WI g1
`
`.. 1 .. 0
`
`i
`i a ...
`;; ..
`;.
`:<: e.
`~ ;! Q.:::
`<:ti -a
`.. o·
`ct. <a
`0 ~
`~
`~ ii'
`::-
`~ .,,
`
`-
`
`g
`
`0
`
`3
`~ :x: -
`g. 0 <:
`~ .., ~
`I -
`io
`°'
`.. <!(lo
`:x:~ :i:
`'* Cill
`~ ~h~~h
`a.:ol:o
`§'. f .?f
`& z I z
`..,
`l:i:I
`.. Z"
`.,.
`:x: I :x:
`()N ()
`I :x: I
`;:;
`:x: h :x:
`l!
`a o:X:o
`:r: 0 !t
`"
`;. h:x:l.
`• nw
`g..
`..
`..::c I .. :i:
`..
`()~ ()
`.. ::c ..
`-Cit -
`0 -
`;. oho
`"i <?:t
`'? .:l:';>
`~·
`8.., 8
`~
`11 U I
`~I
`I
`I
`I
`+ 0
`~
`I
`I
`+ 0
`I
`I
`• •
`
`ca
`
`OI
`
`-
`
`(9
`
`(II
`n>
`
`I
`
`I
`
`'} The C, H, and N micro-analyses were carried
`
`tory for Org. Chem .. Mun. Univ., Amsterdam.
`out by Mr. P. ]. Hubers, Micro-Anal. Dept.., Labora(cid:173)
`
`•) A• •ulphar •.
`•) Isolated as HCJ-salt.
`
`•) J. R. Corrigan c.s .• J. Am. Chem. Soc. 71, 530-1 (19-49).
`•) H. D. Moed c.s .. Rec. trav. chim. 71, 943 (1952).
`1) All the compounds melted with decomposition; m. points are uncorrected.
`*) New compound.
`
`i.76 1.88
`i.17 i.25
`1.38 '1.11
`1.11 4.H
`1.39 1.11
`1.54 4.12
`1.52 1.65
`1.29 1.11
`4.39 1.'12
`1.75 1.65
`1·.54 i.65
`1.51 4.62
`1.75 i.88
`1.71 i.8-1
`5 Ii 5.13
`1.S9 4.98
`
`fi9.63 71.0917.21 7.32
`72.8-1 72.95 8.28 8.21
`72.21 72.39 7.90 7.94
`71 80 72.39 7.99 7.9-1
`71.82 72.39 8.08 7.9'1
`66.3668.11 7.21 7.26
`. 70.93 71.77 7.57 7.65
`72.26 72.39 8.01 7.94
`66.91 68.li 7.18 7.26
`70.65 71 77 7 .65 7 .65
`71.21 71.77 7.65 7.65
`66.81 67.3'1 6.99 6.94
`70.42 71.09 7.37 7.~2
`62. ii 66. 11 6.63 6. 5~
`69.55 70.3i 7.00"6.97
`67.57 68.3319.50 9.62
`
`80-81
`151-152
`162-163
`1'12-143
`168-169
`160-162
`161-162
`li8-I 50
`lil-1'13
`163-16'1
`136-138
`167-167.5
`15-1-155
`122-123
`172-173
`139-139.5
`
`13
`69
`56
`74
`7·!
`77
`50
`66
`35 ;
`80
`81
`17
`37
`56
`80
`79
`
`76 111-115,5 62.06 62.56 8.15 8.06 6.74 6.63 282 3200
`80
`
`•)
`*)
`*)
`•)
`*)
`•)
`•)
`·1 I
`*}
`
`-
`1)
`
`*)
`•)
`*)
`•)
`*}
`•)
`'} •)
`'}
`•)
`
`·) :1
`
`27 c.H,-CH (CH,)-CH,-
`26 C.H,-CH,-CH,-CH,-C (CH,},-
`25 C4H,-CH,-C{CH,} (C,H,)-
`2i C.H.-CH,-CH,-C(CH.),-
`23 p.H,~L;.H4-CH,-C(CH.J,-
`22 p.HO-C..t.H,-CH,-L;(CH.),-
`20 C.H,-CH,-C(CH,}i-
`19 p.HO-C,H,-CH,-CH,-CH(CH3 --
`18 p.H,~C.H4-CH,-CH,-CH (CH,
`16 C11:f .-CH,...:...CH,-CH (CH,)-
`l 5 p.H.~L;,H,-CH,-CH ( CH.J-
`li p.Hu-<;H,-CH,-CH ( CH3)(cid:173)
`12 C,Hl.-Ctt,-CH(L;H.J-
`11 p.H~tH,-CHi.-CH,-
`9 C,H3-CH,-CH,
`8 CH,-C(CH3}.-CH,-C(CH.J,-
`7 CH3-C{CH.J,-
`6 CH,-cHi.-CH,-CH,-
`s
`1 CH,-OH,-CH,(cid:173)
`3 CH.-CH,-
`2 CH.-
`
`171-172 I
`I
`
`(CH.J!.CH-
`
`II H-
`
`R
`
`ADAMIS EXHIBIT 1017
`Page 4 of 10
`
`

`

`926
`
`H. D. Moed, J. van Dijk, and H. Niewind,
`
`Synthesis of P-phenyl-ethylamine derivatives.
