Note: Descriptions are shown in the official language in which they were submitted.
:1053;~S~
This invention relates to phenyl-lower-alkylamines
useful as anti-inflammatory agents.
A v~y la~ge class of organic compounds of widely
divexse structural type~ are known to be useful as anti-inflam-
matory agent~, but many ~f suçh anti-inflammatory agents are
aci~ic, for ~xamplæoC-(3-benzoylphenyl)propionic acid, known
generically as ketopro~en tBritish Patent 1,164,585, published
Sept. 17, 1969~. Such acidio agents are often irritatlng, and
in ~om~ cases are ulcerogenic, to the gastric muco.~a when
administered orally. There is thus a great need for anti-
inflammatory agents, for example compounds having a basic amine
function, which might be expected to be non-irritating to the
1. ga~t~ic mucosa. ~ltho~gh the chemioal literature d~scribe~
.~ numerouæ type~ o~ ~mine-sub~tituted compound~ as~erted to have
anti-in~lammato~y act~vity ~see for example U.S. Patents
3,770,748, pa~ented Nov. 6, 1973 and 3,803,127, patented
April 9, 1974 (N-phenylpolymethyleneimlnes~; U.S. Patents
3,772,311, pat~nted Nov. 13~ 1973 and 3,773,772, patented Nov. 20,
1973 ~pol~methyleneimino-lower-alkanoylpyrazoles); U.S. Patent
3,773,944, patented ~ov. 20, 1973 tl-[3-amlnopropyl]phthalans);
U.S. Pat~nt 3,801,594, patented April 2, 1974 ~3-a~lno-lower-
alkylindol~); U.S. P&tent 3,810,985, patented May 14, 1974
- 1 -
. ~ ,.. ~ -
- ' ' ~
~0~3ZSl
(4-anilino-1,3,5~ azlnes~ 4nd ~re~ Pa~ent 1,549,342, délivré
November 4, 1968, (4-[~e~zQylphe~ylmethyl]morpholin~s)], no ~uch
basic compou~d~ are known t~ be commerclally a~ailable, and none
are known to be under a~van~ed l~ve~tlgatlon ~y pharmacologists
for po~sible comme~al dev~ ment, ~he ~ea~ch for an effective,
non-acidic anti-i~lammatory agent ~or c~mmercial development
has there~oxe c~nti~ed.
The present invention relates to N- 3-[Rl-(phenyl)-C-
(=X)]-phenyl-lower-alkyl amines, which are useful as anti-
inflammatory agents, having the formula:
' . :
;~ " R3
~ ~_ ÇNCH2-21 3
R2
wh~re Rl represents hydr~gen or ~rom one to two, the same or
diffexent, low~x-a~kyl, hydroxy, lower-alkox~, trifluoxomethyl,
~j lower-alky~mercapto~ lower-alkylsul~inyl, lower-alkylsulfonyl
J' 15 or halogen ~elec~ed ~ro~ 1uorine, chloxine and br~mine; R~
I represent8 hydrogen,or lowe~-alkoxy or hydroxy in the 4-po~ition,
~. o~ lower-alkyl in eith~r ~ th~ 2-~ 4-, 5- or 6-po~itions; R3
~apre~ent~ hydrogen or l~wer-a~kyl; the group ~C~X repr~sent~
t ~C-O~ ~C(R3)OH! ~ CtR3)~ CsCH2, _ C-NOH or ~ CHN(R3)2
(where R3 is only hydrogen or methyl in the last case) and N-B
repressnts one of the groups
,:
''
~0S3'~S~ .
R3 R3
~3 ~CH-R4
-NH - C - R5 , -N - C - ~5 , -N
,,
CEI-R
R4 CH2 R4
R~
6 $
~(C~3)n ' ~-N~1~6 -N~
R6
R3
~\ /~4.
-N Z o~ -NHCH (CH2 ) xlN\
6 R4
where R3 represente hydr~gen or lawer-a~l a~d is ~e s~re or differerlt when
occurring m~re than c~e, R4 and R5 each represent lower-a~yl; R6 and R7 eac~h
represent hydroge~, lower~alXyl, cyclohexyl, cycloh~xylmethyl,
2-cyclohexylethyl, 3-cyclohexylpropyl ox benzyl~ Z represents
O, S or N-R8; R8 repre~ts low~x-alkyl or cy~lohexyls and n
repre3ents ons o~ the integ~rs 1, 2 and 3.
Preferred compound~ o~ foxmula I axe tho~0 whexe Rl
repre~ent~ hydrogen or rom one to ~wo, the ~ame or ~l~feren~,
lower-alkyl, lowex-alkoxy or halo~en; R2 repre~nt~ hydro~3~ o~
lower-alkoxy or hydxoxy in the 4-po~i~ions and N~B rep~e~n~
one ~f the gXoup~
R3 R7 R3
~2)n ~ ~N~J or
R6 R6
-NECH (CH2) I,,N
~3 4
--3--
, : . .
~ -
~ ~ :lOS3251
in which R6 repre~en~s hydrogen, lower-alkyl, cyclohexyl, cyclo-
hexylme~hyl, 2-cyclohexylethyl or 3-cyclohexylpropyl; ~7 repre-
: sents hydrogen; Z repre~ents oxygen; and R3, R4 and n have the
meanings given above~
Par~icularly pre~erred c~mpoun~s of formula I ~ithin
the ambit of the invention as ~e~cribed above are thos~ where
Rl represen~s hydrogen ~ from o~e to ~wo, th~ ~ame or di~erent,
lower-alkoxy o~ halog~n~ R2 r~pre~en~s bydx~genJ ~C=x ~epresent~
C=o, ~ CHOH, - CH2, ~C~NOH or ~ CENH2, and NaB rep~sents
one o~ the groups
_~ -N~X~ -N z o~
.~ \~ (CH2 ) n ' ' \+/
i 6 R6
-NHCHtCH2)nN~
R3 R4
"
:, in which R6 represe~s hydrogen, lower-alkyl, cyclohexyl, cyclo-
heYylme~hyl, 2 cyclohexylethyl o~ 3-cyclohexylpropyls R7 repre-
l$ sent~ hydroge~ Z rep~sen~ ~xy~en; n repxe~e~ts the i~ege~s
1 or 2; and R3 a~ R4 have the meanings given above.
Also withln the pur~iew o~ the present invention are
compounds having the formula~
CN-N
Xa
-4- .
lOS32S1
where the group ~ CDX repr~sents ~ C=O and R3 represents
lower-alkyl or where the gxoup ~ C~X represent~ ~cHNH2 ~nd
R3 represents hydrogen.
As used herein, ~he terms lo~er-alkyl a~d lowex-
alkoxy mean satura~ed, ~onova~nt, aliphatic radicals, includi~g
~ranched chain radlcals, of from one ~o four carbon at~m~, ~or
example me~hyl, ethyl, pxop~ Propyl, butyl, $ÇG .-~utyl,
isobutYl~ methoxy, eth~xy, pr~p~xy, ~s~propoxy ! butoxy, ~ec.-
butoxy and i~obut~xy.
The çompounds of formula I in which the group,~=X
represents ~C(R3)OH where R3 i~ hydxogen are prepared by
reaction of an appropriate 3~[Rl-(phe~yl)-CO]-phenyl-lower-
alkanoyl halide o~ ~ormula I~I ~prepared by reaction of ~he
corresponding a~id o~ ~oxmula ~I with a ~h~onyl halide3 with
an appropriate amine of formula IV, H-N=~, and reduction of
the re~ulti~g 3-~Rl-(phenyl3-COl-ph~nyl-lower-alka~oylamine of
~ormula V with a reægen~ e~e~ive to reduc~ ami~es to amine~,
for example an alkali met~l alumin~m hy~ride, a trialkylaluminum
or a dialkylaluminum hydride. The met~o~ is represen~ed by the
~llowlng re~ce1on ~eq~nce~
'
~ 5
.
- iOS3~Sl
" R3 O R3
C ~ CHCOOH ~ C ~ CHCO-Hal
Rl~ ~J ~ Rl~ ~
II III
¦H-N=B
H ~,DH ,3 ~3
Rl ~ C ~ ~ ~ CNC32~ 3 _ ~ ~ C ~ ~ ~ CII~O-N=B
2 2
I v
where Rl, R~, R3 and N~B have th~ meanlng~ ~ive~ above, a~d
~al represent~ halo~en. Th~ pr~paration of the acid halide is
carried out elther with or with~ut a solvent by heating the
acid with a molar excess of the thio~yl halide. Con~ersion of
.~ the halide to ~he amide of formula V i~ effected ~y reac~ing
the halide with the amine in the pre~ence of an acid-acceptor,
for example an alkali me~al carbonat~ or bicarbonate, a tri-
10- lower-alkylamine or an ex~ss ~ e amine, H N-~. The reac~ion
is preferably carried out in an inert organic ~olve~t, for
example methylene ~ichlorid~, ~enzene, toluene or xylene. Redu~-
tion of the amide with an alkali metal aluminum hydride is
carried out in an inert organl~ ~olvent, for example diethyl
e~her, t~trahydrofuran, di~xane or dibu~yl ether.
As indicated by the above reaction/ reduction of the
~ 3-[Rl-(phenyl)-CO]-phenyl-lower-alkanoylamlne~ of formula V al80
'1 effects reduction of ~he ~ar~onyl ~roup sf the Rl-tphenyl~-CQ
moiety to the ~arblnol gxoup, ~CHOH. ~his xeduction can be
--6--
, . . . .
.
~l~S3ZSl
avoided if desired by protect~ng th~ carbnnyl group of thç
Rl-(phenyl~-C0 moiety with a ~e~al group, for example khe
ethylene glycol ketal. The ketal axe prepared by reac~ion
of the carbonyl compound with an alcohol in the presence of
an acid catalyst under dehydrati~g condition~. The ketal group
can then be remov~d by hydrolysis at a later stage after
reduction of the amide ~u~tion.
Alternatively, when the carbonyl group is reduced to
the carbinol group, the c~rbinol6 can b~ reoxldized to the
ketones if aompound~ where ~C=X i3 a oaxbonyl group are desired.
Preferred oxidizing agents for ~chls purpose axe chromic acid
or nitric acid~perchloric acid, and i~ i9 preferred to carry
out the reaction in an in~rt or~ni¢ solven~, for example benzene
when chrom~c ~id i9 the oxida~t and 1,2-dlmethox~ethane whe~
nitric acid/perGhloric acid i8 the oxldant.
Anot~er methcd for preparing the compounds of ~ormula
I, where ~C=X i8 a carbony~l group and R2 19 hydroxy or lower-
alkoxy in the 4-po~itio~, comprlae~ acylat~ng a phenyl-low~r-
alkylamine of ~ormula VI with a benQo~c acid.halide of formula
VII, Rl-tphenyl)-C0-Hal, under Friedel-Cra~ts condition~ as
represented by the reac~ion:
, O
R3 ll R3
R ~ o}~l + ~ CN2 N=B ~ Rl-(phYnyl)~C ~ CH2-N=3
where Rl, R2, R3, N=B and Hal have the meanings given above. The
reaction i~ carried out by adding the amine of formula VI to a
stlrred mixture o~ ~he acid chloride and a suitable Lewis acid
which serves a9 a Frledel-Cra~ts catalyst, for example an
alumi~um halide or ~erric chloride. A preferred catalyst is an
aluminum h~lide.
10$3Z~
The compounds of formula ~ where the group ~ CzX
represents a carbonyl group can al80 be prepared hy reaction
of a 3-benzoylphenyl-lower~alkyl p-toluenesulfonate having the
formula VIII with an aminel H-N=B, in the presence of an acid-
5acceptor according ~o the ~eaction:
R O R
,. ,~ " ,3
~ ~_CHCH2OT~ qr~HCH2-N=~
1 ~ ~ ~ H-N~B ~ Rl
R2 R2
VIII
where Rl, R2, R3 and N~B have the meanings given above, and
Ts represents the p~toluenesulfo~yl group. The reaction is
preferably carried out bv heating the reactants in an l~ert
org~nic ~olvent, ~or e~ample dimethylformamide or a lowe~-
alkanol. Suitable a~id-acceptors are alkall metal carbonate3
or bicarbonates ~x an ~xce99 ~f t~e amlne, H-M~B.
The t~ylat~s o~ ~ormula VII~ are in turn prepared
by a sequence ~f react~ons inv~lving reduction, with an alkali
lS metal borohydride, of a 3-bromophenyl-lower-alkanaldehyde to
the corre~ponding 3-bromophenyl-lower-alkanol; reaction o~ the
latter with dihydropyran in the absence of solvent and in the
presence o~ a few drops of concentrated hydxochloric acid to
prepare the corresponding 3~bromophenyl-lower-alkane tetra-
hydropyranyl ether; r~action o~ the latter with butyl lithium
followed by an appropriate Rl-(phenyl)-nitrile and hydrolysis
of the tetxahydropy~nyl ether ~roup; and reaction o the
resulting 3-be~z~ylphenyl-lower-alkanol with p-toluenesulfonyl
chloride in ~he pr~ence of pyxidine. The method is represented
by the ollowing reacti.on sequenae:
lOS3;~51
Br~ CHCHO 3~C~ICH2011
Rl ~ ~ CHC OII Br ~ CHCE1
~ 1 ~ C ~ ~3C~20~B
: where Rl, R2 and R3 have the meanings given above and Ts rep- ~:
resents the p-toluenesulfonyl group.
The compounds of formula I where the group ,,C=X
represents ~C(R3)0H where R3 is hydrogen or lower-alkyl are pre- .. ~:
` pared by reacting a 3-halophenyl-lower-alkylamine of formula IX
; with a lower-aIkyl 1-ithium in an aprotic organic solvent, for example
diethyl ether, and reacting the resulting aryl lithium of Formula
IXa directly either with a Rl-(phenyl)-carboxaldehyde of Formula XX
(to prepare the compounds wherein R3 is hydrogen with ~ptional pro-
duction of compounds wherein ,,C=X is ,,C=O, as described below)
or Rl-(phenyl)-carbonitrile of foxmula XXI (to prepare the compounds ~:
. where ~ =X is `~C=O, the compounds wherein ~ C=X is ,,C(H)OH being
.4 prepared from the latter by reduction with an alkali metal aluminum
hydride as described aboYe, or with a Rl(phenyl) lower-alkyl
ketone of Formula XXII (to prepare the compounds where R3 is
lower-alkyl). During the course of the reaction of the
aryl lithium with an aldehyde, and for reasons
:
.. . .
_ g _
- lOS3Z5~
not completely understood, some of the çarbinol product (C~X
is CHOH) i~ oxidized to the kekone, an~ in such case~ it is
nece~cary to reduce the cxude pxoduct with an alkali metal
borohydride as desc~lbed he~einb~low.
~he 3-haloph~yl-lower alkyla~ine~ of formula IX
are in turn prepa~d by one of two method~ depending upon the
identity of the groUp N=B in the final product. The compounds
of formula ~X where N~B i~ a ~eoondary amino group ar~
prepared by r~ac~ion of the corre0pondin~ primary amine with a
3-halophenyl-lowar-alkanal of formula X, ~ollowed by reduction
of the resulting Schlf~ ba~e wi~h an alkali metal borohydride.
The compounds of ~ormul~ IX where N=B i~ a tertiary amino
. , .
group are prepared by reaç~lon o~ a 3~hal~phenyl-lower-alkanal
,. of formula X with a secondary ~mine, ~onversiQn of the result-
ing 3-halophenylvinylamine o~ f~rmula XI to the iminium salt
having the ~oxmula X~I by reaction o~ the former with mineral
~, acid, and redue~ of the iminiu~ ~al~ wi~h an alkali metal
borohydride~ The co~densa~icn o~ the aldehyde with the amine -
in the latter procedu;rç 1~ pre~exably carried out in a water
immi~ible solvent, ~r ~xampl~ benzene, toluene or xylene, at
the reflux temperatU$e ~hç~eo~ undex a water ~eparator which
is used tQ collect the water a~ it is produ~ed in the reaction.
1~ The redu~tion o~ the iminlum salt wlth an alkali metal boro-
-~ hydr$de i~ ca~ried out in an i~er~ organic solvent, for example
2S a ~ower-alkanol or dimeth~lformamide (D~F). The ~verall method
j i9 represen~d by ~he ~eactl~n se~uençe:
, ;~
-1~
'~''
,. . .
