Note: Descriptions are shown in the official language in which they were submitted.
HOE 75/F 330
1~'79735~ ~
The pres~nt irlvention relato~ to new ba~ieally ~ub-
stituted indolo derivatives and to the phy~iologically aeeept-
~ble acid addition ~al-ts thore~ s well ~ to a proe~s for
th~ manufaeture of th~se compounds and to th~ pharmaceutieal
compo~itions thereof.
It has now been found that indole d~rivati~es that carry
basie sub~tituents in 3 position ha~e v~luable pharmacological
properties, especially on ~ho l~art~ circulatory system.
H~nce, object o~ this invention ar~ indole derivative~ of
10 the ~ormula I
(R3)m
:ln whieh
R1 ~t~ ds f'or a ehlor:Lno or bromLno atom,
,
~2 stands for
a) an aminogroup of the formula -N~ 6 ~ wherein
R5 is hydrogen and
R6 is . . 7 ,
I) an aminoa].kyl group of the formula -A1-N~ 8
wherein
A1 is a single bond or represents a straight-
chained or branched low-molecular-weight-
alkylene group having up to 6 carbon atoms,. .:
. which may be substituted by hydroxy or alkoxy or
: ;D I acyloxy groups both having 1 to 4 carbon atoms,
and whereln
, ,
--. , , . :. . .
.. , . . . - . , ~ ~ :
: : .
- ~ . . ` ,. ', . .
~LO'7~73g
R7 and R8 may be identical or different and
each represents
1. hydrogen
2. a cycloalkyl group of 5 to 7 carbon atoms
3. a straight-chained or branched alkyl group
of 1 to 6 carbon atoms,
4. a phenyl group which may carry one or more
alkyl groups of 1 to 4 carbon atoms, alko~y
groups of 1 to 4 carbon atoms, methylene-
dioxy, hydroxy, nitro, amino groups or halo-
gen atoms
and if
.~ n
R' and Ru represent alkyl groups, these groups
may
O~) form together with the nitrogen atom a S-,
6- or 7-membered heterocyclic ring which
may be substituted by alkyl groups of 1 to 4
carbon atoms, alkoxy groups of 1 to 4 carbon
atoms, hydroxy groups or alkoxy carbonyl groups
groups o:E 1 to 4 carbon atoms, or
B) form together with the nitrogen atom a
5-, 6- or 7-membered heterocyclic ring
wherein one of the carbon atoms is re-
~ placed by oxygen, sulfur or nitrogen
atom, this latter may be substituted by
1. hydrogen
~ ~ 3 ~
''.
.
, ' . , ~ ' , .
. . .
.~ , . . . . .
'79739
2. a phenyl group which may be substituted
by one or more alkyl groups of 1 to 4
carbon atoms, alkoxy groups of 1 to 4 car-
bon atoms, methylene-dioxyr hydroxy, nit-
ro or amino groups or halogen atoms,
~ 3. an alkenyl group of 3 to 8 carbon atoms,
4. an alkinyl group of 3 to 8 carbon atoms, :~
5u the formyl group,
- 6. an alkyl group of 1 to 4 carbon atoms,
. which may be subs-tituted by one or more
hydroxy, alkoxy groups of 1 to 4 carbon
atoms, ethylene-dioxy, trimethylene~di-
oxy, phenyl groups hav~ng the substitu-
ents men~ioned above (item 2) or amino-
oarbonyl groups of the formula
- 3a -
'
.1 . .
.
.. ~ .: . .....
-
.
~'79~39
~ . .
-CO-N~ , wherein
~R1 0
R9 and R10 have the same meanings as R7 and
R~ with the proviso that they ~ay form to-
gether with the nitrogen atom a 5-, 6- or
7-membered ring which may be substituted
as defined above (itemOC) and wherein one
; of the carbon atoms may be replaced by an
oxygen, sulfur or nitrogen atom, this latter
being, however, unsubstituted
II) a cycloalkyl group o~ 5 to 7 carboll atoms,
whi.ch may be substitut~d by dialky:Lamino cJroups
o 1 to 4 carbon atoms, or
III) R6 forms together with R5 and the nitrogen atom
a 5- or 6-membered ring, in which one of the
carbon atoms may be replaced by a nitrogen atom
which may be substituted as mentioned for R7
and R8 (item B, 1. to 6.) ~11
, b) an.aminoalkoxy .. group ofthe formula-O-A2-N\
, wherein R
A2 stands for a straight-chained or.branched low-
molecular-weight alkylene group of 2 to 6 carbon
atoms which may be substituted by alkyl of 1 to
4 carbon atoms or by phenyl optionally having
.~ the substituents mentioned above (item B) 2.)
and
' R11 and R12 have the same meanings as R7 and R8,
~: .
~ ~ .
1~7S~739
c) a ba~ic radical of the formula -o-(CH2)n-R13,
wh~rein
R13 stands for a 5- or 6-memb~red heterocycl1c
ring containing a nitrogerl atom and
S n stands for zero or 1.
R3 stands for a hydrogen atom, the hydroxy group, an alkoxy
group of 1 to 5 carbon atoms, a fluorlne, chlorine or bro-
mine atom, the nitro, amino or benzyloxy group,
m stands for the integer 1, 2 or 3,
lO R stancls for a hydrogen atom, a saturatsd or unsaturated, ~,
8 tral~ht-ch~.i.ned or branched allphat:Lc hyclrocarbon radi-
ca:L haYirl~ 1 to 5 carbon ~toms, the benzyl or phonyl ~roup,
o~ wh~ch the phony:L nuclou~ may bo sub~t:Ltuted ag de~`lnod
for R2,
and the physiologically acceptable salts of the said com-
pound~ o~ formula I.