`
`74 (1955) RECUEIL 927
`
`In the compounds IV and V, phenol and pyrocatechol form part
`of molecules with a similar structure.
`In fig. I the molecular extinction curves of three representatives of
`IV, IV' and V are given.
`Figure 2 shows the extinction curves of two types of N-aralkylnora(cid:173)
`drenalones (III and III').
`
`5000
`
`The pharmacological research, which will be published elsewhere,
`was carried out by Prof. Dr. F. Briicke c.s. 7 ), Prof. Dr. J. H. Gaaren(cid:173)
`stroom c.s. 8), and Drs. Th. W. ]. Hendriksen 9), who kindly permitted
`us to mention already in this publication the preliminary pharmacology
`of our compounds.
`The arterenols and some derivatives of noradrenalone were screened
`for their bronchodilator effect against acetylcholine-induced broncho(cid:173)
`constriction in the guinea pig 10). The data are also summarized
`respectively in tables II and I. Several amino-alcohols were tested for
`their in vivo effect on the circulatory system in dog (heart rate) and
`cat (blood pressure).
`The therapeutic usefulness of some arterenols has been investigated
`by clinical tests.
`
`Discussion.
`U. V . Absorption spectra.
`
`Tab I e Ill.
`
`).
`
`... ,,
`
`mµ
`
`(ave rage)
`/ •
`mox
`
`IV
`
`H09
`HO-
`
`-CHOH- CH2-NH-R1-0
`
`H0 -0
`HO_/
`
`v
`
`IV'
`
`HO-o
`
`-CHOH-CH2- NH-R1-C
`
`>
`
`Ho-C)
`
`H0-9-CHOH- CH2-NH-R1-Q- 0H
`HO-
`
`282
`
`278
`
`277
`
`273
`
`280
`
`3100
`,
`
`2700
`
`1600
`
`1800
`
`4700
`
`250
`
`300
`
`sso mp
`
`Fig. 2. Molecular extinction curves of the two types
`of N-aralkylnoradrenalones.
`(Ill)
`m,p-(H0) 2C6Hs-CO--CH,-NH-R,-C6H5
`m.p-(H0) 2C6Hs- CO--CH2-NH-R,-C6H4-p.OH (Ill')
`
`_. _. _ =
`-o _ o- =
`
`7 ) Pharmacological Laboratory of the University of Vienna.
`8) Pharmacological Laboratory of the University of Groningen. (Dr. P. Siderius,
`Dr. B. Louwerens, Dr. D. de Wied).
`') Pharmacological Laboratory of N.V. Philips-Roxane.
`10) Method: P. Siderius, Acta Physiol. et Pharmacol. Neer!. 2, 546 ( 1951) .
`
`ADAMIS EXHIBIT 1017
`Page 5 of 10
`
`

`

`928
`
`H. D. Moed, J. van Dijk, and H. Niewind,
`
`Synthesis of P-phenyl-ethylamine derivatives.
`
`7i (1955) RECUEIL 929
`
`The characteristic points in table III refer to the low-intensity B
`bands of the benzenoid systems. It appears that the effect of the side(cid:173)
`chains, in which the absorption of the benzene nucleus is negligible,
`on the U.V. absorption of phenol and pyrocatechol is slight, but
`obvious. As a result of the interaction of the :n-electrons of the ben(cid:173)
`zenoid system with the a-electrons of the adjacent bond, the Amax of
`IV and V have increased by 4 mµ.
`The changes in the tmax• however, are different. In spite of the
`fact that phenol and pyrocatechol have been substituted by the same
`side-chains. the molecular extinction coefficient has increased for IV
`and decreased for V. Apparently, the increase of the chromophore
`area in V has been compensated by a decrease of the transition
`probability.