" ` 10~3~2S~
Na1 ~ CHCHO + H-N~B H~1 ~ CHCH2_N=B
R2 R2
X IX
(N~ is secondary amino)
I (C=X is C=0) ~ I (C=X is C(R3)0H, I (C=X is C(R3)0H,
~\ R3 is H) ~i1 R3 is alkyl)
0 IXa
~CN / ~CH0 /f~C-R3
/Rl~ /Rl~
XXI/ XX/ XXII
Li~ CB2~N=B Ha1 ~ CR3CH2_N~B
R2 R2 :'
IXa IX
(N=~ ls tertiary amino)
I`
Ha1 ~ -CH-N~ H~1 ~ CHCH-~ B X Q
1l " X~ XII
1: ~ ....
NsB
\ Hal , 3
; ~r~ CHCHO -
R2
,' X
~ -11- '-~ ~
.
.
lOS325~
where ~ , R2, R3, N~B a~d Hal have the meanings glven above,
and X ~ repregents an a~ion o a mineral acid.
The metho~s desc~ibed above are u~ed to prepare the
compounds o~ formula I wh~re ~c~x 18 either a carbonyl group,
S ~ c=O, or a csrbinol gr~up, ~`C(R3~0H, where R3 i9 ~ither
hydrogen or l~wer~alkyl. Th~ comp~u~ds of ~ormula I where the
group ~ =x h~s th~ ~th~r meanings given axe prepared by simple
chemical transf~rmations inv~lvin~ ~he carbonyl or carbinol
groups~ Thu3 th~ c~mpounds whexe the group \C=x represents
~ (R3)H, where R3 is ei~her hy~rog~n or lower-alkyl, are
. pr~p~red by ~ataly~i~ reduc~on wi~h hydrogen o~ the correspond-
ing carbinol, ~c(~)o~, ln t~e pxe~ene~ of perchloric acid. A
: pre~erred aataly~t la palladium~o~-~ha~al, and it is preferred
~o car~y oU~ ~h~ ~0a~t~n 1~ ~lacial a~ acid as 501ve~t.
~ 15 Reducti~n ~s carr~d ou~ at a px~9~ure ~n the range ~rom
''
_ 40-loe p.~.i.
Tho compo~n~ ~$ ~o~mula ~ whero ~`C~x is the group
~CH2 are pre~a~ed b~ dehydr ti~ o~ the methyl c.arbinols,
whexe _ C~X i3 tbe ~roup ~C~ , with concentrated sulfuric
acid. The r~a~ti~n ~ car~ied out by r~fluxing a solution of
the ~arbinol ~n~ ~ulfuri~ ~cid in a lower-alkanol solvent.
The compoun~ of formula I where ~ c~x is the group
C~NO~ are prepared ~rom ~he c~rre~ponding ketones ( ~ c~x
is \ C~O~ by heating the latt~r wi~h hy~roxylamine in an inert
. ~S organic ~olv~nt, ~or example a lower-alkanol.
.,l The ~om~ounds ~f for~la I where ~c=x is the group
s~ CHNH~ are pr~ar~d by ~ed~ln~ thq corre~ponding oximes ( \ C=x
~): is ~ C-NO~) wi~h sodlum in a lower-a~kan~l. ~he compounds of
-, formula I wher~ C~X i9 _ C~OH, ~part from their usefulness
;, 30 a~ pharmaceutlcally a~tive c~mpound~ as described below, are
-12-
- . . -.:: -. . . ~ , .
.
iOS3;~
thus al80 useful a~ intermediate~ for preparation of the
compounds wher~ " C X is ~ CHN~2.
The compound~ of formula I in which~'C-X repre~ents
CHN(CH3)2 are prepared from the corresponding primary amines
S by treatmen~ of the latter with formaldehyde in the presence
of formic acid.
The comp~unds of ~ormula Ia where ~5X represents
~ ~ C=O are prepared by reaction of a 3-(phenyl-CO)-phenyl-CHR3
: halide of formula XI~I with morpholine according to the reaction:
~- . O
" R
CH-Hal ~
H~N ~ --~ ~ Ia
XII~
,
where R3 and Hal have the meaning~ giYen above. The reaction
is carried out by reacting a solutlon of the halide with a
molar excess o~ mor~holine at ambient temperature in an inert
~rganic solv~nt, for example methanol, ethanol, isopropanol ox
DMF. A p~efer~ed solvent is ~MF.
The ~mpou~ds of ~ormula Ia where the ~roup ~CeX
repxesents ~CHN~2 are prepared from the corresponding compound~
where ~,CzX repre~ents ~ C~O hy converq~on of the latter to the
oxim~ ~nd reduction o~-the latt~r to the amine as described
abov~,
The ~min-3 o~ formula IV where -N-B is the ~roup:
.
,~ ~
``` iO53ZS~
R3 3 '3
. , / CH-R4 , R4
-NH - C - R5 , -N C R5 , ~N or -NHC~(CH2)nN
CH-R4 R3 R4
R4 CH R4
~3
c6}~5
are known compounds,
The am~e~ ln whl~ the group:
R
l3 7
-N
-~ \~(~ '~
R6
where n i8 2 are also known, having been generally described in
UOS. Patent 3,238,215. A~ described therein, they are prepared
~ by catalytic reduetion over pl~tinum ~xidç of appropriate R3,
i R6 or R7-substltu~ed pyridin~s, which are commercially available.
The amlnes wher~ N~B i8 the group:
..
R3 ~7
J
-N
H2)n
, .
R6
where n i~ tho lnt~ger 1 3nd R7 is hyd~ogen a~e prepared by
i
refluxing a mixture of a~ approp~iate alkanedione, ammonium
acetat~ an~ ~laclal acetic ~cld, ana ~atalytlc reduction over
~ -14~
;: ; 1
10~3ZSl
platinum oxido of t~e xesu~tlng 2~R3-5~R6~py~role accordlng ~o
the xeaction ~oque~
~ H~OA~ ~
6 3 -- ~ R6 H R3
~/
~ ~ N~R3
where R3 ~na P~5 h~a ~anin~ gi~en ~b:ove.
~}ternA~, tb~ s ln which ~.N~ the g~oup:
. ~7
~, ~N
.- -
., ~tc~2)n
' 6
where ~ 19 1 4nd ~?,7 ie ~d~q~an aX~ ~epare~ by reaG~ion of
:~ a G~na~d r~ n~, R6M~ lth a 4~3-4-halobutyr~nitr~ le,
... lq R3-cH-tH~ cH2)2~ eck c~pll~ation of th~ re~u~ting
l-amlno-l-R~4~3-4-hal~bute~e; and catalytic reduction of the
re~ultin~ 2-R~ R3-4/~-dih~dr~pyrrole as indicated by t~e
~, reac~ion ~equen~e:
~, .
.
-15-
3;~
~1
R /~Hal ~ R5MgHal - - ~ / H2N~\
3 3 ~ lal R6
k/~ n
3 , 6 R3 ' R6
H
where R3, R6 and Hal have the mean~n~ given above.
The a~ s ~h~e ~B i~ the gr~up:
. '
~ S ~
a,re a~van,tag~u~ p~e~x~d, like ~he a~;nin~s where -N=B is
th~ sro~
R3 1 7
-N~T
\~(CH2) n
:
, . whe~e n is 2, l~y catal~ xeductlon o-ter platinum oxide o~
13 ~he ~ors~spo~ding ~R6-pyx$dlne ~
he a~lss whexe ~N~ th~ group:
.~ .
~7
-N ~ 2 ) n
:: R
. 6
- -16- ~ -
.", . - ~ - . .
~ ` lOS3;~Sl
where R3 and R7 are hydrogen, n is the intager 3, and R6 has
the meanings given above are prepared by Beckmann rearrangement
of an appropriate R6-substituted-cyclohexanone oxime and reduc-
tion, with lithium aluminum hydride, of the resulting lactam
5according to the reac~ion:
~IION FC~
6 ~ H
~'' ' k~/
,G~
.~ R6
The amines of formula VI where -N=B is the group:
, R3
: i /+\
~ -N Z
.,, \~+/
R6
where Z is O are prepared according to the method described in
Bxitish Patent B35,717 which comprises passing a vaporized
mixkure o~ a glycol ether having the formula
~, O
: 6 t ~ R3
OH OH
,
~ -17-
--' iOS3ZSl
together with ammonia and hyd$ogen over a hydrogenation/
dehydrogenation catalyst baced on either nickel or cobalt at
a temperature from 150 to 25SC. A preferred catalyst i8
nickel on kieselguhr.
The amines of formula IV in which -N~B i~ the group:
R3
-2~ Z
~6
where Z is S are preferably prepared by the meth~ds described
; by Id~on et al~, J. Am. Chem. Soc. 76, 2902 (1954) which
lnvol~es ~ither the reaction of sodlum sulfide with an appro-
pria~e bi~.2-haloethylamine:
.~1 .
:' R3
:. ~-N Hal
.'" ~
~ ~ R6
-~!
~ or the reac~ion af ammonla with an appropriate bi~-2-haloethyl
::`
~ ul~i~e:
" , ~
-S Hal
~ Hal
I i n
1 ~ - 6
1~ ~
where R3 ~nd R6 have the meanings given above, and Hal repre-
ents halogqn.
~.
-18-,
-
~ .
:, , ::~; .: : , . .: .
lOS3;~
The 3-~Rl-(phenyl)-CO]-phenyl-lower-alkanoic acids
of formula II where R~ ls hydroge~ or lower-alkyl are generally
known c~mpo~nds prepar~d by the methods described in British
Paten~ 1~164,585. Although ~he ~ompound~ of formula II where
~2 i~ hydroxy c~n 21so be pre~ar~d by the methods used to pre-
pare t~e compaunds wher~ R2 i~ hydrogen or lower-alkyl and the
compounds of ~ormula II $0 prepared converted, aY described
above, to the fin~l products o~ ~ormula I, lt is preferred to
prepare ~he c~mpo~nds ~f f~rmula I where R2 i~ hydroxy from a
4-lower-alkoxy-ph~nyl-lower-alkanoic acid by conversion of the
latter ~o the ao~esponding açid halide; conversion of the
latter to th~ ~r~esponding 4-lo~er-alkoxyphenyl-lower alkanoyl-
amine by reaction of ~e acid halide with an amine, H-N=B, and
reduotlo~ ~f tho rq~ult~g amide with a reagent effective to
reduce amides to amlne0, for example an alkali metal alumlnum
; hydri~e; react~ f the resulting amine with an acid halide,
:~ R~ h~nyl~carHal~ uslng Friedel-Crafts conditions; and
flnally cleavage o~ the lower-alkoxy group to the hydroxy group,
u3ing well-known met~od~ such as h~ating with hydrobromic acid.
Tbe m-thod i9 repreaonted by the ~ollowing reaction sequence:
.
--19--
,- - , ,. , . . . ~ : ;, ,
. . .
S325i
R4 " ' ''~ ~C!!CO-IIal
N=13
Rç~
' ~
~ R~ ~C~12-N~
-. whero R~ , R4, Uw~3 a~d ~al ~ th~ me~slngs g~ven above.
~k6 ~ac~ c~ tl~n~ Ur x~ac~lons in this
re~c~lo~a 9eqU~ haY~ q~ d~ l a~?v~, a~d aleava~e ~f the
~ther wlth hy~obr~mlc ~eid 1~ ~ c~v~ nal re~tion w~ll
kno~ to the ~rg~ c chR~l~t~
The ~h~ h~yl~ lk~n~ls o~ ~ormula x ~re
pre~a~ o D~z~ l,y~ e~ ~ndens~ti~n by ~eaction
., .
a 3,h~1a~1qw~ w~x~alkyl haloac~atatei
in ~he pxe~en~e ~ n ~lk~ e~ lk~xid~ ~nd ~aponlication
and daa~rboxyla~on of th~ ~e~ultlx~ dic e~ter. Thç ~nethod
.~ i5 rop~e~t~d ~y the ~ w~ng ~Ra~tiot~ ~eque~nce~
'
~ 20 ~
l~S3Z~
Hal~f CC~-R3 ~ Hal~C13COO-Alkyl
~ ~ Ral-CH~CO~Alkyl ~ ~0/
2 2
R3
Ha ~ CHCHO
R2
The nQvel c~mpo~ds ~f ~he instant invention are the
compound~ o~ f~m~las I and I~ a~d the acid-addition salts
S ther~of. T~ com~ou~ds of f~rmulaq I and Ia ln free base form
are convert~d ~ th~ a~ dditi~n salt form by interaction of
the base with an a~id. In like manner, the free base can be
regenera~e~ ~Qm the acld-additi~n ~alt form ln the conventional
~anner, ~ha~ i~ by tx~at~ng t~ s~lts with cold, weak aqueous
~0 ba3e~, ~4x e~ alkali ~etal ~ar~nates and alkali metal
bicarbonat~s F ~h~ ba~es t~us regenerated can then be interacted
with the ~u~Q or a d~exent ~cid ~o give back the same or a
diffe~t acid-addition salt~ Thu~ ~he novel base~ and all of
th~ir acid~ad~ltion ~a~t~ axe x~adily interconvertible.
lt wlll ~h~s ~e ~p~ec~a~ed tha~ formulas I and Ia not
o~ly ~eprese~t t~e ~tru¢~ural ~nfiguration of the bases of
formul~s I and Ia ~ut a~e ~19~ rqpr~s~nta~ive qf the structural
e~itie~ w~iah ~ mmon ~ f ~he compounds ~f formulas I
~nd Ia, whe~hor ln the ~m o~ the free ba~e ~r in the form of
~0 ~he acid-a~diti~n ~alt~ of th~ base, It has been found that by
virtu~ of the~e c~mm~n ~tx~ctural entities, the bases and their
. ,, . ., : - .. . . .. .. .
- lOS3;~Sl
acid-addition sal~s have inh~r~t p~armacological activity of a
type to be more ~ully d~c~ib~d ~ein~elow~ This inherent
phar~acol~gical a~t~ y ~an b~ ~joy~d in useful form ~or
ph~rm~CeU~iCal pUrp59~S ~y em~ yiny the free bases the~selves
S or the acid-addi~io~ ~lt$ ~rmed ~xom ~harmaceutically-acceptable
acids, that i9 acids who~e ~ion~ are lnnocuous ~o the animal
organism in ~f~ective do~e.s o$ ~h~ $~1t~ so t~at beneficial
proper~ies inher~n~ in t~ cv~mon stru~tural entity represented
by th~ free ba3es is nq~ ~itiate~ by side ef.~cts ascribable to
the anlons.
In utilizin~ ~hl~ pharmacological actlvity of the
~al~s o~ th~ inventi~n, it is pxe~exre~, o~ c~urse, to use
pharmaceutic~lly a~eptable 9zl~s ~ Although water-in~olubility,
high toxicity, ox lack of crystalline c~aracter may make some
particular 8alt $pecies un~uitable qr less desirable for use as
such in a given phaFm~ceutic~l application, the water-insoluble
- or t~xi~ ~alt~ can be ~onve~e~ ~o ~he corresponding pharmaceuti-
cally-acaeptabl~ h~e~ by ~ec~mp~ Qf the sal~ with aqueous
ba3~ as e~plai~ed a~v~, ~r altexnatiyely they can bç oonverted
2C to any deslred ph~rmaceuti~ally-a~c~able acid-addition salt
by ~ouble dqco~poFitio~ rea~tiv~s in~lving the anion, f or
exam~le by ion-ex~hange p~o~u~e~.
MoF~ove~ ~part f~om ~h~ir usefulness in pharmaceutical
Rpplications, th~ 3alts are useful as characteri2ing or identi-
~ing de~ivative~ o~ the ~ree ba~es or in isolation or purifica-
ti~n proced~re~. ~ike a~l of the a~id-addition salts, such
chaxacterizing or puri~i~atio~ Ralt derivativesy an, lf desired,
be use~ ~o regener~te th~ pharma~Rutlcally-acceptable free bases
by reaction ~f the qalts with a~ue~us base, or alternatively
-22-
10S3ZS~
can be converted to a pharmaceutically-acceptable acid-addi~ion
salt by, for example, ion-oxchang~ prQcedure~.