Preferred sub~tituents are the follow:ing: for R the
chlorine atom; for R the radical ~NH-N ~ 8 ~ wherein R7 and
, R to~ether wlth the nltrogen atom form a 6- or 7-mambered
r:Ln~ ~or example ll-rnetllyl~ ipara~inylamino or plpexidino-
amlno; ~urthermore, tlle racllcal -N~ -N~'~ , wherein Al
stands for a strai~ht-chainad or branchcd alk~lene group of
2 or 3 car~on atom~, which may bo subs-tituted by hydro~y and
. ' ' ' . . . . .
. - - 4a -
w. ~ - . , ~ ' .
- , .
.
. . ~ .
.~ .
, . .
9~3~ ~[o~ ~
wherein, if R7 and R8 are dLfrer~n-t from each other, R7 i~
hydrogen ~nd R a linear or branched alkyl group of 1 to 3
carbon atoms, or :Lf R7 and R are identical, they stand *or
tlle same alky.l groups of l -to ll carbon a-toms or togsth~r with
g the ni-trogen atolll-th~y foral a 5- OI` 6-m~mbered ring which may
contain anothor hetero a-tom, for example thv morpholino, pi-
per:idlno, pipsra~GinO, l~-methyl-plp~ra~ino or pyrrolidino group.
Fur-ther pre~errecl substituent~ t`or R are the l-pipera~inyl
~roup - ~ ~I-Y, whorein Y is hydrogen, alky:L of 1 to l~ carbon
atoms3 B-hydroxyethyl, 2-(1,3-~:lioxola~-2~yl)--~thy.L, 2-(1,3-
dioxan-2-yl)-ethyl, 3,l~-methyLene-cliocy-ben2yl, pyrrolidino-
ca.rbonylmot}lyL, phenyl, phenyl which is ~ubstituted by metho.Yy,
chl.oro or n~tro, a:Lly:L,2-nlethy.Lal.Ly.L o:r prol)arg,y.l, the amino-
~lJ. Icy l. O Xy ~L'O L~ ~ _o_~2_N R1 whore:ln A2 L d
t:ra:Lght-ohn.Lrlocl or brnllc}locl n.l.~cy.Leno group or 2 or 3 on.r.~bon
aLorll~, and .I~ 1l ancl:RI2 are d:Lr:f`eI-erlt frorn oaeh othel, Rll
i9 hydrogen and R12 a linear or branch~d al]cyl group of 1 to
l~ carbon atoms or a oycloalkyL group oP 5 to 7 carbon a-toms,
or ir Rll ancl R12 aro ldentical, th2y 9 tand for alk~.L groups
o-.~ 1 to 4 carbon atoms, or -togethsr with -the ni-trogon atoms
they stand for a 5- or 6-rnembered rlng which lilay contain
anothe.r hetoro atom, for exarnple the morpho:LLno, 4-lnethy:L-
p:lperaY.:Lrlo~ plpe:ridlno or pyrro.L.Ld:Lno ~roup.
Li:kewise preferred i9 the radical -0-~C1l2)n-nl3 , wherein
2$ n is an integer of 1 or zero and R13 stands for a 6-membered
; cyclic basic radical, for example 1-methyl-l~-piperidyLoxy,
l-msthyl-3-piperidyloxy, 1-mcthyl~3~piperidyl~-methyloxy,
2-pyridyloxy, ~-pyr:idyloxy.
. 29 Tho pre~erred substi-tuents -for R3 are hydroglen and alko~y
_ g _
:
.: .''. '
' : . ' . . :
.: ~ : .. ,
10 ~ 7~9 ~lo~ '~5/F 130
groups of 1 to 4 carbon atoms, ~speclally the mcthoxy group,
pref-rlrably ~n the ll_, 5_ and/or 6-position. . ~
~4 proferably stancls ~or hydrogrerl, methyl, phenyl or benzyl,
or a o-, m- or p-(Cl-CIl)-alkoxyphenyl group1 e~pecial1y
tho methoxy-pheny:L group.
Further object o.~ this inven-tion i.s a process for th~
manu.~ac-ture of the compounds of formula I as we:ll as pharrna-
cQutical colllpositions of these compouncls. ~'
The process for the manufac-ture o r the compounds of the
invention comprises
(a1) reacting a compound of the formula II
,
~0
~ R~
:Ln wh.ich ~, R~ and m are c~le:fin~d as ln ~`ormu.la I, with
phosphorus oxychloride or -bromide and dimethylformamlde
to yi~ld an alcle~lydo of the form~lla III
. . ' //o
,C~I
)m
~a2~ oxidi~ling ~h~ ald~h~rd~ o~t~in~d to y1ulc~ th~3 oarqoxyllG
acid of *he ~ormu:L~ IV
COOH
~ R1 ''' ' ~
" (P~ )m R
w 6 --
.
: . ... :
. .. . . . .
': '" ' ' . . ',' ~
~lO~ 'f5/I~` 330
1~79~39
in which R3, R and m are def'ined as 7 n formt~tla I, and
(a3) roac-ting tho ~o-obtained compound of formula IV ~ith an
amine o~ the fornlula ~IN ~R6 or with an alcohol of the
fo~lnu.la ~O-A -N ~ -l2 or -~10-t~Cfl~)nE~ 3 , whercin A2,
R5, R , R11, R~2 and R13 and rl are defined as in formula
I, or
(bl) reac-ting a compound of the formula II as defln~d sub
(al) w:i-th phosp~lo~ls oxych:loride/dimethylformamlde first
to yleld the 3-dimethyLam:Lno-methy.lene compotlnd of the
formula V
~;~C~ "Cr}13 V
and
(~2) converting the resulting compound of formula V by
roaction with phosphorus oxytrichloride or -bromide into
a compound o~ the formula VI
H Vl
(R3 )m n
and converting this compo~tncl according to steps (a2) and
(a3) into a compound o~ forlllula I, or
(c) reacting a compound of the formula I, in which R to R
and m are dcf:ined as above with -the proviso that R
contains a s~condary amino group, ~ith an alkylating
agent of the formula R1 X7 wherein X stands for a
~ 7 ~-
.