`The arterenols IV' have two isolated chromophore systems, in
`which, just as in IV and V. the :n-electrons interact with the a-elec(cid:173)
`trons of both adjacent bonds in the joint aliphatic side-chain.
`One would expect that for every wavelength the following equation
`holds:
`
`From figure 1 it can be deduced that this is true indeed.
`The molecular extinction curves of the aminoketones have a maximum
`not only at 280 mµ. but also at 312 m,u. As the amino-alcohols do not
`absorb at this wavelength, this difference in absorption has been
`used to demonstrate the possible presence of aminoketones in the
`amino-alcohols. The N-(p-hydroxyaralkyl}-noradrenalone derivatives
`(III') give a greater absorption at 280 m,u as a result of the contri(cid:173)
`bution of the monophenol group in the side-chain (fig. 2, table I).
`
`Structure - Activity R.elationship (tables I and II).
`It appears from table II. that the side-chain R1-Q -R2
`has a great and variable influence upon the bronchodilator activity of
`the basic structure (arterenol). The N-aralkylarterenols form a group
`of active bronchodilators, the activity of which is dependent on the
`structure (length and branching) of the alkylene group and on the
`substitu<::nts in the benzene nucleus of the aralkyl chain.
`The influence of the alkylene group can be found by comparing the
`activities of the arterenols of nos. 9, 12, 16, 20, 24, 25, 26, and 27,
`summarized in table II. These amino-alcohols have no substituents in
`the benzene nucleus. An activity equal to that of N-isopropylarterenol
`is present in arterenols having the side-chain:
`
`R =
`
`I H. CH3 1
`I
`-C-(CH2)n-o~ n =I. 2 (nos 12. 16,20, and 2'1)
`"=
`I
`CHl
`These side-chains are characterized by the presence of one or two
`methyl groups at the C atom beside the N atom and an alkylene
`group with from three to six C atoms. In the side-chain of no. 26 the
`branched alkylene group has been lengthened to four C atoms:
`CH3
`I
`A-
`'
`- C-(CH1h-#'
`"'-=/
`I
`CH3
`This has led to a considerable decrease in activity. The same effect
`is obtained when the methyl group at the a-C atom is replaced by an
`ethyl group:
`
`R =
`
`R=
`
`(no 25 iJl table II)
`
`CH3
`I
`-?-CHi-0
`CiHs
`It is worth mentioning that the isomeric aralkyl chains of nos 24 and
`25 have a mutually different influence on the bronchodilator activity
`of the basic structure. The same is true for the side-chains of nos 12
`and 27.
`The effects of the substituents methyl and hydroxyl in the benzene
`nucleus of the aralkyl group are by no means the same. The methyi
`group diminishes (nos 12 and 15, 16 and 19, 20 and 23) and the
`hydroxyl group (nos 9 and 11, 12 and 14. 16 and 18, 20 and 22)
`increases the bronchodilator activity. A number of N-(p-hydroxy(cid:173)
`aralkyl}arterenols have greater activity than N-isopropylarterenol. It
`~ay be a.ssumed to be highly probable that arterenols with the following
`side-chains are the most active bronchodilators ever examined:
`
`R =
`
`n = I. 2. (nos H. 18, 22 in table JI)
`
`1 H. CH3 1
`I
`-C-(CH2)n-o~ -OH
`I
`-
`CH3
`Comparing the effect of the side-chains R1-Q-R2 and R1H.
`we see little difference after intravenous administration (nos 5 and 12,
`7 and 20, 3 and 9 in Table II). An exception is formed by nos 1 and
`27, where the N-aralkyl derivative is less active.
`With regard to some N-aralkylarterenols we have established the
`fact that, after oral administration. they give protection against
`
`ADAMIS EXHIBIT 1017
`Page 6 of 10
`
`

`

`930
`
`H. D. Moed, J. van Dijk. and H. Niewind.
`
`Synthesis of fJ-phenyl-ethylamine derivatives.
`
`7i (1955) RECUEIL 931
`
`histamine-induced asthma in the guinea pig at lower dosage levels
`last column). This
`the N-alkylarterenols {Table II,
`than do
`shows that the first-mentioned agents are readily absorbed from the
`gastro-intestinal tract of the guinea pig. Apparently. the phenyl group
`is responsible for the greater oral effectiveness of these N-aralkyl·
`arterenols.