It will be appxeciat~d ~om the ~oregoing that all
of the acid-addi~ion ~al~3 ~ ~ha new base~ are useful and
~aluable compounds, regaxdless o~ ca~iderations o~ solubility,
~o~icity, physical ~orm an~ th~ like, and are accordlngly within
the purview of the in~tan~ in~sntion.
The novel f~a~u~ o~ tho ~mp~unds of the lnvention,
th~n, resides in the ~ ep~ he b~es ~nd ca~ionic forms
o~ the new N- {3-[Rl~tph2ny~ Qx~l-phenyl;lowe~-Alky~ amines
. a~d not in any partipular ~Cid moiety ~r acid anion associat~d
wi~h the salt f~3rms o~ t~e comp~nd,~ r~ther, the ~ci~ moietie
or aniona which ~a~ b~ a~3c~ç:iated wi~h ~e salt ~orm~ are in
th~mselve~ nel~her novel n~X c~ l an~ th~rQ~o~e can be any
acid anion or acid-lika ~ubsta~ce capable o~ ~alt formation with
the bases . In façt ~ in a~uaous ~olutl~ , the ba~e form or
water-soluble acid-ad~ o~ ~al~ ~orm of the compounds of the
in~ntion both po~ s a ~mmo~ px~ ate~ ~ation ox ammonium
ion.
Thu3 appr~pFiato aoiq ~ditio~ ~alts are those derived
: from 3uch diverse a~ids as ~ormlc a~id, acetic aci~ obut~ic
aaid, alpha-mercaptopropioni~ acid~ malic acid, fumaric acid,
succinic acid, 8u~cinami~ aci~, tartaric acid, citric aoid,
lactic acid, benz~ic acid, 4 methoxybenz~ic acid, phthaliç acid,
~S anthranilic aoid, l-naphthalo~carboxylic acid, clnnamic acid,
cyclohexanecarboxylio a~1~, man~elic acid, tropic acid, cro~onic
: acid, acetylenedicarboxylic acid, sorbic acid, 2-furancarboxylic
acid, cholic acid, pyrenecarboxylic acid, 2-pyrldinecarboxylic
acid, 3-indoleaaet~ aci~ inic ac.id, ~ulfamlc aoid, methane-
~ulfonic acid, isethionic acid, b~nzenesul~onic acid, p-toluene-
2 3 r
' : " , : ,
- ~053;~Sl
sulfonic acid, benzen~ul~i~iç acld, blltylar~onic aci.d, dlethYl-
phosphonic acid, p-ami~h~ylax~i~ic ac~, phenyl~tibnic acid,
phenylphosphinous a~id, ~ethylpho~phinis ~cid, phenylphosphini.c
acid, hydrofluoric acld, hy~rochlorl~ a~d, hydrobxomic acid,
hydriodic acid, p~rc~loxi~ acid, .nit~ic ~çid, sulfuria acid,
phosphoric acid, hydr~c~nlo acid, phos~tungstic acid, molybdic
acid, phosphvmolybdic acid~ py~ph~phoric acid, arsenic acid,
picric acid, picrolonic aaid ~ b~xbi~u~ic aci~, bor~n trifluoride,
and the like.
The acid-addition salts are prepared by reacting the
free base and acid i~ an organic ~1Yent ~nd isolating the salt
directly or by cancentr~tlon o~ the ~o~utiQn.
Due t~ the prose~ o~ ~t l~ast on~ and as many as
f~ur asymmetric ce~ters in the comp~nd~ ~ ths invention, i.e.
the carbon atom adjacent the phenyl ring to which the group
is attached and the various 4symmetric centers in the group
-N~B to which the groups R~, R~, R5, R6 and R7 are a~tached, the
compounds of ~he inven~io~ ~n exlst ln ~tereoc~emlcally
isomeric form~ whi~h ar~ all co~sid~x~d to be within the pu~view
of the inv~ntion~ If d~sir~d, the i801atio~ or the production
of a particular stereoch2miaal ~orm can be aca~mplished by appli-
cation of gener~l principles k~own in ~he ark.
In standard pha~macolo~laal t~st pr~cedure , the
compounds of formulas I and Ia have beqn ~und to possess anti-
2S infl~mmat~ry activity and ar~ usef~1 as anti-inflammatory ayents.
Certain ~ompound~ o~ ~ormula I have also been found to have
anti-viral activity an~ a~ thus als~ u~e~ul as an~i-viral agents.
Anti-inflammatory activ~ty w~ d~termined using ~1) the inhibi-
tion of carrageen~n ind~uced ~oot edema te~t essentially descrt~ed
3~ by Van Arman et al., ~. Pharmacol. Exptl. Therap. 150, 328
~ 2~ ~
~ ' ' .: , ' ,
1053Z51
(1965) as modified by Wlnter e~ al., Proc. Soc. Exp.
Biol. and Med. 111, 544 (1962) and (2) a modiflcation ~f the
inhibition of ad~uvant-induc~d ~rthri~i~ test ~escribed by
Pierson, J. Chronic Di~eases 16~ 863 ~1963) and Glenn et al.,
S Am. J. Vet. Res. 26, 1180 (1965).
~he ln vltro antl-vir~1 a~tlvi~y o~ the compounds
: against herpeQ simplex viruses type~ 1 and ~ wa~ demonstrated
by the addition o~ ~he comRounds to ~i5R~e cultures lnfected
with herpes virus. Monolaye$s o~ tiq~ue cul~ures (~SC, cell
line, monksy kidney) we~e i~ected w~h one hundred TC~D50
(Tissue Cul~ure Tn~e~tiQu~ ~oseS0) o~ infe~tiouQ virus, After
one hour of v~ru3 ad~osption~ f~h main~e~a4ce mediu~ containing
v~rious concentra~ion~ o~ ~h~ te~t compound was added to the
monolayexq.. Culture~ we~e ~hen incu~ated at 36-37C., and after
1~ forty-eight and ~event~-two houxs, cultures were examined micro-
scopically. In t~e in~ected ~ontr~l tubes a~ well as in tho~e
~ntdining inactive compound~, viral ~rowth is indl~a~ed by ~he
production o~ char~cte~istic cy~pathi~ effect~ with the
des~ruction o~ the cells. I~ the pr~sence o$ an active ~ompound,
~ cell_ grow norm~lly ~im~la~ ~ tho~e in the tlssue culture
: control. Simultane~u~ly wi~h ~he ant~-~lr~l ev~luation, the
toxicity of each compound. wa3 evalua~ed in separate cultures.
~: Identical concentrations of the test c~mp~und were added to the
tis~ue culture monolayers in ~he ab~ence o~ viruR. Tho~e con-
~ as centration~ of ~he compound wh~ch show toxi~ effects on the cells
:,~ were not con~idered in the an~i-viral ~v~luation. The activity
~:~ of the compounds wa~ expres~ed in terms o~ the Minimal Inhibitory
Concentration ~NIC)~ where the MIC i~ descrlbed a~ the lowest
:~ con~entration of the t~,t compound whlch aompletely inhlbi~s the growth of th~ virus.
. O 25 -
1053ZSl
The compounds of ~he i~en~i~n can be prepared for u~e
by incorporating them in unit do~age fo~m a~ tablets or cap ule~
for oral administratio~ ei~he~ alone or in combination with
suitable adjuvant~ such as c41cium ~xbonate, starch, laqtose,
talc, magnesium steaxa~, gUm ae~cia, a~d the like. S~ill
~ur~her, the c~mpou~s c~n be ~ormula~ed ~or ~ral administration
in aqu~ous alcohol, gly~ol or oll solu~ions o~ wA~sr emulsions
in the same mann~r a~ conve~tionAl ~ed~cin~l substanc~s are
pxepared.
The mole~ulax ~U~u~e~ ~f t~ compound~ of the
. i~venti~n we~a a~lgn~d o~ ~h~ o~ ~tudy cf their i~rared,
.
- ultraviolet, a~d NM~ spectra~ a~d con~irm~d by ~he c~rr~spondence
between calculatod and ~und ~alue$ ~r elementary analyses ~or
the elements.
The following example:~ w.ill further illustrate the
lnven~ion without, howeve~, limtting it thereto. ~11 meltin~
points are uncorrected.
PreDaratlon of Amine I~termediates
Pra~arati~n I
~0 In three separate run~ 33.8 g. (0,20 mole) portions
of 2-benzylpyridine, each in a solution of about 225 ml. o~
ethanol and 22 ml. of concentrated hydxochloric acid, were
reduced over 4.0 gO portions of platinum ox~d~ catalyst under
about 54 p. 8 .i. of hydrogen at a temperatu~e of about 55-61C.
When reduction was complé~e i~ each case, the cataly~t was
removed by filtratio~, washed ~th ~mall ~or~ions of ethanol,
and the combined ~iltra~es ~v~porat~d to a volume of about 80 ml.
.~ and diluted to appr~ximately 5~0 ml. wi~h ~iling ace~one. The
~- ~olid which p~cipi~ated wa3 collected, w~shed with acetone and
dried givin~ a combinod yield o~ 124.~ 2 cyclohexylmethyl-
- 26 ~
.
~OS3;~Sl
piperidine hydrochloride, m.p. 211~213CC. The ~ree base was
regenerated ~rom the hydro~hlo~ide by neutrallzatlon ~f ~n
aqueous solution of the latter with pota~ium carbonate, ext~ac-
tion o~ the oily ba~e in~o benzene, evapoXation of the benzene
solution to dryne~, and di~t~ tion o~ the residual oil
in vacuo at 55-59C./0.27 m~. There wa~ thus obtaine~ 89.4 g.
of 2~cyclohexylmethylpiper~din~.
mixture of 1S.52 ~. (0~10 mole) o~ 2-phenylpy~idine,
~ 15 ml. of c~ncen~ra~ed ~yd~oahlorl~ a~ nd 2.0 g. of platinum
oxide in 185 ml. o~ e~han~l in a ~r~s~r~ bottle was haated and
~h~kon in 8 Parr hydr~enator unde~ 5S p.~.i. of hyd.rogen at a
`~ temperatu~e aXQU~ 60C. Whe~ r~duo~lo~ Wa~ complete in about
aigh~ hours, th~ ca~aly~ w~ r~moved ~y ~iltra~ion and ~he
lS filtrate cun¢en~a~e~ ~o a~oU~ S0 ~ nd diluted ~lth 200 ml.
of ace~one. The ~olld which s~parated wa~ collected and dried
to glve 14,54 g. o~ 2-cy~lahexylpiperldi~e hydrochlorlde,
m.p. 2S1~253C.
Pre,~a~a~io~n 3
~a A mixture o~ 9~1 g. ~O~Q$ ~ole) o~ 2-~tilbazole
(Shaw çt al., J. ~h~m. Soc. 19~3, 77-73~ and 1.0 g. o~ plati~um
oxid~ in a ~olution o~ 244 ml. o~ ~thanol and 10 ml. o~ concen~
trat~d hydrochloric acid in a pres~ure b~ttle wa~ heated and
shaken on a Parr hydrogenatqr under about 5~ p.s.i. of hydrog~n
~S at a temperature o~ abou~ 60C. When ~eduction was complete
in about eight hour~, the catal~st was removed by filtration,
the fil~rate ~on~en~r~t~d to a volume of abou~ S0 ml. and d~luted
wi~h about 200 ml. o~ ace~one. The ~olid which separated wa
collected ~nd dried ~o glve 9.6 ~. ~f 2-(2-cy~lohèxylethyl)-
piperidine hydrochlorlde, m.p~ 155 156C~
:
. .
lOS3ZSl
~E~
A solution of 78.1 g. (0.84 mole) of 4-methylpyridine
and 89.0 g. (0.84 mole) of benzaldehyde in 103 g. of acetic
anhydride was heated with Etirring under reflux for twenty-foux
hour~. The mixture wag ~hen conoentrated to a thick oil ln vacuo
and the re~idue diss~lved ln ho~ ethanol. The solid which
separated was coll~cted and rec~ystallized from ethanol to give
57.9 g. of 4-styrylpyridine, m.p. 131,5-133C.
The latter (36.2 g., 5.2 mole), dissclved in 220 ml.
o absolute ~thanol and 30 ml. of cQn~entrated hydrochlorlc
aoid, was reduced ~ver 3.Q g, of pla~inum oxide un~er a hydrogen
pre~sure of ab~ut 55 p.s.i. ~he px~duc~ was worked up in the
manner de3~cxibed above in Prçpa~tlc~n 1 an~ isolated ~ the
form of the hydro~hloxid~ salt to giVe 43.5 g. of 4-(2-cyclo-
15hexyletllyl) plperidine hy~roahlGride, m.p. 246-248nC .
4-Phenylpyrid~ne (lS.5 g., q.l mole) dissolved ln
185 ml. o~ ab301ute ethanoi and 15 ml~ of concentrated hydro-
~hloric acid wa~ reduced wi~h hyd~ogen over 2 g. of platinum
oxide under a hydrogen pxe3sure of about 55 p.s.i. The product
wa~ worked up in tho manner described a~ove in Prepara~ion 1 and
isolated ln the ~orm of the hydrochloride ~alt to give 15.3 g.
of 4-cyclohexylpip~ridine hydrochloride. iThe free baqe gives
m.p. 106-109C.)
. Preparation 6
To a mlxture of 8.6 g. (0.36 mole) of magnesium
tu~nings in 150 ml. o~ dry ether wa~ added in ~mall portions
with co~ling and stlrring a ~olu~ion o~ 4S.0 g. (0.36 mole) of
: ~n~yl chloride in 75 ml. o~ anhydrou~ e~her. When addition
:30 was complete, the mixtu~e wa~ stirred for about one hour an~
,~ .
- 2~- _
. ~ .. . , , ~ ~
,, ~ .
~OS3;~51
then treated dropwi~e with a Yolution of 26.6 g. o~ 4-chloro-
butyronitrile in 95 ml. of e~h~x. When additio~ wa~ complete,
tho ether was gradually dlstlllçd off whlle xeplacing with an
equal volu~e of toluene. The mixtux~ w~s heated under reflux
S (at about 109C.) fQr ab~ut thirty minut~s, cool~d to about
15C., treated dropwise with ~00 ml. of 10% aqueou ammonium
chloride, filtered and the organio layer separat~d. The latter
: was washed with three 100 ml, portion~ of dilute hydrochloric
~cid, and the combined ~cid extxaot~ were ba~ified with solid
pota~3ium caxbonate, Extraction of the mixture with ether and
remGval of the solvent ~rom the ~ombined organic extract~
afforded an oil whi~h wa3 distilled in vacuo to give i3.05 g.
~f 2-benzyl-4,5-dlhyd~p~rrol~, b.p. la~-125C./13 mm., nD~5
1.s4~5,
lS The latte~, dl~ol~ed ln 210 ml. of ethanol and 15 ml.
o~ ~oncentrate~ hydrochloric a¢id w~ reduc~d with hydrogen over
2 g. of plati~u~ ~xide undor a hydrogen pre~sure of about
S0 p.~,l. The mixtuFe wa~ w~k~ up in the m n~er de~cribed
, a~ove ln Propax~ n 1 and th~ ~roduct i~olated in th~ ~orm o~
.;
. ~Q ~h~ hy~rochlori~ ~alt to ~1Y~ 16~ f 2-cyclohexylm~thyl-
' pyr~olidine h~drochlorido, m.p. 130.S-131.5C. ~rom acetono).
- ~o ~ p~ n ~ 11.2 g. ~1,6 molei of llthium wir~
.
ln 600 ml. o~ anhydrou~ ~h~r w~i 4dded dropwlsa 125.6 g.
tO.~ mole) o~ kromoben2~ne. Whe~ additlon was oomp}Rte, the
mixture wa~ s~irred for about a hal~ hour and then tre~ted
dropw~e first with a solution of 74.4 g. (0.8 msle) of plcolina
in 100 ml. of anhydrou3 athex and then, after ~tirrlng for ~ift~en
:~ minutqs, wlth a solution o~ 74.0 g. (0.4 mole) of 2-phenylethyl
;~ '
- 29 ~
... .. .