~79739 ~IOE 75~
chlori~e or bromitl~ atom and R1 for an alkcnyl group of 3
to 8 carbon atoms or ~or an alkinyl group of 3 to 8 carbon
atom~ or for an ~lkyl group of 1 to 6 carbon atols-s ~hlch may
be substituted by hydroxy, alkoxy o~ 1 to 4 carbon atoms,
ffthylene~dio~y, trime-thylene-dioxy, optioncally ~ubstituted
phenyl or by -the group -CO-N ~ 10 ~ whereill ~9 and R are
defined a~ abo~e,
The oxo-indole of formula II used zls star-l;:ing compound
for the proces~ of the invention i9 known in th~ art and may
be prepare~ accordillg to t~l~ method of 1~.E.Sch~1lte, J. Reisch
and U. Stoess (Arch. Pharm. ~0~, ( 1972), p. 523) and }I.A.H.
Beclcett, R.W. Dalsl~y, J. WaLk2r (Tetrah~dron 24 (1968), p.
6093),
~ocor~lLr~t,~ to methocl (a)~ ~ho oxo Lndolo o~' ~orl1lu1a :C:C i~
1~ ~eactod Ln knowr1ll~ar1llor nccoxclll1~r to 'Vll~imo;i.er tLaaolc (O, Bayor
in llouben-Weyl: Me-thod~n deI organlschen Chernie, 4th edition,
Y. Tlliome, Stuttgart, 1954, Vol, 7/1 p. 29). The a'Ldehyde of
formula III is then oxidized according to known methods, for
oxample u~ing po-tassium pormanganate, to yield the car'hoxylic
acid of formuLa IV,
Thc compound of ~orn1ula II'L (~ C6~5, R3 i~ }1) is
cllsclo~ecl in tho art, Its prep,lratlon by kho Vllsmoier ~orlny-
latlon of' N-phenyl-oxo-indole (K.E. SchuLte, J. I~Qisch and
U. Stoess, Arch. Pharm. 305, p. 523 (1972)), howeYer, leads to
mixtures of products, from whlch the pure compound of formula
III can be obtained only aftar complicated pur~fication opera-
tions (L. Marchetti and A. Andreani, Annali di Chimica ~ ,
p. 681 (1973)).
29 ' When, howevar, according to method (b), N-phenyl-oxo-
- 8 -
.
.~. . .
.
'~ ' , " " . '
: . ' , : ' . ' ~ ' , ,
~7~739 ~ F~30
indole is react~d wLth dim~thylformamido/p}losphorus oxychlo-
ride at a t~rnperature of from O C to 30 C, the rosul-t ia a
puro product Or formula V iith a very good yield. As solvents,
there are mentioned inert anhydrous organic so.Lvonts, such as
chloroform, carbon tetrach.Loride, dio~a~, berlzena, to.Lu~ne,
chlorobenzene, N,N dimethylformaillide. The compowld of formula
V .is then convorted into th~ compound of fo.rmula YI by reae
tion ~i-th POC13 or POBr3, using the phosphorus oxychloride or
-bromide in at least equi.valerlt amounts, pr0f~rab.Ly :Ln a 3-
tO to 5-fold excess. ~s so.lvents, there are used inHrt apro-tie
solvents such as ben~.ene, to:luo.ne, chloroben~ene, chloroform
or carbon tetrachloride. 'l`he .roact.Lon ls generally carriecl out
nL -tolllperatllr~s o~`.t`rolll 30 to l()f)C, r>roE`~:r~b.l.y *rom 50 to
f3
~l5 Utlcl~r t~lo ~lL~l oollcL:LL.Lorls, aL.L the ol;ho.r oompourlds o~
rormu.La Il may also b~ reacted to yie:l.d compouncls of formula I.
T.he compounds Or formula V.l obta.lnecl according to (b)
aro then converte(l according to methods (a2) and (a~) into
cornpounds of t`ormula I.
Aeeording to method step (a3), the earboxyl:Le ae;Lcls o~
formu.La IV are eonverted aceordLng to thc usual mothods of
ostor or an~ o format.lon, for exalrlp.l.e v:La aaid eh:Lor-idc~ o:r
mixed allhydrides, lnto the e.st~r~ o.r am:Lclos. I~`or esteri~l-
ca-tion with a.leollols stil.L conta:Lning seeondary amino groups,
the salts of the am:Lno aleohols are used.
According to method (c), the secondary amino groups are
alkylated aceording to known methods usin~ alkylating agents
Or the de~ined ~ormula XR
i~
29 The co~pound.s of the inventlon have valuable p.harma-
- 9 ~
.
'' ' ~
.: , :, . . . :
:, . .
,
.. . .
1~7g73~
cological. propertles. Thu~ ~or example, ln addition to other
properties, they have an ef~ect on th~ coronary circulation,
which appears :in a hy~otensive effect and especially in an
antiarrhy-thmic activity. These compounds are the:rafore suit-
ab.Le for the troatmen-t of disturbances in the cardiac rhythmQ
This antiéarrhythTnic activity was establish~d on a dog that had
been poisoned with s-trophanthln, on a cat exposed to hypo-
thermia and by means of the cllgltoxin-acon:i-tin fibrillat-ion
test on -the guinea pig-Langendorff heart.