`It is interesting to compare our results with those of Ludwigs and
`Schneider u). These investigators studied the effect of various aralkyl
`side-chains upon the bronchodilator activity of a number of basic
`structures {P,.phenyl-ethylamine derivatives). One of these basic struc(cid:173)
`tures was arterenol. Ludwigs and Schneider arranged the side-chains
`in the order of their bronchodilator activity (activity series). Apparently,
`their starting point was the unproved premise that the influence of
`the side-chains would be similar for all basic structures. We believe
`.-
`this assumption to be erroneous.
`In our opinion, it may be assumed that each type of epinephrine
`derivative has its own rules concerning the influence of the side-chain
`structure upon the pharmacological activity of the compound. Ludwigs
`and Schneider included only a relatively small number of N-aralkyl(cid:173)
`arterenols in their investigations. On the other hand, we have been
`able to prepare and to te!:t a more complete series of N-aralkylated
`arterenols. The difference between their activity series and that which
`can be deduced from the bronchodilator activities of our arterenols
`(Table II) must be ascribed to this fact.
`Of our aminoketones, derivatives of arterenone ( noradrenalone).
`HO~-CO-CHz-NH2.
`HO-r
`adrenalone is the most active bronchodilator. In this series there is
`no evidence of any connection between the bronchodilator activity
`and the side-chain structure.
`Ludwigs and Schneider also included some derivatives of noradrena.
`lone in their research. From Table I it can be deduced that our results
`do not agree with the mentioned activity series either.
`The N-aralkylarterenols described in the present paper lower the
`blood pressure of the cat and accelerate the heart rate of the dog in
`different degrees after intravenous administration. It has been shown
`that in the compounds mentioned as a rule the tachycardia in the dog
`and the bronchodilator effect in the guinea pig are parallel. Clinical
`tests have shown that the bronchodilator activity of N-(p-hydroxy-
`
`") N. Ludwigs and M. Schnelder. Arch. exptl. Pathol. Pharmakol. 218, 432 ( 1953).
`
`phenylisopropyl)arterenol is much greater than that of epinephrine and
`isopropylarterenol.
`
`Note. After the completion of this investigat.ion we read the publication by
`John H. Biel c.s. about bronchodilators, N-substltuted derivatives of arterenol 11).
`The pharmacological activity of some of these compounds has been publ!shed by
`Seibert and Handley Ua).
`During our investigation we became acquainted with John H. Biel's preliminary
`communication (Abstr. of Papers, !21st meeting Am. Chem. Soc., 1952) about the
`same subject.
`
`Experiment a I. lS)
`A. Amlnes (H2N-R) (table I).
`These data refer to new compounds and to those amines for which we deviated
`from the directions given in the literature.
`a) The amines H,N-R 10, 13, and 15 were prepared by reduction with LiAIH.
`of the corresponding arylnitroalkenes 14), obtained from the aromatic aldehyde and
`a nltroalkene (Table IV).
`
`Table IV.
`
`Arylnitroalkenes
`
`Amines
`
`Yield
`%
`
`B.p .. 'mm
`
`Yield
`%
`
`B.p./mm
`
`CH1-C,H,-CH-C(CH,) NO, *)
`CH,O-C,H,-CH- C(CH,) NO,
`CH,O-C,H,-CH-CH-NO, 1>)
`
`55
`54
`
`135-139/10
`174/3
`
`82 I
`
`HzN-R1s
`H1N-Ru
`H1N- R10
`
`103-105/ 10
`67
`60 I 129-132/8
`132-136/ 12
`69
`
`l-p-Tolyl-isopropglamine-2 ( H,N- R,s).
`A mixture of 50 ml (0.65 mol.) of concentrated ammonia, 60.2 grams (0.375 mo!.)
`of nltroethane, 4 ml of n-butylamine, and 35 ml of absolute ethanol is refluJ<ed for
`6 hours. after which the solvent is distilled a.nd the residue fractionated in vacuo.
`Yield: 19.4 grams of 1-(p-to/gl)-2-nitropropene.
`A solution of this nitre-compound in 200 ml of absolute ether is slowly added
`with continuous stirring to a solution of 20 grams of LtAJH, In 500 ml of absolute
`ether, so that the reaction mixture Is just boiling. By cautiously adding wet ether
`
`ll) John H. Biel c.s., J. Am. Chem. Soc. 76, 3119 (1954).
`Ila) R. A. Seibert and C. A. Handley, J. Pharmacol. Exptl. Therap. 110, 304
`( 1954).
`U) In collaboration with D. Trap and W. van Wageningen. The micro-analyses
`were carried out by P. ]. Hubers. The melting and boiling points have not been
`corrected. Compounds marked *) are new.