. '. ' ~ -' ".' ' . '-' ' ~
;- . : , - .. :
S3ZSl
bromide in 100 ml. o~ e~hex. Thb mix~uxe wa~ ~tirred at
ambient temperature for about ~wel~ hour~ and then poured with
stirxing onto 300 g. of i~e. Wh~n all eX~QS~ hium had ~e~te~,
the layers were ~epara~ed, ~he ~ueou$ l~yer washed with ~d~l-
tional ether, and the o~mbined ~ganiç portionY were ~ashed withb~ine, dried and tak~n to d~yn~s~ to gi~ a re~idual oil ~hi~h
was distilled ln vacuo to gi~e ~1.3 g~ ~f 2~(3~rphenylpropyl)-
pyridine, b.p. 76-78~ .05 mm., nD25 1.~592.
The lat~e~ ~19.7 g~ 0.1 mole) di~olved in 235 ~1.
of ethanol and 15 ml. of con¢~txat~d hydrochloric acid was
x~duced with hydrogen oveX 2 g. o~ platinum oxide under a
hy~rogen pre~suxe o~ aroun~ ~5 ~ at about 65C. The p~od~t
was worked up in th~ man~er de~c~ibed above in ~reparatlon 1
and isolated i~ th~ f~rm o~ t~e hydxochloxide salt to giVR
~2.2 g. of 2-(3-cycloh~xylpx~p~l)piperidine hydrochloride,
m.p. 175-176.SC. (~rom o~yl ace~a e).
P~eParati~n 8
Catalytia r~duc~lon of 3-benzylpyxldine ln glacial
AC~tlC acid ~er a platinum oxide catalyst a~d i~olation o~ ~he
pxoduct u3ing the proceduxe d~scribed above in Preparation 1
af~ord~ 3-benzylpiperidi~e.
~=
~}~
A -~olution o~ 25.4 g. (0,1 mol~) ofdC-(3-benz~yl-
2~ phenyl)~propionic acid in ~0 ml~ ~f ~Qnz~ne wa~ added to 19.8 ~.(0.166 mole~ of ~hionyl ~hl~ride and ~he solution Fefluxed ~o~
t~o and a hal~ h~u~ he ~olve~ was the~ removed in ~acuo,
and ~he resulting oil t2~ g. ~ ~on~iQ~ing of 0c- (3~benzoyl~ez~
pxopionyl chloride wa~ d~ ssolved in 40 ml. of diethyl ether and
30 added with stirring over ;1 ~hirty minute p~riod to a -~olutio~
- 30 -
.
lOS3~Sl
of 2-cyclohexylmethylpiper~dlne in ~0 ml. o~ diethyl ~ther.
The mixture was ~tlrrad ~or about fo~ty-eight hours ~t ambl~nt
temperature, th~n filte~ed, the filt~r washed wi~h ether, And
th~ combined filtra~e wash~d ~n~e with dllute acld, on~ with
brlne, once with a~ueQ~ pota~sium bl~arbon~te and ovaporate~
to dryness to give 4~.2 g~ o~ 2-cyclQhexylmethyl~ C-t3-
benzoylphenyl)propi~nyl~pip~ri~ine.
The latter t35~5 g~, o . oas male) wa~ di~ol~ed in
20Q ml. OI diethyl e~her and ~he s~luti~n added dropwi~ wlth
10 stirring to a mixtu~e of ~.08 ~ .21 mol~) of lithium ~lumi~um
hydride in 200 ml. of e~er while maintaining the tempe~a~ur~ at
10-15-C. The reactl~n mixturQ wa~ ~ir~ed at amb1ent t~mperature
for three and one hal~ hours, do~omposed b~ the dropwi~ addition
of 8.1 ml. o~ w t~, fQll~wed ~y ~ f 15~ 30dlum hy~xoxidç
and an addit~onal 22.2 ml. of wAteX, The mixture wa~ then
~tirred ~or one h~u~, ~ilker~d, and t~e ~iltrate evaporat~d ~o
d~yness to gi~re 34.0 gr ~ an ~i~" 10~5 g. o~ wh~ch ~ra~ chxomato-
- gx~phed ~ver 2ûQ ~. Q~ alu~ a ~nd elu~qd with ~ ~olu~ion of
60% h~x~ne/40~ ~ther. ~ha ea~l~ f~ac~io~ wer~ removed ~JId
20 ~vaporated to dryne~3 to ~lve 8 ~ g. o~ a~
a~ a viscous
~il.
Anal CalcdO ~o~ C2~H39N~: C,82~91; H,g.69; N,3.45.
Foun~: C,83.12; H,9.80s N,3.49,
Following a pr~e~ur~ 3imilar to that de~cribe~ ln
Example 1, the ~ollowing compo~nd~ of ~ormula I were simil~riy
:: prepared:
: ~ 31 ~
lOS3251
Exam~le lA
ethyl~ ~ie~ridine, m.p. 122-124C. (5,8 g. from benzene/hexane)
prepared by reaation o 42 g. (0.16 mole) of 3-benzoylphenyl-
acetyl chloride (German Patent Appln. 2,243,444, published
S Mar. 8, 1944) with 31~7 g. (0.175 mole) of 2-cyclohexylmethyl-
piperidine in 150 ml~ of ether in the presence of 19.4 g. (0.192
mole) of triethylamine and reduction of ~he resulting 2-cyclo-
hexylmethyl~ (3-benzoylphenyl)acetyl]piperidine (46 g.) with
13 g. (0.35 mole) of lithium aluminum hydride in 325 ml. of
ether.
Anal. Calcd. ~or C2~H37N0: C,82.81; H,9.52; N,3.58.
Found: C,83.01; X,9054; N,3.52.
~ 2 6-D~meth 1~ 2-~3-(oC-hydroxYbenzyl)phenyl]eth
E~E~ridine, m.p, 115-117C. (9.53 g. from be~zene/hexane~ pre-
pared by reaction of 42 g. (0.16 mole) of 3-benzoylphenyl-
acetyl chloride ~ith 19.8 g. ~0.175 mole) of 2,6-dimethylpiperi-
dine in 15~ ml. o4 ether in ~he presence of 19.4 g. (0.092 mole)
of triethy~amine and reduction of the resulting 2,6-dimethyl-1-
[(3-benzoylphenyl)acetyl]piperidine (49 g.) with 13.9 g.
~0.365 mole) ~ lithium aluminu~ hydride ~n 300 ml. of ether.
; -
Anal. Calcd. ~or C~aH29N0: C,81.69; H,9.04; N,4.33.
Found: C,81.83; H,9.04; N,4.32.
Exam~le lC 4-[2-(3-Benæo~il ~ ethyl~morpholine hydrochloride
monohydrate, m.p. 177.5-180C. (29.0 g. from acetone) prepared
by reaction of 46.5 g. (0~18 mole) of 3-benzoylphenylacetyl
chloride with 17.2 g. tO.198 mole) of morpholine in 225 ml. o~
methylene dichloride ~n the presence of 21.5 g. (0.211 mole) of
-~ trlethylamine; conver~ion of the resulting 49 g. of 4-[(3-benzoylphenyl)acetyl]morpholine to the corresponding ethylene
. ~
3~ glycol ketal by reaction of the former with 125 ml. of ethylene
_ 32 -
`
.
~: .
~053ZS~
glycol in 1250 ml. of benzene ln the px~sence of 2.5 g. o p-
toluenesulfo~ic acid; ~nd rq~uetlon of the ~esulting ketal
(58.6 g.) with 11.8 g. (0,31 mole) of lithium alumlnum hydri~e
in 280 ml. of ether, foll~wed by hy~r~lysis of the ketal by
stirring the product at 5S-60C. with 300 ml. of l.$N hy~ro-
ahloric acid for forty-five mlnutes.
~ 19 21 2 Cl-H2: ~i61o21~, H,6,Sl;- Found: C,65.38; H,6.88;
1~ C1,10,19.
Exam~le lD N-[ ~ methylamin~
rop~l)amine ~ ~ , m.p. 194-197C.
~11.1 g. of the free base obtained as a dark oil, a small
amount converted to the dihydrochlorida~ prepared by reaction of
46.3 g. (O.I67 mole) of 3-b~n~oylphenylacetyl chloride with
30.2 g. (0.3 mole) of 3-dime~h~laminopropylamine in 200 ml. of
methylens dichloride ln th~ Pxesence o~ 20.1 g. (0.2 mole) of
triethylamine; aonv~rsi~n o~ ~he ~e8ultlng 9 g. o~ N-1(3-
benzoylphenyl)acetyllrN-(3-dimethyIamlnopropyl)amine to the
c~rresponding ethyl~n~ gly~ol ketal by reaction of 15 g. of the
former with 37.S ml. o~ ethylene glycol ln th~ presence of
9.75 g. of p-to~uene~ul~on~¢ a~id in 39S ml. o~ benzene; and
~eduction of the r~sult~ng ket~l tl5,6 g,) ~ith 3.2 g.
~O.OR4 m~le) of llth$wm aluminum hydride in a ~olution of 5~ ml.
S of diQxane and SO ml. of dl-n-butyl ether, followed by hydrolysis
of the ketal by wa~mi~g $~ for one ho~r in 200 ml. of dilute
hydrochlori~ acid at 55~.
Anal. Calcd. fo~ C~oH~N20.2HCl~l/2 H~O: C,61 22, ~,7.43;
Found:.C,61.97~ H,7.48;
Cl,17.7~.
, ~
,.
. . .
- : ,
.. .
105325~
Following a procedure sim~lar to that described in
Example 1, 2,6-dimethyl~ oC-~3-~enzoylphenyl~proplonyl]piperi-
dine (14.3 g. a~ an oll) wa~ prepared ~rom 12.7 g. ofGC-~3-
~enzoylphenyl)propionic Acid, lO g. (0.~84 mole) of thionyl
chloride, 6.22 g. (0.055 mole~ of 2,6~dimethylpiperidine ~n~
6.05 g. ~.06 mole) of triethylamine, and the resulting amidç
(1~.3 g.) reduced with 3~9 g. (0.103 mole) of lithium al~minu~
hydride in diethyl ether t~ give 13.2 g. o~ 2,6-dl ~ehvl~ 2
~ as a yeliow oi~.
~nal~, Calcd- for C23H3lNO: C,82.34; H,8.71; N,4.18.
Found: C,82,22, H,8.82; N,4.?15.
Example~ 2A-D
Followin~ a procedure ~imilar ~o th~t described i~
l$ Example 1, th~ foll~wlng ~ompoun~ o~ ~ormula I are simila~ly
prepared:
- Example 2A ~
benzyl3~henyl~pr~ amlne prepared by reactlon ~foC-~3-(4-m~h~l-
2-chlorobenzoyl)phenyl]prop~onyl chloride wlth t-buty}amin~ an~
reduction, with lithlum alumi~um hya~lde, of ~he resulting ~-t-
butyl-N-{dC-[3-(4-methyl-2-chlorobenzoyl)phenyllprop~ony~ mine;
Example 2B N-Be~z ~ ~-t-butyl-N- f2-13- ~oC-hYdroxy-3-tri~
, methylben~yi)~h~yll~rop~l~amine prepared by reaction o~ ~-13-~
trifluoromethylbenzoyl)phe~yllpropionyl chl~ride wi~h N-benzyl-
N-t-butylamine and reduçti~n, with lithium aluminum hydride, Qf
the re~ultin~ N-benzyl-N-t-butyl-N-~dC-[3-[3-tri~luoromethyl-
benzoyl)phenyllpropionyl~amine;
~ N
: ~ prepared by reaction o~ 3-(2,~
~ 30 dichloxobenzoyl~ph~nyl]propionyl ~hloride wlth N,N-di-isob~tyl~
,
~ _ 34 _
. . . . , ~ . ~ ~
.
-` lOS3ZSl
amine and reduction, with lithium aluminum hydride, of the
resulting N,N-di-isobutyl-N-~-[3-t2~4-dichlorobenzoyl)phenyl]-
propionyl~amine; and
Exam~le 2D 4-(2-Cyclohex~lethy~ 2-[3-(0C-hydroxy-2-bromo-
benzyl)-4-methylphenyl]pr~pyl~piperidine prepared by reactio~
ofdC-~3-(2-bromobenzoyl)-4-methylphenyl]propionyl chloride with
4-(2-cyclohexylethyl)piperidi~e and reduation, with lithium
aluminum hydride, of the resulting 4-(2-cyclohexylethyl)~
[3-(2-bromobenzoyl)-4-methylphenyl]propionyl~piperidine.
Exam~_e 3
To 220 g. (1~65 moles) of aluminum chloride was added.
with vigorous stirring over a wenty minu~ce period 81 g.
(0.67 mole) of acetophenone. The resul~ing mlxture was trea~ed
dropwi~e with -~tirring over a ~orty minute period with 12Q ~.
(0.8 mole~ of br~min~. Whe~ addition was complete, the mixture
waa ~tirred fox an additional fifteen minutes and then extrac~ed
with four 150 ml. portions of ~ther. The combined ether
extractY were washed once with water~ once with 1~% p~tas~ium
bicarbonate, once with saturated brlne, dried over anhydrous
~odium sulfate, and evaporated to dryness to give 141 g. of an
oil which was dl~tilled in Ya~uo to give 108.7 g. of 3-br~m~-
i acetophenone, b.p. ~1.5-76C./0.5 mm.
~, To 2,200 ml. o~ isopropanol in a three-necked round
. bottom flask flushed ~ith ni~rogen was added in pieces 60 g.
i~ 25 (2.6 moles) of sodium. When all the sodium had dissolved, the
mixtuxe was cooled to about 7-8C. and treated over a period o~
thirty minutes with a ~olution o~ 318 g. ~1.6 moles~ of 3-bromo-
acetophenone and 352 g. (2.88 moles) of ethyl chloroacetate.
The mixture was stirred at 7-8C. for five hours ànd then at
:~ 30 ~mbient temperature for abcut forty-eight hours, refluxed for
:,
- 35 -
~0~3ZSJ~
one hour, distilled to remove about one llter of i~opropanol, and
the residue diluted with 19~0 ml. of water ~nd 1200 ml. of
toluene and stirred. The layer~ were separated, the aqueous
layer was extracted with additional toluene, and the combi~ed
toluene extracts were washed with ~aturated brlne, dried, andi
evaporated to drynes~ to give 558.8 y. of a brown liquid which
was combined with a 801ut~ on ~ 70 g. of sodium hydroxide in
225 ml~ of water and 1200 ml. of absQlute ethanol and refluxed
- for about twelve hours. The mixture was then taken to dryn~s
~n vacuo to give 575.6 g. of a ~olid which was dissolved in
water, acidlfied wlth dilute hydrochloric acld, and the mixture
extracted with benzene. The benzene extracts were taken to
dryne~ to give 4a5.4 g. of material whlch wais steam distilled
: affordlng 272.5 ~. of ~ ~3=bro~o~h ~ d hvde.
A solution of the latter with 465 g. (2.~ moles) of
2-cyclohexylmethylpip~ridine in 6 liter~ of benzene was refluxed
und~r a Dean-Stark trap ~or abou~ twelve hours. The -Rolvent WA9
removed ln vacuo giving 712;1 g. of an oil which was distilled
: in ~acuo to remo~e lower b~iling lmpuritie~. There was thus
:~ 24 obtained ~9 a htgher boiling pot re~ldue 357.2 g. ~f
h~yl et ~ ~ 2-~3-bromophenyl)-l~propenyl~pipe~ldine.
~: The lat~0r ~0.95 mole) wa~ dissolved in 3 liters of
hexane, and the solutlon cooled ln an i~e bath and treated wi~h
220 ml. (1.20 m~le~) of 4.9N ethereal hydrogen chloride. The
whit~ gummy solid which $eparated, ~cn~istlng of the imini~m
hydr~chloride, was c~llected, fllt~red, washed with fre~h hexane,
dis301ved in 3.5 liters 9~ dlmethylf~rmiamide, and the Q~lut~on
tx3ated wlth 72 g. ~ mole~ of sodlum borohydrlde added in
~mall amoun~s o~er a ten minute pariod. The mixture was then
s~irred at ambient temip~ra~ure for about an hour and a hal~,
.'
- 36 -
.
. . , , ~ . ~
..... ,, . . . . . , . , .. , ,:, .....