The novel compourlds may bo used aLone or lrl actn~ixture with
pharmacologically acc~ptable carrier materia:L. l~`or oral ad~
mini.stration, the acti~e compounds are mixed with the usual
substances a~cl brought lnto thi~ us-~a:L closa~e un.iL .~orms by
Icnown mo thocl~, .f`o.t.~ ~xartlp.l.o l~f.~b l.c ts, ge La t:Ln onpsu.Lo4, a~ eo-l~,
ls al.oo~lo.l.lo or o:L:ly :~u.3[~n~:Lolls or nclu~ou3, a.Lco~lol.Le or o:l..ly
so~ t.lon~ .Lr~xt oarr:lor materLa.L, thore mé~y be u9ecl, for
example, magnesium carbonate, lactose or corn 9 tarch, in con-
junetion with other ~ubstances, ~or example magnesLum stea-
rate, T.he eom2os:Lti.orl may be ln the form of dry or mois-t
granuLes. As oily carrier material or solvents, -there are
ospecially usod vegotable and animal oils, for example sun-
rlower ol:L or castor oL:L.
~ peo.ially aclvantagrcous 19 t~lo :Lntrav~xlous adm:Lnistrat.ioxl.
~or this purpo4e, the active compounds or the physiologically
acoeptable salts thereof are dls.solved together with -the usual
subst~nces .
Such physiologically acceptable sal-ts are foulld with the
-~ollowing acids, fo.r example: hydrochloric aoid, hydrobromic
29 acid or hydrolodic acid, phosphoric acid, sulfuric aoid,
,
-- 10 ~
~.. ;, . . .
"~ ' ' . : .
.
' ' : '
~IOE 7 ~F~
739
methylsulfur~c acicl, amidosulfonic aci~l, ni.trlc acid; formic
ac:lcl, acet.~c atid, propionic acld, s~lccin.ic ac-i.d, tartaric
acid, lactic ac:id, malonic acid, ~umaric aclcl, oxalic ac.id,
citric acid, ma.Lic acid, mucic acld, ben~Joic acicl, salicylic
acid, aceturlc acid, embonic acid, napht}lalene-1,5-disulfonic
acid, ascorbic acid, phenylacetlc acldl p-amino-salicylic acid,
hydroxyethane-sulfonie acid, benzone-sulfor1ic acid, or syn-
-thetic resins containing acid groups, for example thosa having
an ion exchanger effect.
~s solvents of the corresponding ph~ls.iolog:ical.ly ~ccept-
able .sa.Lts Or the actlve compounds suitable for intravenolls
admin:i~tratLon, thero are mentloned,~ for exaltlple, water, a
phy~:Lo;log.ica:L socl:L~Inl ch.l.orldo ~o.l.utios) or tl:Lcl)ho:Ls~ Por examF)lo
oth~ ol, r)ro~nallo cl:l.ol or ~:Lycero:l; rurtlle:rllloro, ~u~;ar so.lut:l0ns,
f~or ex;.lmp.Lo ~I.U~O~Jt~ 0~ Inar~ .Lto.l. sol.ut:Lon~, or Inlxtu.res o~' t.tlo
varlous solvents rlleIIt.tolled.
~or oral administrat-ion, the sing:Le dose Ls wi-thin the
range o~` from 50 - 1,000 mg, preferably from 100 - 500 mg, for
the intra~enotns o.r intramu~scular admlni.stra-tion, it i~s within
-the range of froln 20 - 100 mg, proferably 50 mg,
The da.ily dose ln each case is ~or t.he oral admll1is-tra-
t:l.on w:Ltllln t}l~ range of frolll 50 - 2,00() mg" preferably 500 Ing,
~or the lntravonous or lntrallluscu:Lar adm:LI1Lstrat:Lon wlth:Ln
the range o~ from 20 - 500 mg, preferably 100 mg.
The pharmacolog.ical effeet has been tested on rats.
The compounds of formula I may also be ~1sed as inter- `
msdiate produets for the manufacture of i~dolo derivativv~ -
which carry basie substi-tuents in -the 2~ and 3-positions.
29 The following Examp:Les lllustrate the invention.
': ' , ' , " , . :
. ., ' . ~ ' ~ , '' '
'
~79739
E X A ~I P L E 1: ,
2-Chloro-1~pherly.L-:indole 3-earboxy.lic aeid ~-m~thyl) pipera- -
~ f3
(a) 2-Chloro-l-phe~.l-indo.Le ~-carb~a~ cll etlvde
To 130 ml o-f N,N-dimethy:Lf'orma~ .do, 130 ml Or phosp~lorus
oxych.Lorlcle were aclcled dropw:i~e whl.le eooling, so that
the temp~rature di~l not exce~d ~25C. S~irring was con-
t:inued ror 30 tllinU te~ at room te~nperaturf3, L~oO rnl of an-
hydro~ls -toluerle w~re adcled, and then 209 g (1 mol) of N-
p}lenyl~oxo-inclole wero :int:roducecl portions~.Lse wh-ile
eoolLng to ma:in~;ain the -telllpera-tL~re between 30 and 35 C.
Stirring was eont:irlued :~or 2 hours at room tempera-turo,
1 .l Or eh;Lo~o.,ornl wa~ aclclud, arl(l tho m.Lxture was ~ash~d
sov~ral t:lm~3~ wi.th wate.r, at ,I.ast w:lttl an iaqueou~ socllum
b:l-earL)ollato st)'l.ut.Lo~ lo so.Lvl3rlt w~l~ f3.Llm.lnatocl ln VUCUO,
and tho erystall.L~ed r~esldlle was washf3d with dii~oproprl
ether to yie.Ld 230 g of a brown-colored 3 climethylamino-
methylene-1-pllenyl-2-indolinone melting at 130 - 132 C
(87 ~ of t.he theoretiea:L y:Lold).
The produet was heated to the boil .E'or 6 hours .Ln a `
mixture of l~50 ml o~ ehloro~orm and 225 m:L o~ pho.sphorus
oxyeh.l.orldo, tho ooo.l0d solut:l.on wa9 washed wLth water,
arlcl tho solvent was ellm:Lnatod ln vaeuo. The erystal:Li~d
residuo (1~2 g _ 86 ~ of -the theoretieal yie:Ld) melted
upon washing with diisopropyl ether at 132 - 134 C.