`") P. A. Ramirez and A. Burger, J. Am. Chem. Soc. 72, 2781 (1950).
`15) K. W. Rosenmund, Ber. i2, 4780 (1909).
`
`ADAMIS EXHIBIT 1017
`Page 7 of 10
`
`

`

`932
`
`H. D. Moed, J. van Dijk, and H. Niewind,
`
`Synthesis of P-phenyl-ethylamine derivatives.
`
`74 (1955) RECUEIL 933
`
`and water, the reaction mixture Is decomposed. The hydroxides are filtered with
`suction, and the filtrate is shaken with 2N hydrochloric acid ( 150 ml); then an
`excess of 50 % caustic soda solution is added and the oil layer is dissolved in ether.
`After drying over NaOH, the ether is distilled and the residue fractionated in vacuo
`(11.0 grams).
`·
`
`Analysis:
`C10H 15N. Cale.: Equivalent weight 149.
`Pound:
`149.
`b) The amines H2N-R 20, 21, 24, 25 and 26 were prepared by hydrolysis of
`the formamides R-NH-CH=O, which were obtained from the carbinols R-OH
`and HCN 1•) (Table V).
`
`Table V.
`
`Pormamides :
`
`Yield
`%
`
`B.p.fmm
`
`Amines:
`
`'
`Yield
`°lo .
`
`B.p./mm
`
`R10-NH-CH = 0
`R11-NH-CH=O 18)
`R14-NH-CH=O *)
`R.,-NH-CH=O
`R20-NH-CH=O *)
`
`65
`19
`65
`58
`27
`
`186/20
`ca. 200/ l 11)
`165-712
`160-180/5 11)
`188/2
`
`Rw-NH2
`R11-NH2
`R:M-NH2
`R15-NH2
`R26-NH2
`
`87
`52
`75
`95
`91
`
`86-8/13
`133-5/8
`114-8/20
`117-120/H
`126-130/ 16
`
`-
`
`Instead of with caustic soda solution U), the intermediates were hydrolyzed with
`6N hydrochloric acid:
`The formamide (200 grams) is refluxed for half an hour with 450 ml of 6N
`hydrochloric acid and, after cooling, the reaction mixture is extracted with ether.
`Theo an excess of 50 % caustic soda solution is added, the amine is dissolved in
`ether, the solution is dried over Na,SO,, the ether Is distilled, and the residue is
`fractionated in vacuo.
`The amine H2N-R.23 •) was obtained in a different way 19):
`p-Tolyl-t.butglamine (H.N-R21 )
`A solution of 187 grams (2.10 mo!.) of 2-nitropropane, 210 grams (1.75 mo!.) of
`p-tolylaldehyde, and 9.2 grams of sodium in 700 ml of absolute methanol, after
`standing for 24 hours is acidified with acetic acid and the methanol Is distilled. The
`residue is dissolved in ether, extracted successively with a sodium bisulphite solution
`and water, dried over Na,SO ,, and then the ether Is· distilled.
`To a solution of the residue in a mixture of 370 ml of ethanol, 380 ml of glacial
`acetic acid, and 490 ml of water are added, with continuous stirring, 195 grams of
`zinc dust, and the reaction mixture is heated to 70° for six hours. It is then diluted
`with 875 ml of water and, after filtration, an excess of 50 % caustic soda solution
`
`U) J. J. Ritter and/. Kalish. J. Am. Chem. Soc. 70, 4048 (1948).
`17) The product contains carbinol.
`18) From p-CH,0-C6H4-CH=C(CH3) 2 and HCN; U.S.P. 2.597.446.
`") B. L. Zenitz, B. B. Macks. and M. L. Moore, J. Am. Chem. Soc. 70, 955
`(1948).
`
`is added. The mixture is extracted with ether, dried over Na,SO,, and acidified
`with SN alcoholic hydrochloric acid.
`The hydrochloride of 1-( p-tolyl)-2-amino-2-methylpropanol-1 *) Is filtered and
`dried (40 grams). M.elting point 262-263° C (decomposition).
`
`Analysis:
`C 11H 110N. HCl Cale. : C 61.27; H 8.36; Cl 16.45;
`Found:
`.. 61.26; .. 8.24; .. 16.25.