., ., - : . ~ . . .- , :: . : . ... :
` lOS3Z51
treated with one liter of 10~ ~odium hydroxide and 6 liters of
water, and th~n extracted with hexane. The combined hexane
extracts afforded 305.4 g. of a yellow oil which was distilled
in vacuo to give 189~6 g. of m~terial, b.p. 143-161C./0.06 mm.,
which was redistille~ at 0.5 mm. (b.p. 167-187C.) to give
158.5 g. of 2-cvcl~ r2-(3-bromophenyl)propyl]-
~-
Anal-, Calcd- for C21H32BrN: C,66.66; H,8.52; Br,21.12.
Found: C,66.71; H,8.36; Br~?l.2~.
A solution of the latter t37.8 g., 0.1 mole) dis~lve~
in 80 ml. of di~thyl ether was treated dropwise wlth 165 ml.
(0.18 mole) of a 1.~8M ~oluti~n of n-butyl lithium in diethyl
ether while maintaining the temp~rature around 10C. When
a~dition was complet~, the mixture was stlrred fer thirty mi~u~s
at-about 10C., then at ambient temperature for one hour,
, refluxed for about thirty mi~utes, cooled once again to 10C.,
:.~, and treated with a ~olution o~ 25.8 g. (~.19 mole) of ~-methoxy-
be~zaldehyde in 50 ml. of ether while maintaining the tempe~t~e
~ ~roun~ 15-20C. The mixtUre was then refluxed for twenty minute~,
.1 2C cooled, ba9ified by ~he addltion of 110 ml. ef 10~ sodium
hy~roxide and ~tlxred ~o~ ten minute~O The mixture was thon
filt~red, the organic layer ~eparated, and the aqueous layer
extracted with additional diethyl ether. The combined organi¢
~,, extracts were washed with ~aturated brine, dried over sod~um
.~ 2S sulfAte, and evap~rat-d to dryne~s t~ ~ive 55 g. of an oil whiçh
was dis~olved in 150 ml. of ab~olute me~hanol. The solution
was ~rea~ed cautl~u~ly with 7 g. of sodium borohydride, stirred
at 15C. f~r twenty minute~, carefully ~cidified by the add~tiqn
: of 15:0 ml. of ~ulfuric acid and extra~ted three times with
hexane. The a~u~ouJ ~lution was ba~ified with 150 ml. o~ ~0
37
.
., . . , ~ . . .
10532~1
sodium hydroxide, dlluted wi~h water and extracted four times
with hexane. The combined hexane extract~ afforded 32 g. of an
oil which was chromatographed on 500 g. of alumina using 1.5%
isopropylamine in hexane as eluent. The first 3 liters of eluate
S were collected and set aside, and the next 3.7 liters collected
and evaporated to dryne~s to give 20.4 g. of 2-cyclohexylmethy
2-[3_~-hydro~y-4-methox~benzyl)phRny~l~propyl~piperidine
as a yellow oil.
Anal. Calcd. for C29H41NO2: C,79.95; H,9.49; N,3.22.
lQ Found: C,78.88; H,9.43; N,3.07.
Ex~mDl~s 3A-3~
Following a procedure ~imila~ to that deQcribed in
Example 3, the oll~wing GQ~pounds o~ formula I are pxeparad:
., ,_
:~ Exam~le 3A 2-Cyclohe~ylmeth~ 2-[3-~-hydroxY-3-chlox~
~ ~ ~26.8 g. as a y~llow oil) prepared
,, by reaction of 37.8 g. ~.1 mole) of 2-cyclohexylmethyl~ 13- -
bromophenyl)propyl]piperldine with 0.19 mole of n-butyl lithiu~ -
~;~ and reaction of the resulti~g lithio dexivative with 28.0 ~.
. ~0.2 mole) of 3-chlo~obenzaldehyde in ab~ut 250 ml. of diethyl
e~her.
`' ~ 1 Calcd ~ ~ H ClNO: C,76.4~; H,8.70; N,3,18,
Found: C,76.64; H,8.98: N,3.16
' Example 3B 2-Cyclohexylmethyl~ 2~[3~ hydroxybenzyl)phenyl]-I pr~pyl~pyrrolidine (5-3 Yt as a tan ~i~aous oil) prepaFed by
2S reaction of 10 t 8 g . (0-03 mcle) of 2-cyclohexylmethyl~ 2-(3-
~'~. bromophenyl)propyl~pyrrolidine with 0.06 mole of n-butyl lithium
a~d reaction of the re~ultlng lithio derivative~with 7.0 ~.
~0.066 m~l~) of benzaldehyde.
Anal- Calc~- f~ ~37H37No ~,82.81; ~,9.52; N,3.58.
~ound: C,82.29; H,10.03; N,3.51.
.
,, .
~ - 38 -
"
. , .
. ~ t ~ `
. . .: ` . .
i~fs3
Example 3C ~
benzyl)phe~yl]~fropyl~iperidine (12.3 g. as an oil) prepared by
reaction of 37.8 g. tO.l mole~ o~ 2-cyclff~ffhexyl~ethyl-1-[2-(3-
bromophenyl)propyl] piperidine wlth 0.19 mole of n-butyl lithi~
S and reaction of the resultlng ll~hio dfffafrivative with 35.1 ~.
(0.2 mole) of 3,4-dlchlofrfofbfffnzaldehyde in diethyl etheffr.
2-Cy¢lohexfylmet~yl-1-{2-~3-~dc-hydroxy-2-chlorobenz~
henyl]pro~ff ~ ~30.7 g. a3 an oil) prepared by se~ctlon
of 37.8 g. (0.1 mole1 o~ 2-cyclohexylmff3t~yl-1- [2- t3-brom~ffphenyl) -
propyl] piperidinffa with 0 .19 mole of n-butyl lithium and re2f~ticffn
of the re~ulting lithio derivative with 28.0 g. tO.2 mole) off
2-chl~xobenzaldfffffhyde in diethyl ether.
Exam~e 3E ~
henyl]propyl~plporidine 15.4 g. a~ a vlscous oil) prepfared by
rffff~faction of 12.2 f~f~ (ff~f.03 mole) o~f 2-(3~cyclohexylpropyl)-1-[2-
~3-bromophenyl)pxopyl]plperidlne wlth ff~ . 68 mole of n-butyl lithium
and reaction of ~he resultlng llthio derlvative with 7.0 g.
(f~f . 06 mole) of benzaldehyf~e ih diethyl fafther.
: Anal^ ~alcd- for C30H43NO: C,83.09; H,9.99f; N,3.23.
FQund: C,82.92; H,10.26; N,3.19.
2-Cyclohaxyl~ethy~ {2-ff3-~c-hy~roxy-4-meth~lmer-
capto~enz ~ ph ~ prepared by reaction of 2-
cyclohexylmethyl~ 2-~3-bromophenyl)propyl]piperidine with
n-butyl llthium and rf~aGtion Qf ~he ~esultiny lithio defriv~tivq
2~ with 4-methylmercaptobf~nza~dehydfeff.
2-Cycl~fhff~fxylme~ 2-r3~ hydrfrfxy-4-methylsul~inyl-
_ pr~pa~ed by rea~tion o~ 2-c~clo~ :
hexylmethyl~ -[3-(oc-hydroxy-4-methylmexcaptobenzyl)phenyl] -f
propyl~ pfipff3ridine f~escrlhff ffd in E~f~mple 3F wlth Onff~f mOflar eff~Ui
l~n~ amfrffUnt of hyff~ff;ffgon Fffexoxlde in i~Onl~fiC acid.
: .
.
:, '
. .- . . . .
.
~ lOS3'~51
Exa~ 3H ~ ~ ~
~ulfonylbenzyl)phenyl~propyl ~ ridlne prepared by reaction
of 2-~yclohexylmethyl~ 2-~3-~c~-hydroxy-4 methylmercaptobenzyl)-
phenyl]propy~ piperidine de~c~l~ed ln Example 3F with two molar
equivalents of hydrogan peroxide in formlc acid.
, ~ .
Following a proGeduxe ~imila~ to that described in
; Example 3, 18.9 ~. ta.O5 mole) o~ 2-cycl~hexylmethyl-1-t2-~3-
br~ ophenyl)propyl]pi~sridine was r~a~t~d wlth 0.1 mol~ of
n-butyl lithium in diethyl ~th~r and t~e re~ulting lithio
. der~vatlve rea~ted direatly with 12~3 g. ~0.103 mo~e) of 4
m~thylbenzal~hyde to glv~ 16.9 g. ~f 2~ Qh~xylmethY~
~2-~3- PC- ~ z~ han~ll ~ ne as
a yellow oiI.
Anal C~l~d. ~or C29H41NO: C,83.00; H,9.85; N,3,34-
F~und: c,83.04; H,10.01; N,3.31.
E~ 5
Followin~ ~ pxo~ur~ slm~lar to that do~¢xlb~d in
Examplo 3 ~bQv~, 18.9 ~. (0.05 mo~) of 2-oycl~h~xylmsthy~
~ 20 ~2-(3-bromoph~n*~l)px~yl~p~poridln~wa~ ~ea~to~ with 0.1 msl~ ~
of n-~utyl li ~lum ~n ~e~hyl ethor and tho rasulting ~lthio
~ derivativo r~actod dlractly w~th 15,5 g. ~0.11 molo) of 4!
; chlorobo~zald0hyde. The ¢rude ~roduct w~ r~duced wlth 4~5 g.
~tl2 mol~) o~ sodlum ~o~ohyarldo ln math~nol tQ gi~e 16.6 g.
of ~
~ ~ a~ an oil. :-
: An~ Calcd- ~r C28R38ClNO: C,7G.42~ H,8.70~ Cl,8.06.
Found: C,76.82~ H~8.76~ Cl,8.1~.
3~ Followlng ~ ~r~dux~ ~milar to that doscri~ed ln
.
~ 40 ~
.. . .
, . . . . . .
lOS3'~51
Example 5, the follow1ng compound of formula I was similarly
prepared:
ExamE~le 5A 2-cyclohexyl~eth~ 2-[3-~c-h~droxx-?~6-dichloro-
~ (yellow oll~ prepared by reaction
of 18.9 g. (0.05 mole) of 2-~yclohexylmethyl-1-~2-t3-bromophenyl)-
propyl]pipexidine with 0.1 mole of butyl lithium in diethyl ether
followed by 19.2 g. ~0.11 mole~ of 2,6-dichlorobenzaldehyde to
~ive 19.3 g. Qf product.
Anal- Calcd- for C28H37cl2No: C,70.87; H,7.86; Cl,14.94.
Found: C,71.06; H,8.08; Cl,14.81.
: ~
Following a procedure s~mllar to that described in
Exa~ple 3, 37.8 g. (0.1 mole~ of 2-cyclohexylmethyl-1-[2-(3-
bromophenyl)propyl~plperidlne was reacted wlth 0.18 mole of n-
~utyl lithium ln diethyl ether and the re~ultlng lithio deriva-
`~ tive reaated directly with 27 g. (~.23 mole) of acetophenone
to give 11.8 g. of 2-c~clohexylmethy~ 2-~3-t~c-hydroxy-d
as a yell~w oil.
Anal- Cal~d- for C29H41N~: C,83.00; H,9.85; N,3.34.
F~und: C,83.34; H,9.97; N,3.23.
;~, ~
~ , .
A solution of 0.15 mole of n-butyl lithium 90 ml.
of diethyl ether w~ p~epa~ed by addition of 20.5 g. of n-butyl
bromide in 30 ml. of ether to 2.58 g. (0,375 mole) of lithium.
Su~ficient ~olume ~f the e~lution to provide 0.~3 m~le was
~dded to a solutioh of 19.4 g. (0.051 mole) of 2-cyclohexyl-
methyl-l-t2-t3-brom~phenyl)propyl]p~peridlne (described above in
~xample 3) in 100 ml. of ether. The mixture wa~ stirred for
thirty minutes while main~aining the temperature below 10C.,
refluxed for thirty minute~, cooled once again below 10C.,
.
- 41 -
'
', ' ' ' ' ' ' ' ' ~ , ' .
' ' ' , ' ' : ' ' . ~ ' '' ' ' ' ',', ~
~OS32Sl
.
~reated over a ten minute period with a solution of 13.3 g.
(0.10 mole) of 4-methoxyb~nzo~itrile ln 80 ml. of ether, stirred
for an additional hour and a half at below 10C., then ~tirred
overnight at ambient t~mp~rature and treated with 110 ml. ~
a solution prepared by dl3sol~ing 9 ml. of concentrated sul~uric
acid in 45 ml. o~ water and 108 ml. of dioxane. The solution
was refluxed ~or two hours, cooled, ba~ified with 100 ml. of 104
sodium hydroxide, the layers separ~ ed, and the a~ueou~ layer
extracted with e~her. Th~ ether extr~ts were washed with brine,
dried and ta~en to dryne~Q t~ give 32.6 g. of material which wa~
dissolved in hQxane and 2xtracted with a solution of 8 ml.
of concentrated sul~uric acid, 136 ml. of water and 144 ml. o~
m~thanol. The extract~ were ~ndered ~a~ic with 10% sodium
hydroxide, the mlxtuxe ext~acted ~nce again wlth hexane, a~d
lS th~ hexane extr~cts washed with:~xine, dried and taken to drynes~
to give 28.1 g. o~ materlal which was chromatographed on 400 g.
of alumina and eluted with 50%.benzene~50~ hexane. The first
1~50 m~. of eluate w~5 ~ak~ to dryne~, the r~sidue heated
in vacu~ at 0.1 mm~220C. ~bath t~mperature) to drive o~ some
4-m~thoxybenz~ni~rile, and the residue once again chromatograph2d
on al~mina (25Q g.) uslng 15% ether~85% hexane. The first 400 ml.
of eluate was disaarded and the next 1200 ml., on evaporation ~o
dryness, a~forded 7.1 g. o~ 2-cyclohexylm ~ -[3-t4-met~
~ a~ a yellow oil.
:- 25 Anal. Calcd. or C2gH39NO2 Cf ao.33; H,9.07; N,3.23.~und: C,80.50; H,9.17; N,3.14.
Follow~ng a procedure similar to that described in
Ex~mple~ 3, 4 and 5, tha ~llowlng compounds of formula I are
3G simllarly pxepar~d:
- 42 -
.
. , - , ~ .
1053251
Example 7A 2-CYclohex~lmethyl~ 2-t3-benzoylphenyl)propyl]-
pyrrolidine, (vi~cou~ amber li~uid) prepared by reaction of
21.3 g. (0.1 mole) ofdC-t3-bromophenyl)propionaldehyde with
31.4 g. (0.2 mole) of 2-cyclohexylmethylpiperldine in benzene;
conversion of the re~ulting 33.7 g. of 1-~2-13-bromophenyl)-
l-propenyllpyrr~lidin~ ~o the iminium chloride with ethereal
hydrogen chloride; reductlon of the iminium chloride (34.0 g.)
with 6.4 g. (0.17 mol~) of ~odlum borohydrlde ln dimethylform-
amide; reaction of 9.8 g. tO.027 mole) of the resulting
tl8.8 ~.) 2-cyclohexylmethyl~ 2-(3-bromophenyl~propyl~pyrro-
lidine (b.p. 135-136~C./0.~2 mm.) wlth 0.05 mole of butyl
lithium followed by 6.2 g. (0.06 mole) of benzonltrlle in diethyl
ether and decompo~tion o~ ~h~ product wlth a ~olution of 4 ml.
of conc~ntr~ted sul~uric acld in 20 ml. o~water and 50 ml. of
. lS dioxane t~i ~ive S.l g. of product.
$ An~l. Cal~d, for C27H35NO: C,83.24; H,9.06; N,3.6Q.
~ou~d: C,82.77; H,9.05; N,3.64.
Examplo 7B 2-Cy~lohexylm~thy~ 3-~4-fluorob~nzoyl)phenyl]-
~ _ idl~ (y~llow oll~ p~apared by reaction of 18.9 g.