~b) 2-Chloro-1-phenyl-indole ~-carboxy.Lie aeid
.
256 g (1mol) of 2-ehloro-1-phenyl-incloLe 3-earboxaldehyde
were suspended in a mixture of 3.5 1 of aeetone, 2.5 l of
29 Im phosphate buffer (pH 7) and 1.7 1 of wa-ter, and 230 g
~ _ 12 -
... : . .
... . . .
"....................... .
1~73739 ~0~ ` 3 ~o
Or pota~siUnl permarlganate were added portions-~ise while
stirring a-t 40 C within ~ hours. 5t:irring was continusd
for 2 hours, and ,'0 g of sodium b:lsu,Lfate wero added. The
precipitate was ~uction-flltered, washed -tw:lca with 300 mL .'
o:f water each time, the faintly ye.llow Piltrate was s-trong- ,
ly acidified with concerltrated hycl:rochlorid acicl. The pre-,
cipi-tated acid was suct:ion-f`iltered and washed with va-ter
until neutral.
Yield: 190 g (7-i ~ of the theoret:ical yi~ld), m.p. 220 -
221C.
(c) 2-Chloro 1-phenyl-indole 3-carboxy'Lic ac:icl (4-mQthyl)-
a~,:ide ~
135.5 ~ (0.5 mo:L) of' 2-o~lt.oro~ erlyl-Lrlclo:Le 3-carboxyl.Lc
~c:ld ~ d 110 Inl. ('I.5'mol.9) o:f th:Lo.rly:l. c~ rlcl~ w~ro hocit~d
I ~; E.lt t.llO ~ .1 Lul~.L.'I. tho ovo:Lut:Lon o.t` tra~ oea,~cl; ~XC~9~thlonyl chlorlcle wa~s e,l:llll:Lnated ln vacuo, and the crude
crystalli~ed acicl ch,Lorîde was dissol.vod :in 500 ml of
chloroform. J~t -20C, a mixture of 75 g (0.75 mol) of N-
methyl-pipora~irle and 55 m:L (0.7 mol) of pyridine in lO0
ml o-f chloroform was added while coo.lLng and stirring, so
that tho temperLIture did not exceQcl-~10 C~ St:i.rrin~ was
cont:L;nuo~ ~or.~ 3 hours at room tempora-ture, the solution
wa~ wash~d three tLnlos w:l.-th wa-tor, Qnd th~ 301vent was
eliminated :Ln vacuo. The residue was freed from pyridine
sti'Ll present by dlsso1ving it twice in -toluene and eva- .
porating the toluene in ~acuo. The crude resinous base was
dissol~ed in 250 ml of acetone, and an excess of ethanolic ',
hydrochloric acid was added. 1`he crvstal. mass was suction-
29 fil-tered and washed with acetone.
.
. , 13
. '
~ :
!
.. . .
;
~V7~739 ~OI~ 5 ~
Yielcl: 1~8 g (8G 'J.q of the theoretica:l yield), m.p. 248 -
25()C.
E ~ A ~1 ? L E 2;
2-Chloro-1-T)herly.l.-.incLol.Q ~-carbox~ic acid pi~eraz.ide
S (a) 2-Chloro-l-pherlyl-inclole 3-carboxylLc acid (4-formyl)-
pi~erazide _ _ _ ~ __ _
Th:is compound was prcparecl as in Examp:Le 1 (c) from 2-
chloro-1-pheny.L-iIl(lole 3-carboxylic acicl chloride and N-
fornly:L-plpera~.ine. Tho react.ion solution was washed
successive.Ly with water, 2N hydroch:Loric acicl and water.
After the so:Lvent had been e1:Lminatccl an amorphous brown
COlllpOUnd l~aS obtained, w}l:Lch was un:L.form accorcling to the
thisl.Layor chrolllatotsralll.
(~)) ?-C~Ir~~!~L~ r~ r. ~ lcL~ r~ L~Io,
1.5 0.l3 mo.L o~` tho N-f`ot~myL co~ )o~ncl obtalned sub (a) was
cllssolved J.n 350 nl.L o~` ethlrlo'L, and after acLcll*ion of lOO
ml of a 30 % sodium hydro~icle so:Lu-tion, the solu-tion was
stirrecl for 6 hours at roorll terllpera-ture. Then, 400 ml of
water were add~d, and the mix-ture was ext,racted three -times
wi.th methylene ch:Loride. ThQ res.inous res:Ldue o:f t}le or-
ganic phase was clissolved in acetone, ancl a so:Lut:lon of
an ~quiva.1ent alllollnt o.~ rmale:1c ac:ld in acetono wa~ ad~ed.
T.he cry6tal mas~ was suction-fi.Ltered and wa~hecl with
acetone.
Yield- 54 g (91 % o~ the theoretical yield), m.p. 147 C
(maleinatc).
The substi-tuted 2-chloro~1-phenyl~indole 3 carboxylic acid
. ~ derivatlve~ Or the Examples listed in Table 1 and the pharma-
29 colo~ically useful salts were prepared from 2~chloro-1-pIle~yl-
- 14 _
,
. .
lV~739 llo_z.~ ~ :
i ndo l ~ 3- c arbo xyl i c ac i d ch L o ri do and thc c o rrc sponding
. .
bascs accord;.ng to Examplc 1 (c).
T A :B I, E
~C OR
C6~15
- 15 -
.
. ~
'' , .
,
. , .,., .. , , ~, .
.
~ 9739
?
o~
o o o
,~
V~ '~ A --~ o ,,, C,, _~
~ ~ . o o ~ ~
' ,s: ~- r- ~_
h O O h
_~ (~ h
C) ~ o
o a~ h h
~ ~ a ra ~ ~ v ~
P~ rl rl ~rl rl rl ~ 2) 0
~ h h h h h O O rl h
Ei O O o o o o o h
_, ~ ~ ,I h h O
r-l h h h h h 'q O ~d
u~ ~d 1~ ~ ~ ~cJ ._ .~~, ...