`
`A mixture of 42.5 grams (0.197 mo!.) of the hydrochloride, 8 grams of red phos(cid:173)
`phorus, and 70 ml of 57 % HI-solution is refluxed for 25 hours and then poured
`into 270 ml of water. The reaction mixture Is filtered, and an excess of 50 % caustic
`soda solution is added; the mixture is extracted with ether, dried over Na,SO,, and
`fractionated in vacuo, after distilling the ether. Yield: 24.5 grams (0.150 mo!.) of
`p-tolyt-t.butylamine *) or 76 %.
`Boiling point: 100-102° C/10 mm.
`
`Analysis:
`
`Cale. : Equivalent weight 163.
`Found:
`164.
`c) The amines H2N-R 16, 17, and 19 were obtained by reductive amination
`of the corresponding beozal acetones !O).
`p-Tolyl-sec. butyiarnine (H.N-R19 ).
`A mixture of 50 ml (0.65 mo!.) of concentrated ammonia, 60.2 grams (0.375 mo!.)
`of p-methylbeozalacetone, 200 ml of ethanol, and 20 grams of Raney nickel catalyst
`is hydrogenated at room temperature and atmospheric pressure. The reaction mixture
`is filtered, acidified with hydrochloric acid, and the alcohol distilled in vacuo; the
`residue is dissolved in water and the non-basic compounds are extracted with ether.
`Theo an excess of 50 % caustic soda solution is added, the amine is dissolved
`in ether and dried over sodium hydroxide; the ether is distilled and the residue is
`fractionated (29.0 grams= 47 o/o). Boiling point: 115-117° C/ 10 mm.
`Analysis:
`C,1H 11N. Cale.: Equivalent weight 163.
`Pound:
`163.
`
`B. Amino-aceto-nitriles (table I, I).
`The preparation took place according to Biltz and Slotta U) (I, 1.2) and according
`to Knoevenage/ and M ercklin !!) . The impure hydrochlorides may be contaminated
`with some R-NH2 • HQ.
`
`C. ·w-Am.ino-m,p-dimethoxy'!cetoph~nones (table ·I; II).
`.
`.
`.
`These were prepared according to the directions given in a former publication u).
`Instead of with alcohol-acetone, the N-aralkyl derivatives were washed con-
`
`tO) L. Haske/berg, J. Am. Chem. Soc. 70, 2811 ( 1948); R. A. Davies and R. D.
`Howard, J. Chem. Soc. 1947, 191.
`21) H. Biltz and K. Slotta, J. pract. Chem. 2 113, 252 (1926).
`t:!) E. Knoevenagel and H. Merck/in, Ber. 37, 4089 (1904); Org. Synth. 27, 20
`(1947).
`U) H. D. Moed c.s .. Rec. trav. chim. 71, 940 e.v. (1952).
`
`ADAMIS EXHIBIT 1017
`Page 8 of 10
`
`

`

`934
`
`H. D. Moed, ]. van Dijk, and H. Niewind,
`
`Synthesis of P·phenyl-ethylamine derivatives.
`
`7i (1955) RECUEIL 935
`
`P-phenyl)ethylamino-m.p-dihydroxyacetophenone, 100 ml of ethanol, 50 ml of 1 %
`PdO, solution, 50 ml of water, and 3 grams of norite is hydrogenat.ed. The catalyst
`Is filtered, the ethanol is evaporated in vacuo under N1, and ammonia is added.
`Yield: 10 grams (74 %). Melting point 80-90• C (dee.). The crude base is
`purified by crystallization from methanol.
`Yield: 7.5 grams (56 %) of N-( (a-methyl-«·ethyl-P-Phenyl)ethyl)arterenol.
`Melting point 162-163° C (dee.).
`
`Summary.
`I ) A number of ,8-{m,p-dihydroxyphenyl) -,8-hydroxy-N-aralkyl(cid:173)
`ethylamine derivatives were prepared in order to obtain broncho(cid:173)
`dilators (table II).
`,8-(m,p-dihydroxy(cid:173)
`2) These sympathomimetics, derivatives of
`phenyl)-,8-hydroxyethylamine ( arterenol), were obtained by catalytic.
`reduction of the w-aminoketones, which had been prepared by
`.w-aralkylamino-m.p-dimethoxyacetophenones
`the
`demethylation of
`synthesized according to Houben Hoesch {table I ).
`3) The bronchodilator activity of arterenols with the side-chains
`1 H or CH3 1
`
`R =
`
`-?-
`
`(CH:i)n-0
`
`(n = I, 2: table 11)
`
`secutively with ether and with water, In which these hydrochlorides, which arc
`soluble in ethanol, a.re practically Josoluble. The impure hydrochlorides, which were
`contaminated with Al Os . 6