"
~: 20 tO.05 mole) o~ 2-oyçlo~xylmethyl-1-[2-(3-bromophenyl)propyl]-
piperidin~ with ~.1 mole o~ butyl lithium in ~iethyl ether
~ followed by 12.8 g. ~.11 mole) of 4-fluorobenzonitr~le and decom-
'~ po31ti8n of the product with a 501ution of 3.8 ml. of concen-
trated sulfuric a~ld in 19 ml~ of water and 45 ml. of dioxane
to give 6.5 g. o~ product-.
Anal. Calcd. for C28~36FNO: C,79.77; H,8.61; N,3.32.
` Found: C,79.60; ~,8.76; N,3.Sl.
Exam~ple 7C 2-519~ x~ 2-[3-(4-methylbenzoyl)pheny
. p ~ ~ si~ln~ (9.7 g. a~ a yellow oil) prepared by reaction
3~ Q~ 18.9 g. (~.05 m~l~) Qf 2-~yclohexylmethyl-1-~2-(3-bromophenyl)-
- 43 -
., . ~ . : - -
lOS3i~Sl
propyl]piperidine with ~.1 mole ~f butyl lithium ln diethyl ether
~ollowed by 12.4 g. ~0.11 mol~J of 4-methylben2Onitrlle ~nd
decomposition of th~ product wlth a solutlcn o~ 3.8 ml. of conc~n-
trated sul~uric aoid in 19 ml. o~ w~ter ana 45 ml, of dioxane to
$ give ~.7 g. of ~o~u~t.
A~l. Calc~. fo~ C29~39N~: C,83.40; H,9.41; N,3,35,
Found: C,83.34: H,9.61; N,3.30.
~iperidine tyellow ~il) prep~red by reactl~n o~ 12.2 g. (0.03
mols) of 2-(3-cycl~hoxylpropyl)-1-[2-(3-bromophenyl)propyl]-
pipexidine with 0.06 mol~ of bu~yl lithi~m in diet~yl sth~r
~oliow~d by 7.2 ~, (0.~7 m~l~) o~ ~n~o~itrile &nd decomposition
. of ~he product with a olutio~ o~ 8.3 ml. ~f ~ncentrated
: ~ulfuric ~cid in A2 ml. u~ w~t~r and 100 ml. of dioxan~ to gi~e
.. lS 6.2 ~. of ~ro~u~t.
An~. Calcd. ~ox C30~41N0: C,~3.47~ Ht9.57; N,3.24.
~ou~d: C,83.28; H,9.77; N,3.05.
x~mple 7E
(l~ght tan oil) pr~par~d by re~ction of 12.7 g. ~a . 035 mole) of
2-cycl~h~xyl-1-[2-(3-bromoph~nyl)~r~pyl]pi~eridine with 0.07 mole
', o~f butyl lithium in dl2thyl ~th~r followed by 8.9 g. (0.~77 mole)
of benzonitr~lo and de~ompo~ition o~ the product with a ~olution
of 9 ml. of ~on~entrated ~ulfuric ao~d 1~ 45 ml. of wAter and
lQ0 ml. of diox~e to giv~ fi.l g. og product.
Anal~ Ca~cd. ~o~ C27H35NO: C,83.~4; H,9.06; N,3.60,
F~u~d: C,83.16; H,9.16; N,3.q4.
eridine ~palo ta~ llqui~) prepa~ed by reaction of 13.7 g.
t~.Q35 mole) of 2-(2-cyc~ohexylethyl)~ 2-(3-brQmophenyl)pxopyl]-
piperidin~ with 0.07 ~le of butyl lith~um ~n d~ethyl ethe~
.~
.
.
t
lOS3~S~
followed by 8.9 g. tO.077 mol~) of benz~nitrile and decomp~itlon
of the product with a ~olution of 9 mlO ~f concentrated culfuric
acid in 45 ml. o~ wate~ ~nd 100 ml. of di~x~ne to give 8.9 g. o~
product.
Anal. Ca~cd. fQr C29H39N0: C,~3.40: H,9.41; N,3.35.
Found: C,83.57; H,9.40; N,3.35.
Exsmple 7G
~ (pale yellow oil) pr~pared by reactlon ~f 10.6 g.
: (Q.OS m~le) of ~-t3-bromophen~l)propionaldehYde with 14.3 g.
~0.1 mole) of 1,4-diox~-8-a~a~plrol4,53decane ln benzene;
conversi~n o~ th2 r~sulti~g 15.7 g. of 8- r2- ~3-bromophenyl)-1- :
~: propQnyl~-1,4-diQxa-8-~zA3~1r~[4,5]decane to the iminium chlorlde
with ethereal hyd~en ch~orid~; redu~ion of the iminlum
chloride with 3.8 ~. ~0.08 mole) of ~odium ~orohydride in
l$ dimethylformamides r~a~ti~n of the re~ultlng 17.5 g. (O.OS mol~)o~
8-[2-~3-Src~phenyl~propyl~-1,4-dloxa-8-azaspir~r4,5~decane
with 0.1 mole of butyl lit~ium follow~d by ~5.5 g.-tO.15 ~ol~
~f b~nzonitrile ~n diethyl ~th~r ~nd d~co~p~ltion of the produçt .
with a ~olutian of 6 ml. ~f con~antrat~d ~ulfuric acid in 3a ml.
o~ wat~r an~ 7~ ml. of dioxane to glva 5.1 g. of product.
A al C~l~d for C H N03: C,75~58; H,7.45; N,3.B3.
~oun~: C,75.60; ~,7.69; N~3.~7.
~pAle y~llo~
Gil~ pr0pared by resction ~f 21.3 ~. (0.1 mole) ofd~-(3-br~mo-
ph0~yl)propiona~dohyde wi~h 17.4 g. t~.~ mola) o~ morpholine in
~enzene~ c~nv~r~i~n Q~ th~ ~sultin~ 27.3 g. of 4-[2-t3-b~omo-
. phonyl~-l-propenyl]morphbll~e to th~ lminium chloride wi~h
~there~l hydrog~n ohloridet reductlon of the imlnium chlo~id~
with 7.6 g. ~0.2 mole) o~ ~odlum boro~ydride in dimethylform~mlde;
re~c~i~n of ~h0 rosul~lng 13 g. of 4-[2-~3-bromoph~nyl)propyl~-
,
. - 45 -
'
. , . .. . , . , _ __ _ . ~ ,
3ZS~
morpholine (b.p. 99-120CC./0.0~ mm., nD -1.5477) with 0.1 mole
of butyl lithium followed by 15.5 g. (0.15 mole) of benzonitrile
in diethyl ether and decomposition of the product with 150 ml.
of a ~olution made by dlssolving 6 ml. o~ concentrated sulfuric
acid in 30 ml. of water and 72 ml. of dioxane to give 7.5 g.
of product.
Anal. Calcd. for C20H23NO2: C,77.64; H,7.49; N,4.53.
; Found: C,77.62, H,7.37; N,4.~1. ;
A small amount o~ the free base was converted to the
1~ hydrochloride salt t~ give 4-~2-(3-benz~ henyl)pro~y~]morpholine
hydrochloride mon_hydrate, m.p. 151-155C.
Anal: Calcd- f~r C20~23NO2.HCl.H2o , Cl,9.74.
Found: C,66.37; H,7.24;
Cl,9.59.
Example 7J 2,6-Dimet~ 1-4-[2-~3~benzoylphenyl)propyl]morphol~ne
cYclohexanesul~amate prep~red by reaction of 21.3 g. (0.1 mole)
o~ ~-(3-br~mophenyl)propionaldehyde w~th 23 g. (~.2 mole) of 2,6-
,' dimethylmorpholine in benzene; ~onversi~n o~ the resulting 28.4 g.
of 2,6-dimethyl-4-[2-(3-br~mop~enyl)-1-propenyl~morpholine to the
iminiu~ chloride with ethereal hydrogen chloride; reduction of
, the iminium chl~ride with lQ g. (~.26 mole) of ~odium borohydride
`~-
; in dimethylformamide; reactl~n o the re~ulting 15.5 g. of 2,6-
dimethyl ~-[2-~3 bromophenyl)propyl]m~rpholine (b.p. 125-129C.
, 25 0.01 mm., nD24Yl.5294) with 0.1 mole o~ butyl lithium followed
,1 by 11 g. tO~ll mole) of benzonitrile in diethyl ether and decompo-
1~ ~ition of the product with 150 ml. of a solution prepared by
! - di~olving 45 ml. o~ concentrated sul~uric acid in 225 ml. of
water and 540 ml. of dioxane. The product was converted to the
¢yplohexanesul~amate salt whlch w~ recrystallized from acetone
.1
! . _ 46 _
,,
:
-:
.
~O S 3~ 5~
to give 7.7 g. of product, m.p. 156-158C.
Anal. Calcd. f~r c22H27No2~c~l3 3 S,6 20.
Found: C,64.86; H,7.72;
g S,6~22.
hexYlmeth~ 2-~3
cr~dlno prepare~ by reactlo~ ~f 2 bromo-6-bromomethyl-
toluene [described by Lind~ay e~ al., J. Am. Chem. soc. 83,
943-949 (1961)] with po~a~um cyanide i~ refluxing ethanol;
reduction of the resulting (3-hromo-2-m~thylphenyl)acetQnit~ile
with diisobutylaluml~um hydride; reaction of the resulti~g (3-
bromo-2-methylphenyl)a~etaldehyde with 2-cyclohexylmethylplp~ri-
dine in refluxing ~nzene un~er a D~an-Stark ~rap; reduction
w~th sodi~m bor~hydride of ~he iminium hydrochloride of the
lS resulting 2-cyclohe~yl~th~ 2~3-br~mo-2-methylphenyl)-1-
ethenyl]piperidine; ~nd rea~t~o~ of th~ resulting 2-cyclohexyl-
methyl-1-[2-(3-brom~-2-me~hylph~nyl)ethyljp~peridine with
n-butyl lithium in diethyl ether followed by reaction o~ the
resulting li~hio derivative with benzoni~rilQ.
Exam ~ L ~
~repared by reactiqn ~ ~3-~remo-2 methylphenyl)acetaldehyde
with mGrpholine i~ refluxing benzene und~r a Dean-5tark trap;
red~ction with ~odium borohydride ~ the ~minium hydrochl~rld2
of the resulting 4-~2-~3-bxom~-2~methylphenyl)-1-ethenyl]~
` ~S morpholine; and rea¢ti~n o~ th~ resulting 4-[2-(3-bromo-2r
m~thylphenyl)ethyl~morp40-~ne with ~-butyl lithium in die~hyl
ether followed by reactiQn o~ th~ re~ultlng lithio derivative
with benz~nitrlle.
., ~ ,
~o Foll~wlng a pro~dure ~imilax ~o ~hat descr~ed in
: Example 7, 18.~ g~ (Q.05 mol~) of 2-~yclohexylmethyl-1-[2-[3-
- 47 -
.. .
- : . ; :
.
.
10530~51
bromophenyl~propyl~plperldinQ w~ reacted wlth 0.095 mole of
- n-butyl lithium in diethyl e~her and the re~ultlng lithio
derivative reacted direatly wi~h 12.4 g. (0.106 mole) of 2-
methylbenæonitrile t~ give 4~85 g. of
~3-(2-met~ylbenzoyl)phenyl3pr~py~ erl~ine a~ a yellow oil.
Anal. Calcd. ~or C29~39NO: C,83.40; H,9.41; N,3.35.
~ou~d: ~,83O14; H,9.54; N,3.67.
. ~!
Followlng a proqedure 3im~1ar to that de aribed ~n
Ex~mple 7, lB.9 g. tO.05 mole~ of 2-cyclohex~lmethyl-1-[2~t3-
br~mophenyl)propyl]pipe~idin~ wa~ react~d with O.Q95 mole o~ n-
butyl lithium in die~hyl ether ~nd ~he r~ulting lithlo deriva-
tive react~d dira~ly wl~h 1~.4 g. ~0.106 mole) o~ 3-methylbenzo-
nitrile to give 10.7 ~, o~ 3
benzoyl)ph~nyl]pr~pyl~ip~rldin~ a~ a yellow oil.
; nal. Calc~. ~or C2~3~NO: C~83~0; ~,9.41; N~3-35-
~ ~ound: C,83.~6; H,9.3a; N,3.4~.
, ~
A sol~tion o~ 1-3.0 ~ lB.~ mole~ ~f 2-cyclohexyl-
z~ methyl-l-f2-[3-(~C hydx~xybe~yl)ph~nyl~p~opy~ piperidine
: ~described 2bov~ in Ex~mple 1) ln 167 ml. of gla~ial ~ce~ic
acid and 33 ml. ~f perQhloric acid wa~ placed ln a Parr hydro-
~- genator and reduced over 3.5 ~, of 10% ~alladlum-on-charcoal at
ambient tempera~uSe under a hydro~en pressure of 54 p.s.1. When
reduction wa~ c~mplete, th~ cataly~ W~8 removed by filtration,
thQ filtxate wa~ taken t~ dryne~s, and the re~idue rendered
b~ with 10~ -~odlum hydroxlde an~ extracted ~our timeq with
~` hex~ne. The combined h~xane extract~ were dxled, taken to
dryn~ss, and th~ ~sidue ~hroma~o~r~phed on 22Q g. of alumina~
~nd ~luted with 10~ e~her~8~ hexane/1% 18~pr~pylamine. The
- - 48 ~
.
~053'~51
first 350 ml. of eluate when taken to dryness afforded 10.6 y.
of 2-cyclohexyl ~ ropyl]pi~ridine ~s
a yellow oil.
Anal. Calc~. ~or C28H39N~ C,86.32; H,10.03; N,3.59.
Found: C,86.18; H,10.34; N,3.Sl.
Exam~le_ll
Following a procedur~ ~imllar ~o that described in
Example 10, 11.1 g. tO.027 mole) ~f 2-cy~loh~ylmethyl~ 2 ~3-
(~-hy~roxy-~ -methylb~n2yl)phe~yl]pr~pyI~piperidine ~described
in Example 6) di solved in 180 ml. of gla~ial acetic acid and
. 20 ml. of 72~ perchl~ric ~cid was re~uced with hydrogen over
O.8 g. of palladium-~n-~haro~al t~ give 10.3 g. of 2-a~clo-
as a yellow oil.
Anal. Calcd. ~or C29H41N: C,86.29; H,10.24; N,3-47-
~ound: C~86rO4; H,10.21; N,3.70.
. ~
~ solution o~ ~.8 g. ~0.065 mol~) o~ 2-cyclohexyl-
methyl~ 2- r3- (c~-hydroxybenayl)phenyl~ropyl~piperidine
~described ab~ve in Example 1) i~ 140 ml. of benzene was
vigorously stirr~d and ~ooled t~ lG~C. and then treated drop-
wise over a perlod o~ ton minutes with 5~ ml. of a solution
prepar~d by dissolvln~ 26.7 g. of chromium t~ioxide in 23 ml.
o~ concantrated ~ul~uri~ açid ~nd diluting with water to 100 ml.
2~5 The mixture was ~lrred ~lth cG~ling f~r about one hour and
forty-five minu~e~, ~he b~æ~n~ laye~ removad, and the aqueous
layer made basic by a~d~tion ~ 120 ml. of lO~sodium hydroxide
an~ ex~racted with b~n~e~e. The orga~ic extxacts, on washin~
onco with dilute alkall, on~e with b~l~e, ~nd evapo~ation to
dryn~s~, a~forded 21.8 g. o~ an oil which wa9 chromatographed
.
~ 4~ --
.
.
... - . : , , , . :
: , . . .
lOS325'1
over 300 g. of alumina usln~ 3% lsopropylamine in hexane as
eluent. The flrst 600 ml. ~f elua~e was collected and tsken
to dryne~s to give 1~.2 g. of
ph~yl~propyl]~ipe~ldin-~- aY a pale yell~w vi~cou~ oil.
Anal. Calcd. ~r C2BH37NO~ C,83.33; H,9.23; N,3,~7.
Found: C,83.30; H,9.33; N,3.45.