~ ;~
_ ~ O O ~ 0~
o R R ~:: R i: ~ ~ '^P'
. rl .l ,1 ,~ ~1 h h o h
P~ u) u~ O O ~ O
~ h h h h h ~ ~ `
___ ~
~ .
~1
r~ 'n ~ .
~ ,r~ ,r
t~ r 5 ~ r U
~ 3 ,~
o . ~
e
æ ~ ~ ~ O
.
1 6
. .
.: :
'
.' '
~013 7~
,_ ,'
O ~ _ I
oO O ~'.
oO '\
O. ,,~
P ~ . ~, .
o ~ ,\ p~ h ~P
~ o ~ 1 o E~ O
~ h S1 o --- o ~
O ~ , ~ a ~
~ 0 2-- `_ h '~~ho
Ei o ~ ~ rd ~
_, ~ I' h h h t) h O
~ ~ O o o o ~ o
,,
(drl `~ o () t) ~ ~r1
0~ ~ O O O O
h h h
~~n 0 ~ ~ ~ ~ 0 0
O
h h ; rl r~ h h h .
Ç3 ~ ~ h h h 9 ~ ~ ~
_ ~
. ~ '' , .
~,
P; rc r~Z
_ ..
1~ I
_ 17 -
' ~.,., .!; ,
: '
.' , . " . , ' ,~
~97~3735~ ~OI~, 7 ~/F 330
,_ _
o o
o O
U~ ~
~o /~
.
O O
o o h h
U o o
~ ~ a) e
O ~ ~~
_~
V ,, ~ . .,~ .,, r~ .rl
o h `-- h ~ h h
O o o o O
.
. o ~ , ~ ~ U ~
~ O ~ o o o o
_ h h h h h h
~ o
.~ ~ ~ `~ ~ ~
~ ~ t ,Ct ~. ~t
U~ ~ O ^ ~
~I h ~O ~n v) ~n
~ r ~ t
V ,~ ~ r- o O O
o
. ~ h h h
r~ ~O Irl O O O
r- o~ t E3 E~ a
~ , .~
_ ~
~-. . .
~'J ~It . .
P~
C~
Z . .,
~ .
~1
~ o .,. ~ , ~ ~p .. ."
x .~ ~ .
. . .
. ..
'
_ 18 --
,
: . ' . .- .... . :
~IOE 7 ~F ~0
1~79739
X A ~I r L E 26: ~
2-Chloro-5-1netlloxy-1-rll~thyL-lndole 3-carboxylic acid (l~-me-
th ~ p pera~ido _ ~ _
(a) ?-C~Iloro-5-rnothox~- ! -me-tllyJ -irldo Lc _~-carh ald~x~
To a mixturs of 33 ml of N N-dimethylforlllalllide and 30 ml
of chloroforn~, 22 ml of phosphorll~ oxychloride were add~cl
dropw:iso, whi;L~ cooling wi-th ic~. A~-ter 20 minu-t~s, a
solutLon of 20 g o~ 5-methoxy-1-mothyl-oxo-indoLe in 30 ml
of chloroform was added dropwisc so a~ to maintclin -the
temperature bctwson 25 and 30C. Th~ mixture was alLowed
to stand for 3 hours ~t room temperatur~, and then a mix-
turo of l~oo ml of sa-turr-ltod aqUeOIlS ';OdiLllll biCarbOrla te
solution wa~ acldocl~hil~ stlrrlng. r~ or~;anic phase was
r~opar.ltocl, waflil~d with wator rlncl ttlo solverll; wa~ ol;lml-
slatol in ~nc~lo. Tll~ claLIc-r~l olly ~o~l.clue wa~ oklromtlto~
grapsled l)y mearl~ o~` ~illca geL 60 (o.o6 - 0.2 mm, do-
activatecl by 10 ~ of watcr, column siYe 3.5 x 80 cm) and
a toluene/ei;}lyl acetaie 8~1 mixture. After a first frac-
-tion of 200 ml, the abo~ro-specifiod compound was elut~d.
Yield: 1 1 g of light ysllow crys-tals, m.p. 115 C.
(b) 2-Chloro-5-me-t~ __clole_~____b~ io aoicl
~1 ~ of potas~lunl pcrlllanganato wer~ adcled portions~lse at
35C wlthLn 1~ hours to a susporlsiorl of t6 g o~ 2-chloro-
5-methoxy~ ethyL-indole-3-carb aLdehydo in 280 ml of
ac~tone, 210 ml of phosphate buffer (pH 7) and 140 ml of`
. .,
water. Stirri~g was continued for 2 hours until the vio-
let color had disappeared, 3 g of sodium bisulfite were
~ added, and artsr standing overni~ht, the precipita-te wa9
29 soparated by suction-filtration. A~ter acidiflca-tion,
- 19 -
,`
1~79739 ~
1 g of` carboxflic acid WCa9 precipltatd from th~ ~iltrat~.
Tho preclpitatc was dig~-ted twice with 100 ml o:f N,N- -
climetllyl.-~ormalnidc CaC}1 time, undi.sctolv~d ~substance was
separa-ted by filtre~tion, ancl tho.fi.ltrat~ was diluted with
/~00 ml Or water. The s~para-t~cl crye;tal mass was ~uc-tion-
f`iltcred and t~ashcci with wat~r -to yiold 10 g.
The ove:rall -yielcl~as l1 g (6l~ % o~' th~ theorctical yi~lcl),
m.p. 2It2 - 24ltC.