~a~
Following a procedure slmilar to that de~cribed in
Example 12, 15.2 g. tO.3~ mole) o~ 2,6-dimethyl~ 2-[3~(dC-
l~ hydroxybenzyl)phen~l~propyl3piperidins ~described above in
Example 2) was oxldized with 34 ~1. o~ a solution prepared by
dissolving 13.4 g. o~ chrQm~um txloxide in 11.5 ml. of concen-
trated sulfuri~ a¢id an~ dilution with wa~er to 50 ml. The
pr~auct, in the ~Qrm o~ the ~e~ ~a~e, wa~ puxified by chroma-
tographing-on alumlna usln~ 10% eth~r~3~ isopr~pylamine/87%
h0xane a~ sluent. Th re wa3 thus o~alned 4.8 g. of 2,6-
dimet ~l~ (3~ pr~l]~iperidine as a colorless
s viscous oil.
~nal~. Calcd. or C23~29NO: C,~2.34S H,8.71~ N,4.18~
Foun~: C~82.23; H,8.82; N,4.15.
. Exam~les 13
P~ooe2ding in a m~n~e~ 4~milar ~o that described i~
. Exampl~ 1 and 12, thQ ~ollowin~ compound~ o~ ~o~mula I ~re
. ~bta~ned:
'~ as Ex2mple 13~ ~
,
~ . eneimin~ prepared by ~a~tion ~ C ~3-be~z~ylphenyl)propionyl
:- ahlo~ide with 2-m~tbylhexam~thyla~e1~ine ~Mueller et al.,
,~ Mon~tsh. 61, 212-218 (1932)~7 reduction with li~hium alumin~m
.: hydride o~ the xe~ulting 2-methyl-1~loC-(3-benzoylphanyl)-
prop~onyl]hexamethylenel~.nine; ~nd chromlc acid oxidation of
the resul~ing 2-mothyl~ r3-(oC-hya~oxybenzyl)phenyl~propyl~-
~' hex~methylenoimine.
. ~ . .
- 50 ~
i
.
.
1053ZS~
Exam~_e 1 3B
piperidine prepared by reaction of ~-(3-benzoylphenyl)pxopionyl
chloxide with 4~cyclohe~ylpiperidlne, reduction with lithium
aluminum hydride o~ the r~ul~ing 4-cyclohexyl-1-[oC-(3-ben
phenyl)propionyl]piper~dlne~ and chromi~ acid oxidation of the
resulting 4~cyclohexy~ 2-l3-(~c-hydroxybenzyl)phenyl]pr
piperidine.
Example 13C 3-sut~l-q~[2-(3-benzoyl~h~nycl~propyl]mor~holine
~repared by reaction o~C-~3-~nzoylphenyl)propionyl chloride
with 3-butylmorpholln~; r~duction wit~ lithium aluminum hy~ride
of the resulting 3-butyl-~-[~C~3-benzoylphenyl)propionyl]morpho-
line; and chromic acld oxidati~n o~ the resulti~g 3-butyl-4- ~2-
~3-(o~-hydroxyben~yl~ph~nyl~pxopy~ ~oxpholine.
: Exa.mple 13~. 3-Ethyl~ [2~(3 be~o iomorphotli,ne
.
prepared by reac~ion o~ ~-(3-benzoylphenyl)propionyl chloride
wi~h 3-ethylthiomorphol~e; conv~slon of the resulting 3-ethyl-
4-[o~-~3 benzoylphenyl~propionyllthiomQrpholine to the correspond-
: lng ethylene glycol ~etal; reduction with lithi~m aluminum
hydride o~ the resulting ketal: and hydrolysis with dilute
mineral acid of the resulting 3-ethyl-4-~2-(3-benzoylphenyl)pro-
pyl]thiomorpholine ethylene glycol ketal.
~:, ~ 4-Me~ ~1-1-[2-~3-benzoylphe~y,,l?propyl]piperazine
prepared by reaction of ~C- ~3-benzoylphenyl~propionyl chloride
with l-methylpip~razine~ redu~tion with lithium aluminum
: 2~ hydride of the re~lting 4-methyl-1-[~-~3-benzoylphenyl)pxo-
` pionyl~pip~razine; and chroml~ acid oxidation of the resulting
--~ 4-methyl-1-~2-[3-t~C-hydr~ybenzyl)phenyl]propyl3piperazine.
: Exam~le 13F 3-~enzYl~ 2-~3-be~zoYlP~onYl)propyl]piperidine
preparQd by roa¢tion of~ 3-~enzoylphenyl)propionYl chloride
- 39 with 3-benzylpiperidine~ r~duction with lithium aluminum
. ~,
-- 51 --
.~
:... , . . . . .
.. . . . .
lOS3;~51
hydride of the resulting 3-benzyl-1-[~C-(3-benzoylphenyl)pro-
pionyl]piperidine; and chromlc acid oxidation of the resultiDg
3-benzyl~ 2-[3-(oC-hydroxybenzyl~phenyl] propyl3 piperidine.
~ prepa~ed by reaction of ~(3-ben2~yl-
phanyl)pxopionyl chloride wlth 5-~N',N'-dimethylamino)-2-pentyl-
amine: reduction with lithium aluminum hydride of the resulting
N-[5-(N',N'-dimethylamln~)-2 pentyl]-N-~-(3-benzoylphenyl~-
propionyl]amine; and chromia acid oxidation of the resulting
N-[5-(N',N'-dimethylamino)-2-pentyl~-N- {2-~3-(oc-hydroxyben~yl)
phenyl]propyl~amine.
~3~
Follow~ng a pro~e~ure ~imilar ~o that described ~n
Example 7,-5.0 g. (13.2 mole) o$ 2~cyclohoxylmethyl-1-[2-t3-
l$ bromophenyl)propyl]piperldine wa3 r~acted with 0.026 mole of
n-butyl lithium in diethyl ether and the resulting lithio
derivative reacte~ dire~tly with benzonltrlle to give 4.0 g. of
2-cvclohexylmeth~ 2-(3 benz~ylph ~ r~p~ 3pi~erldine
id~ntical with the ma~erlal descrlbed in Example 12.
~ 5
A mixtUre of 37.5 g. (0.093 mole) of 2-cyclohexyl-
m9thyl~ [2-(3-ben~oylphenyl~propyl]piperidine (de3eribed in
~xam~les 12 and 14 above~ and 10.0 g. ~0.14 mole) of hydroxyl-
- amine in 125 ml. of ~5% ekhanol a~d 25 ml. of water was treat~d
wi~h stirring with 19.4 g. o~ powdered sodlum hydroxide and the
mixture refluxed ~or a hal$ hQur. The mixture was then cooled,
diluted with hexane, th~ a~ueous layer ~eparated, and the
~rganic layer, after drying, was eYaporated t~ dryne~s to give
41.6 g. o~ a yellow oil which was chromatographed on alumina
in 30:70 diethyl ether/hexana tQ give 37.3 g. o~ 2-cyclohe
i
``- 10S32Sl
m~~ as an c~il.
Anal. Calad. for C28H38N2O: C,80.33; H,9,15; N,6.69,
Found: C,80.03; H,9.42; N,6.44.
;
~ollowin~ a procedure sim~lar to that described in
Example 15, the ~ollowing compound3 of formula I were similarly
prepared-
Example 15A ~
(m.~. 117-134C~, ~rom benzene~hexana) prepared by reac~ing
1~.15 g. (O.OS mole) of 4-[2-~3-~enzoylphenyl)~thyl]morpholine
. hydrochloride wi~h 5.6 g. ~0,08 ~ ) o~ hy~roxylamine hy~ro-
ahloxide in the pres~nce Q~ 12.S ~. t~.31 mole) o~ sodiwm
hydroxide in 70 ml. of e~h~ And 18~5 ml, of wat~r to ~ive
14.06 g. of poduct,
lS Anal. Calcd. ~or Cl~H~2N2O2: C,73.52; H,7.14; N,9.03.
~o~n~: C,73.79, H,7.26; N,~.72.
Ex~mF~ 15B 4-~3 ~ 1ine oxime (m.p.
145-167C.) prepa~e~ by r~ac~n o~ ~8,62 g~ (0.09 mole) o~ 4-(3-
; benzoylphenyl)methylmorphollne hydx4c~1Or1de with 9.63 ~. (0.14
mcle) of hydr~xylamin~ hyd$ochloxide in the presence of 21.68 g.
(0,54 mole) o~ ~odium ~ydroxida in 35 ml. of ethanol and 27 ml.
~: of w~ter to giv~ 13.3 g. o~ product.
;. ~ 4-~2-(3-B~n2c~ he~yl)pro~ morpholine oxime
. ~m.p. 117-130C., frQm i~p~opan~l) prepared by reaction of
:. 25 27 g~ (0.078 m~le) of 4-~2-(3-benzcylphenyl)propyl]morp~ol~ne
. ~ ~
` hydrochlorlde with 8.2 g~ ~0.117 mol~ of hydroxylamine hydr~-
'. ` chloride in ~he pr2~nce ~ 18.~ g. ~.47 mole~ of ~odium
` hydr3xide in 115 ml. o~ ~thanQl and 27 ml. of wa~er to give ~,2 g.
o product.
, .. . .
- 53 -
`~ .
- .
- , : ` , ' :
"~- 10~3ZSl
A olution of 17 g. (0.041 mole) of the 2-cyclo~exyl
methyl-1-[2-(3-benz~ylphenyl)propyl~piperidlne oxime described
above in Example 15 in 110 ml. of ~hanol was brought to re~lux
and treated with lQ g. (0.043 mole) o$ sodium metal, added in
small pieces. Refluxing was continuçd until all ~odium had
dis~olved, and the ~olution was then c~oled, diluted with
140 ml. of water, evapoxated t~ a volu~e of ahou~ 150 ml.
in vacuo, and then extracted with ~hree portions of benzene.
1~ Evaporation ef th~ b~2~n~ ~xtra~t~ t~ dryness af~orded 14.2 g.
of an oil which wa~ con~erte~ t~ th~ acetate salt by di~solvi~g
ln chloroform, addin~ gla~al acetic acid and evap~ratio~ to
dryne~s. The ~c~ate sal~ wa~ ag~in ~issolved in chlero~orm
and chromat~graph-d on alumina, elutin~ wl~h ~hloroform. The
; 15 aoetate hydrolyzed o~ the ~olumn, and the free ba~e obtained
.~ from the eluat~ w~ di~s~lve~ ~n ethanol, and the ~olution
. .
.. acidlied with etheraal;h~ r~ge~ chlorid~ and evaporated to
. drynes~ tQ giv~ 6.38 ~. ~f 2-~Y~l~he~ _
benzx~)phenyllpropyl3piperiaine dihyd~Q~hl~ride, m.p. 167-195aC.
- ~0 Anal. Cal~ ox C2~H41N2.2HCl: N,5.87; Cl,14.85-
~ Gund: N,5.61; Cl,14.66,
.
Exam~,e~ 16A-;16C
Following a pxocedure similar to that descri~ed in
.... .
:~ Example 16, th~ ~ollowi~g compounds of formula~ I and Ia were : 25 ~imilarly prepared:
4-{2-[3-~oC-~minobenzyl)~henyl]ethyl~morpholins
dihydrochl~r~de, m.p. 260-263C. (15.42 g. from methanol/diethyl
e~har) prepared by r~du~i~g 14.55 g. tO.047 mole) of 4-[2-(~-
b~zoylph~nyl)e~hyl]m~spholino oxime with 11.5 g. (0.$0 mQle)
54 -
,,
,' ~ ' ' .
, ~ .. , ~ 1
. ' - ~ , .
~OS3~
sodium in 100 ml. of ab~olut~ ethanol,
Anal. Calcd. for C19H24N20.2HCl: C,61.791 H17ilO2o
Found: C,61.88; ~,6.90~
Cl,19.16.
ExamE~le 16B 4-~[3- (o~-Aminobe~nzyl)ph~nyl]methyl~morpholine
~b~ ~i m.p. 270-274C~ t8.3 g., from
meth nol/ether) pr~pared ~y reduction o~ 8.12 g. (0 . 027 mol~?
of 4-[(3-benzoylphenyl)methyl]mQrpholine oxime with 6~45 g.
10tO. 28 mole) of sodlum :~n ab301ute ethanol.
Anal, Calcd- o~ ClgH22N20.2HCl.H20: C,60.84; H,6,Bl,
Found: C,60.68; H,6.83;
Cl, 20 . 27,
Example 16C 4-~2- C3~ ln~b~nz~phenyl~ropyl~morpholine
~3.~:o~lLLL L~ m.p. 25S-265~C. (9.5 g., ~rom meth~nol/qiethyl
eth~x) prepared by reduc~ion o~ 1~.0 g. (0.03 mole~ of 4~r2-(3-
benzoylphenyl)~ropyl]m~xph~line o~ime with 7.1 g. (0.31 mole) ~f
sodium in 65 ml~ of absolu~ eth~nol.
Anal. Calcd~ fox C20H2~N2O.~H~l: C,62.66; Hi7i36,
~ound: C,61.78~ H,7017;
Cl,18.01.
,' ~
A ~oluti~n of 13.0 ~ (0.031 mole) of 2-cyclohexyl-
met~yl-l-l2-[3-(oC-hydroxy-~C-methylbanzyl)phenyl~propy~ plp~ri-
dine (described in Example 6~ ln 130 ml. of methanol and 3 ml. of
o~centrated su7furlc acid wa~ stirred and refluxed for foxty-
five minuteQ, then co~lsd, diluted with 100 ml. of water,
ba~i~ied with 5 ml. of 35% ~odium hydroxide and extracted wi~h
h~xano~ Th~ combin~d hexane extract~, on washing with brine,
drying and evaporation to drynes~ gave 14.2 ~. ~f an oil which
: ~a~ ~hr~matographed o~ 2~0 g. of alumina in 8:92 diethyl eth~x~
,
- . 55 _
.
1053ZSl
hexane. There was thus obtained 9.8 g. of
as an oil.
Anal. Calcd. for C29~39N: C,86.72; H,9.79; N,3.49.
Found: C,~6.79; H,9.76; M,3.28.
4-Methoxyphenylaaetlc aaid (41.5 g., ~.25 mole) wa~
converted to the corr~spondlng acid chloride with 47.7 g.
(0.4 mole) of thlonyl chloride in benæene using the procedure
described abo~e in E~ample 1. The acid chloride ~hus produced
(36.B g., 0.2 mole) was re~ted with 24.1 ~ .21 mole) of
2,6-dimethylpiperidine ln eth~r in the pre~ence of 24.2 g.
(0~24 mole) of tri~thylamine u~ing the procedure described
above in Example 1. The r~ul~ing 2,6-dimethyl-1-[(4-methoxy-
phenyl)acetyllpipe~ldine ~38.8 ~., 0.15 mole~ was r~duced with
lithium aluminum hyd~ide and th~ pxodu~t i~olated in the fa~m
of the hydrochlorid~ ~alt to giv~ 1$.32 g. of
, m.p,
1~5-20QC.
The la~t~ ~l.Q g., 0.00~ m~le), ln the form o~ th~
free ba~e, wa~ add~d in ~mall p3rtl~ns to a s~irred mixture of
1.21 gO (0.009 mol~ of ~luminum chl~ride and 1.28 g. tO.OO9 ~le~
. .
o~ benzoyl chloride. The re~ulting vi~cous mixture was stirred
for about twelve ho~rs at ambient temperature and the~ mixed
- with ice, 2 ml. of concentrated hydr~chloric acid and 2 ml. of
water. The resultlng ml~ture was extracted with chloroform, and
the chloro~orm extrac~s washed with brine, dried and evaporat~d
~o drynas~ t~ giv~ 2,6-dimeth~
,
ethyl]piperidine a~ a yellow o~l.
Exampl~ l9
.
. 3~ A mixture of 45 ~. tO.13 mole~ of 2,6-dimethyl-1-
, . . .
. . - 56 -
"
., .
: ... . .. . . . . .. . . . . .
~S3~S~
~2-(3-benzcyl-4-methoxyphenyl)ethyl]piperidine (described abav~
in Example 18) and 34.9 g. (0026 mole) of aluminum chl~ride i~
tetrachleroethane was heate~ and ~tirred at 50C. for about
twelve hours and then poured i~t~ a ~olution of 30 ml. of
concentrated hydrochloric acld and 30 ml. of ice water. The
mixture wa~ ba~ified wlth sodium carbonate, extracted four
times with chloro~oxm, and the chloroform extracts washed with
saturated brine, dried and evaporated t~ dryne~s to gi~e crude
product which was once agaln hqa~ed for twel~e hour~ at 5~~.
with 30 g. of aluminu~ chloride ~nd 30 ml~ of tetxachlor~ethane.
on working up as before, thexe wa~ ebtai~ed 8 g. of crude
material which was di~solved in chl~roform. The organic solution
wa~ washed five ~imes with 10~ sodium carbonate, once with
brine t then dried and taken to dryness. The residue wa~
dissolved in acetone, and the ~olution wa~ treated with ethere~l
hydrogen chloxlde to ~ive solid material whioh was recry~tallized
frcm i30propanol. There wa3 thu~ obt~ined 5.8 g. of
1-~2-( ~ dine h~drochloride,
m.p. 217-219~C.
for C22H27N02HCl: C~7~-67; H,7.557 N,3.75.
Found: C,70.87; H,7.58; N,3.7~t
`. A soluti~n o~ 13.2 ~. tO~03 mole~ of 2-cyclohexyl-
~ me~hyl-1~2-~3-toC-hydrox~ 4-chl~ro~enzyl)phenyl]propyl~piperi-
.~ 2$ ~ine (~escribed abov~ in-Example 5~, 16 ml. o~ concentra~ed
nitric acid and 32 ml, of 50~ perchloric acid in 160 ml. o~
1,2-dim~thoxyethan~ was haa~ed under raflux ~or ~ne and a
~u~rter hours, then ~ooled, diluted with 50 ml. of water,
~. .
b~ified wLth 150 ml. o~ 10~ sadium hydroxide and extracted
with hexane. Th~ h~xane extra~t9 w~re wa~hed once with water,
.
- 57
... . . . . . . . . .
``` iO53ZS~
once with brine, dried and evaporated to dryness to give 12 g,
of crude product which was chromatographed on 200 g. of alumina
using 10:90 ether/hexane a~ eluent. The fir~t 75 ml. of eluate
was discarded and the next S00 ml. was taken to dryne~s to
yield 9.2 g. of 2-cyclohe ~ ethyl~ 2-~3-(4-chlorobenzoxl)-
phenyl]propyl~p-E~ dine.
Anal. Calcd. for C2~H36ClNO: C,76.77; H,8.28; C1,8.~9.
~ound: C,76.85; H,8.35; Cl,8~7
Exampl s 20A-20D
~ollowing a procedure similar to that described in
Example 2~, the ~llowing comp~unds o~ ~ormula I were similarly
prepared:
xamRle 20A 2-Cyclohexylmeth~ (3~benzQylphenyl)ethyl]
piperidine (yellow oil) p~epared by oxidatlGn of 14.0 g.
(0.03 mole) of 2-cy~lGhexylmethyl~ 2-~3-~dC-hydroxybenzyl)-
; phenyl]ethyl piperidin~ (described above in Example lA) in
227 ml. of a solu~ion prepared by di~olving 44. 5 ml. o~ ?2%
perchloric acid, 2~ ml. of watar ~nd 32 ml. o~ concen~rated
,
nitric acid in 323 ml. of 1,2-dimeth~xye~hane. There was t~u~
obtained 8~74 g. of product.
~nal. Calcd- ~r C27M3SNO: C,83.24; H,9.06; N,3.60,
. Fou~d: C,83.46; X,9.26; N,3.75
:~ Exam~æle 20B 2-CyclohexYlmethYl~ 2-~3-(3-chl~robenzoYl)~henYl]
~ro ~ ~ (yellow oii) prepared by oxidation of 17.0 g.
2~ (0.039 mole) of 2-cyclohéxylmethyl-1-~2-~3-(oC-hydroxy-3-chloro
benzyl)phenyl]propy~ Piperidine (described above in Exampl~ 3A)
in 244 ml. of a ~olutl~n pxepared by dlssolvlng 48 ml. of 50%
perchloric acid and 24 ml. of concentrated nitric acid in 240 ~1.
"r,
. . .
_ 58 -
- . .: , : " :
.:
"--` 1053ZSl
of 1,2-dimethoxyethane, There wa~ thu~ obtain~d 9.65 g. of
product.
Anal. Calcd. for C28H36ClN0: C,76.77; H,8.28; N,3.20.
Found: C,76.86; H,8.36; N,3.13.
Example 2~C 2-Cyclohexylmethy~ a-[3-(3~4-dichlorobenzoyl)
phenyl]propyl~iperidine (yellow oil) prepared by oxidation o~
11.9 g. (O.25 mole) of 2-cyclohexylmethyl-1-{2-[3-(dC-hydroxy-
3,4-dichlorobenzyl~phenyl]propy~ piperidlne (described ab~ve in
Example 3C) ~n 156 ml. of a solution prepaxed by dissolving
24 ml. of 50~ perchloric aci~ and 12 ml. of conGentrated nitr$c
acid in 120 ml. ~ 1,2-~im~thoxyethane. There was thus obtained
5.2 g. of product.
Anal- Calcd- ~o~ C28H35C12N0: C,71,18; H,7-47; N~a~96-
- Found: C,71.47; H,7.82~ N,2.96.
Example 20D 2-Cyclohexylme~hyl~ 2-~3-(2-ahl~robenzoyi
propyl~p~eridine (~ellow oil~ prepar~d by oxldation of 15.7 g.
a .036 mole) of 2-cycl~hexylmethyl~ 2-r3-(o~-hydroxy-2-chloro-
benzyl)phenyl3propy~ piperidine (descrlbed above ~n Example 3D)
in 225 ml. of a ~oiution prep~red by dissolvlng 48 ml. of 50~
2~ perchloric acid and 24 ml. of ooncentrat~d nitric acid in ~40 ml.
of 1,2-dimethoxy~than~. T~ere was thus obtained 6.4 g. o$
product.
: Anal. Calcd. for C28N36ClN0: C,76.77; H,8.2B; N,3.20.
~! ,. Found: C,76.47; H,8.58; N,3.09.
Example 21
A ~olution of 11.0 g. ~0.126 mole) of morpholine in
24 ml. of dimethylformamide wa~ stirred with external cooli~g
in a water bath dnd treated over a ten minute period with a
solution of 17.35 g. ~0,.06 mole~ of 1-(3-benzoylphényl)-1-brom~-
ethane in 24 ml. of dimethyl~ormamide. When a~dition was
- 59 -
., .. .. .. . -, - , . :
- .~ . . . . .
lOS3ZS~
complete the mixture wa~ 3tirred ~or an additional hour at
ambisnt temperature. The mixture was then flltered, the ~ilter
wa~hed wi~h ether, the filtrate poured in~o 125 ml. of ~ater and
the mixture extracted twice with ether. Isolation of the product
in the form of th~ free base ~rom the ether extract~ in the con~
ventional manner a~orded 14~8 g. o~ olly product which was
chromatographed ~n alumina using a 1:1 ether:hexane solution as
eluent t~ g~e 12 g. of 4~ 3-benzoylphenYl)ethYl]morPholine
a~ a pale yellQw oil.
Anal. Calcd- ~or ClgH21No2: C,77.26; H,7.17; N,4.74.
Found: C,76.95; H,7.11; N,4.61.
.' ~
4-~2-~3-(GC-Aminobenzyl)phenyl]ethy~ morphollne
~15.6 ~., 0.05 mole, d~cribe~ in Example 16A) W~-5 mixed with
13.8 g, (0.30 mole) of 97~ formic a~id a~d 9.4 g. ~0.11 mole)
.1, of 35% ~ormaldehyd~ golution. The mi~tUre wa~ heated to 95C.
to e~fect complete solutlon of the gummy ba3e, heating was
continued for ten hour~, and the ~clution was cooled and poured
lnto a dilute sodlum hydroxide/lce mixture. I3clation o~ the
orga~ic material in the u~ual manner by extraction with ether
1 aff~rded 15.6 g, of an oil whlch waqi ~hromatographed on 400 g.
;l af aluminA u5ing 1.5:98.5 i~opropylamlne:he~ane as eluent. The
first ten ~racti~n~, 75 ml. each,we~e collected and 3et aside,
and the next ten fractions, 75-100 ml. each, were combin~d and
taken ~o dryne~s to gi~é 10.6 g. of 4-~ -E~-(oC ~imethylamino-
. ~ as an oil whlch crystallized on
,~ itanding, m.p. 60-63C,
An~l. Cal~d. for C21H28N20~ C,77.74; H,8.70; N,8.63.
~ound: C,77.20; H,8.60s N,8.48.
-
_ 60 -
~10~3251
Example 23
Reaction of the 2-cyclohexylmqthyl~ 2-[3~4-m~thoxy~
b~nzoyl~phenyl]pxopy~ piperldine de~crlbed above in Example 7
with hydrobromic acid in glacial acetic acid, and isolation of
the product from a neutral me~ium affords 2-cy~clohexylmeth
~2-[3-(4-hydrcxybenzoyl)phenyl~propy~ ~perldine.
Exam;~le 24
Reduction ofoC-(3-bromophenyl)propionaldehyde with
~odium borohydr~de using the procedure described ln Example 3
and reaction of the re~ulting 2-t3-bromophenyl)propanol with an
exce~ of dihydropyran at amblent temperature ln the presence
of a few drops o~ conc~ntrated hydrochl~ric ac~d affords 2-(3-
~r~mophenyl)propane tet~ahydropy~anyl e~her~ Reac~ion of the
latter in diethyl ether wlth n-butyl~lithium followed by reaction
of the re~ulting lithio derlvatlve with benzonltrile using the
procedure described in Example 7 affords 2-(3-benzoylphenyl)-
propanol which, on reactio~ with p-toluenesulfonic acid in the
pre~ence of pyridlne, affo$d~ 2-t3-benzoylphenyl)propanol p-
toluene~ulfonate. Reacti~n o~ the latter with l-cyclohexyl-
: 20 piperazine in D~F in the presence:of anhydrous potassium
. c~rbonate af~ord~ 1-[2-~3- ~ )propyl]-4-cyclohe
piperazine.
BIOliaGICAL TEST RESULTS
: The N-~3-~Rl-~p~enyl)-C(~X)~-phenyl-lower-alkyl~ ami~es
of formulas I and Ia o~ the invention have been tested in the
çarrageenin ed~ma ~CE) and adjuvant arthritis (AA) tests and
found ~o have anti-inflammatory activity. Data so obtained,
. ~tated in term~ o~ perc~n~ inhibition at a dose exprassed in
terms of millimol~3 (~M)fkg., are given in ~ABL~ A below. For
comparative purp~e~ data obtained ln the carrageenin edema
- _ 61 _
,, ~
1053~51
test on the reference ~mpound ~designated "Ref."), 4-[(3-benzoyl-
phenyl)methyl]morpholine, disclosed in French Patent 1,549,342,
are also given. All data were obtained on or~l administration,
TA~E A
S ~ Dose C.E. A.A.
. . .
1 0~005 13 56**
0.02 23 73**
- Q.08 60** 91**
0~324 73**
lA 0.004 0
0.02 0
0.08 51*~ -
.324 62**
.
lB 0.004 0
; 15 0.0~ 0
0.08 13
. 0.324 Tox~c
lC 0,08 40~. -
0.324 77**
lD 0.08 36*
0.324 65**
3 ~.005 0
0.~2 3 2
0.08 35~ 30
! 25 3A 0.004 0
, 0.02 0
'. 0.08 34**
0.324 75~ -
3B 0.08 19
0,16 - 91**
0.324 63~*
3E O.OQ4 14
2 34**
: 4 0.0~4 0
0.02
. 0c08 18
i~ 0.324 72**
l~ 5 Q.~04 14
'3~ ~ 005 - 64**
i 40 0.02 41 70~*
, ~,0~ - 88**
.~
, ~ .
' :
~ ~ 62 -
~ j .
. , .
/
- .~. ~ ~ . . .
1053251
TABLE A ~Cont ' d?
E~x~le ose C ;E:. A.A.
SA O . OG4 0
0.02 0
O. 08 58~ -
O. 324 68**
6 O. 004 14
0.02 S
O . 08 2~*
û. 324 55**
7 O. 004 0
O . 02 22
O . 08 - 63**
7~ O. 08 45~ _
~ . 16 - ~**
~. 324 6~**
7B O . 004 3
O. 005 - &1**
O. 02 3~8* 55*
0~ OB - 85**
2Q . 7C 0-004
0,02 1~ -
O ~ ~8 58~*
O . 324 ~5**
7D O . 08 37**
2S 0. 16 - 100**
:, O . 324 49**
7E O . 08 33* 92**
O, 324 58**
` 7F O . 08 33** 91**
,~ 3~ 0 .16 - Toxis
'~ O, 324 51~* ~
,~
7G ~ . 00~ 33**
~ ~ . 02 42**
'~ O . 08 - 7~**
3S 7E~ (ba~e~ 0. 004 29*
. 0 2 4 4 * *
', ` ~, 08 - 81*~
:1, 7EI(~Cl) O. 08 68**
0 . 324 73*~ -
'; 4~ 7J 0 . 08 62**
;~i O . 32 4 6 6* *
8 ~. 004 ~ -
. O . 02 21
i ~ . 08 33**
: 45 0.324 68**
. . .
~; 6 3
., .
.
.: . . . - . . .
:
l~S3Z51
~1~ A (c~'~
Dose C .E . A.A.
9 a . 004 0
0.02 o
0. 08 21
0. 324 47**
0 . OOS 7 25
0 . 02 26* 63*
o. 08 6~** ~l**
lP 11 0 . 004 0
0 . 02 15
~ . 08 29*
0. 324 ~4**
- 12, 14 0 . OOS 21 69*~
C, 02 41** 81**
0 . 08 51** 87*~
0, 324 69**
13 0 . Oû4 0 37**
t 015 15 52**
0 . 06 37~ 78*~
0 . 08 54**
0 . 324 56**
0 . Oû4 16
0. Q2 43** 92~*
- 0. 08 91~*
`~ 15A 0.C8 27
B. 324 29
!- 16 Q . 004 16
. O. Oû5 - 80**
0 . 02 31* 89**
.08 ~ 108**
16A ~ . 08 27
0 . 324 39*
16B a . o~ o
. 3?4 36*
16C 0 . 08 49**
0 . 324 84*~ -
-J~ l? û. 004 9
;~ 0.02 16
',~ 4~ 0, 08 47**
0 . 3 2 4 6 7 * ~ -
- 1 9 0 . 0 2 5
. 0 8 ~ _
0.16 - 1
~ ~ 45 ~ . 324 23*
.,
,,
~ - 64 _
~ .
10~i3ZSl
~ABL~ A ~C-~nt ' d~
Exa~le Do~e ~ E A A
0.004 16
0.005 - 63~*
0.02 52** 9~**
0.08 - T~xic
20A 00004 9
.02 ~5
~.08 46*~ _
0.324 70~*
20B 0.004 1~ -
0.02 0
0.08 2~*
0.324 65~*
~OC 0.~04 17* _ :
0.02 15
0.08 19*
0.324 51*~ -
~OD 0.004 0
Q,005 _ 35~
. O.Q2 36*~ 54*
0.08 - 79**
;
21 0.08 32
Q.324 46*~ -
22 Q.08 29
Q,324 63**
Ref. 0~8 0
0.324 23*
* St~tist~ca11y d1~erent ~rQm con~ro1s p.~.O5
. 30 *~ Statistica11y d1~xont fr~m c~trols p, ~.01
;~ Certain o~ the N-~3-[R1-(pheny1)-C(-X)~-pheny1-1Qw
a1ky1~amine~ of ~or~ula I o t~q invention have baen test~d f~
,. aAti-viral activit~ again t h~rpe~ clmp1ex viru~ type~ 1 a~d ~
'. and have been ~und to hav~ ant1-vira1 activity. Data ~o-obt4~n-t,
s .
,~ ~ 35 exprsssed.~ n terms o~ ~h~ Minimu~ In~i~itory Concentra~ion
` (mcg./ml.), are given ln TAB~ B bel~w.
,~
65 _ .
,~ . .
10S3Z51
T~B~E B
Exan~ple MIC
lE~5 0 m~g . /ml .
6 mcg./ml.
10 6 mcg~/ml.
12,14 . 6 mcg.~ml.
. ~ , .
.,: , .
. :
,j ~ .
.
,:: ' ., :
.
, ;, ~
,. ~ ~ '. .