Acid ch.Loricl~: f`rom the acid alld thionyl chlor:ide~ :
~I.P. 132 - l3ll C
(c) 2-Chloro-5-m~-thoxy-l-mothyl-inclole 3-carboxy:Lic acld
__ido _ _
Tllo abovo ..l~lb~t ta~lco ~ S p.r~JI)arQcl acco:r~l.l.llg to l~xanlp.Le
I ~o) f`rotrl 2-cil.Loro-5-nl~tho:xy~l-nlot}ly.L-ll1clo.Lo 3-carboxyL:Lc
ac.kl cll.l.or.Lclo arlcl N-rrlothy.L-~ )oraY~:ltlo :LII o~l.Lo:roro.rrll,
rn.p. l2l~ - l25C.
M~ E_ ~I~
The substitu-tod 2-chLoro-5-mc-thoxy-l-mothyl-inclole 3-
carboxy.Lic aci.ds of ~ormula I and t,ho pharm~co.Logiccllly U90-
:~ul salts theroo~ woro proparod ~rom 2-chloro-5-mo thoxy- 1-
rn~thy.L-indolo 3~carboxy.L.Lc acid chloricio and tho correspondLn~
~acto~ ~ocordlrlg to th~ ~`xartlplos ~ (c), 2 (a) ancl 2 (~). Tho
basos arld tho racllcals ~2 a:r.~o ll~tec~ :Ln Tab..Lo 1.
CII30 ~ ~ ~ COR'
'N~ Cl
C~I3
E X ~ M P L E 28:
~-C.hloro- 1- ( 3-mc thox~flvhenyl ) -indolo 3-carboxylic acid (I~-Tni~ -
- 20
,
'' ,''
' ' ' '~ ' . ,' . " '
"1~79~39
t~
_ . _
(a) 1~ lothox-~ph ny.L)-2-indol.lnone
To a stirred mi~cture o:f ~15 g~ (1.5 mo:ls) o~ N-pheny:L-N ~ :
(3-methoxy-l~heny:L)-chloroace-tic acid amido and 600 m.L of
o-dichLoroberl~etle, 300 g of ~lCl3 wore addcd at room tern- ;
pera-tu-re. After the exothermi.c reaction had died down,
duri:ng which the temperature had r:Lsen to 100 C, another
300 g of AlCl3 -we.re acldccl. The m:ixture WQS heated to -the
boil and mai.TItai.rled there at 180 C :for 30 m:inutes. The
m:ix-ture was t.hell placed oll ice, the preclpitate was stirred
several times with wa-ter, and after aclclltion of 500 m:L of
ethex, :it was suct.Lon-f':i:LterQd, Tho fil-trato ~as wa~shed
w:lth ~thor ancl ~tharlo.l,
~le:l.d: 30() g~ (~6 ~ o:~ tl~e theorQI::laa:l y~ l.cl) o:~ clarlc-
r~ ~rowrl cry~tn:ls~ n~E). 20fi - 20r~ a. Af`tot- rec.ry~t.l:l.'l:L~.~at:l.or
~`rorn ethano:L the me.Ltlng point was 2'l4)C.
(b) 1- ~ n th ~ 2~indol.inone
23 ml (o.24 mol) of dimethylsu:L.ra-te were added dropwise to
a solution of ~5 g (0.2 moJ.) o~ (3-hydroxypheny:L)-2--
:indolinone in 150 m:L of 2N NaOlI and 50 InL of` water. Cooling
kept the temperiltllre between 25 ancl 30 C. Stlrr:Lng was con-
t:lnuod ~`o:r 'l7 hour~ at rooln temp~ratll:ro, thQ p:reclp:ltate
was suct:Lon-~l.Ltered, wn~hecl with water ullti.L neutral and
then washed twice with 20 ml of othanol each time.
Yield: 32 g (68 ~0 of the theoretical yield), m.p. 104 -
1 o6c .
(c) 2-Chloro- ~ ~ indole 3 c~arb a].clsh~de
To a reaction product according to Vilsmei~r prepared
29 according to Example 1 from 30 ml of N,N-clir.lethy:Lf`ormamide
.
'~ . - 21 -
- ' . : ' . , . '
,: . : :,
.. . .. .. .
~ 5/F 330
~L~7~73~
ancl 30 m.L o~ phosphoru~ oxychlorid~, 80 ml of anhydrous
to'l.uene we.re added, arld whi.Le ~t,irringr L~8 g (O.Z mol) of
'I-(3-methoxypherlyl)-2-indol1none were introduced portions-
wi~e so as to maintain tho temperal~ure betweerl 25 and
30 C, wh~n Coo~ }g slight:Ly. S-tirr:ing was cont:lnued for
30 minut~s, the nlixturo ~a~ di.luted wi-th 500 m:L of chlo-
roform, and the ~OlUtiOII was wa~hec~ ~everal tlmes with
water and aqueous sodium b:icarbonato solut:ion. After the
solvent had been evaporatecl in vacuo, 3-clime-thylalJJino-
methylcne-l (3-rsle-ttloxy-pheny.L) 2~:inclol:Lnone remalnod a3 a
crystQlli~ecl re~-Ldue which me:Lted at 98 - 99 C
The crys-tn1.li.~ed product wa~ d:i.s~.;olved :in 200 ml o:f to-
.L~eno, an-l a.fter acld,lt:Lorl o:f 70 Itl.l O f l~ho~ o:ru~ oxy-
ohlorl.do, t~lo so.l~lt.lotl ~a~ ~t;,l.rrod .t`-.~r l~5 ll~i,.rlute~ at 75 C.
I5 ~:t`tor coc1L:Ln~, 5~ r O~` Lco arlcl ~00 Ill.l of` Lco wnl;o.t~ w0
adclocl in OtlQ po:rt:Lon to th~ so.Lul;Lorl, wller~upon tha
-temperQture of tho mixture reached 55C af-ter 10 minutes
hen stirring. The cry~tal mass which had f`ormecl at the
~am~ timo ~la~ S~lC tion~`i.l.-tered afte~r addi-t:Lon o:f 'lOO ml
of ethcr, wa~hecl~i,t}l wa-ter un-til neutral ar~cl washed
twico w:ith ether.
Y.lelcl: 29 g, rll.p. 'l67C. Concentrat:i.o~ of the mother
.Llquor yl,olclo~ :~urther 9 ~r~ m. p~ 166 ~ 167C~
Overall yiolcl: 38 g (70 ~o Or the t~eoretical y~eld).
(d) 2-Chloro-- ~ etho~-yphenyl)-indole 3-carbox~.lic acid
This compound was obtained as in Example -I (b) from 27 g
~0.1 mol) of 2-chloro~ (3-methoxyphenyl) indole 3-
carb aldehyde in 500 ml o.f acetone, 3GO ml of im pho~-
29 phate buf~er (pH 7) and tOO ml of water by o~yclation
. - 22
- ' , : ' ',
.
.. . . .
', .' , : ' :
_ 1
lV797~3~
w:ith 40 g of potassiulll permatlganato.
Yie.Ld: 18 g (60 ~ of the theoretlca:L yie].d), m.p. 196 -
193C
Ac:id chlo~:icle: From the ac:id and thlony.l chloride,
m.p. 1l~2 ~ 3C.
~e) 2-Chloro-1-(3~methoxyphenyl)-:Lndole 3-carboxyLic acid
era~.-icle _ _ _
Thi.s compo~ncl was prepared as in Exarllpls 1 (c) from
2-chloro-l-(3-methox~ phenyl)-indole-3-carboxylic acid
chlorido and M-methyl-p:i.per.lz:i.ne.
Yield: resin, hydroch.loricle; decomposition above 250 C,
85 ~ of th~ thooretical yi.o:ld.
X A M P 1, E ~9:
~___._... __ .
Thc sub~it~ltocl 2-ohl.o .t`O- t ~ ( '3-nlethoxyl~llerly~ nclol~
3-cnrboxyl;i.o ao:ld.~ o~ .fox~lllu.l.~ :~ aslcl ~h~ rmaco.lo~.~lc~.L:Ly
use.f'ul ~alt~ thereof' wero p:repar~d f:rom 2-chloro-l-(3-nlethoxy-
phenyl)-indole 3-carbo~ylic acid chloride and the correspon- .
d:ing bases accordiJIg to Examples 1 (c), 2 (a) and Z (b). The ~:
ba~es and ~;he rad:icals R aro li~ted in Table 1.
~$ ~ I
OClf3
E X A ~
The following 2-chloro-indole carboxyl:ic acids of formula
I listed in Table 2 were prepared according -to Exatnples 1, 2,
27 and 29 from the corrasponding carboxylic acid chloridos and
th~ amines oP the rormula HR2.
. ' ' ' .
_ 23 - ~
, . , .. ~ . : . : . ; : . . . ~:.
. .~. . . . . .
:.: . : . . . . . .
, . , . : . ~
~!!~ 3 30
73
2 .
1~3~lCl
_ .~
~3 n R2
_ ~ _ _
4-C:L f[ 4~ thyl-l-pip~raz~ y:L
s-Br H 4-11yclroxy~t~lyl l-piperazinyl
7 Cl H I-piporazinyl
5 N02 H 1~ hyL-l-p:Lperayinyl
5-N112 H Il-nlo thyl~ l-plporaz,:lrly:L
~,7-D:I-Br ~1 4~1l~L~yl. I~plE)oraY,~rly.L
tl 6 5 2 I ~Ll)~ L`~Z.. ltl~ L
s-F C~ I~-mothy.L-I-plporaz:lnyL
s-F c2~[5 I-piperazinyl
5-Cl 3 7 4 motl~yl l piperazinyl
s-Br n-C4~1g die-thylaminoethylam:ino
S-~N2 C~13 4-methy:L-1-pipo:razinyl
5-NH2 C~13 4-methyl~l-p:LE~oraY.irly:l
4 CH 0 C~13 I-p:iporaz:LIly.L
7-CH~0 CH3 morpho.LinoHthy:Lalll:Lno
5 C2H5 CH3 4-hydroxyothy:L-l-piporazinyl
5-C3H70 CH3 4-phonyl-1-pipera~inyl
S-CL~H90 6 5 4-m~thyl~1-piperazinyl
5-C5H11 C~13 4-methyl-1 piperazinyl
6 C2H5 C6H5 l-piperaziIIyl
6-C3H70 C6H5 piper:idinoamino
_ 24 _
'` ' ~ . ' ' : ,
. .
11:979739
~3 R R2
~_~
~-CI~I90 CH3 ~-methyl-l-p:ipera~.inyl
6-C6l-[5CI-I20 C6~I5 I~-methyl-l-piperazirlyl an~ino
5,6~Di-CH30 CI13 4-rnQthy:L-l-piperazinyl
5,6-Di-C2~I50 C6H5 l-~)iperil~i.nyl
5-C2I~50,6-C~I30C~l3 ll-methy.L-l-piE~erzlzinyl
5,6-D.i-C3~T70 ~ ~ Il-methyl.-l-p:Lperazinyl
E X A ~I P L, E 31:
2-Chloro-l-phel1yl-ir~clol.o 3-carboxyl:ie ~ei.d 2-d.iethyLi~mino ethy:L
ostor
27.l ~ no.L) o.~ 2-ol~;Lot~ovl-E~horly.L-lrldol.~.3 ~-eLI:rboxyl:le
aol.cl w(l;re ro~`.Luxocl w.i.t.h 30 m.l. o:t' lvhLorly.L oh:l.or.i.(.lo ~rltl.L tlle
ovolut:Lorl Or ~as had eoasocl. Excoss t.h:Lony.L oh.lor~ was el~
minatod in vaeno, ancl the crude acid ch:Loride was d:Lsso:lvod in
lO0 ml of anhydrous chloroform. After cooling to 20 C', a
mixture of 15.2 g (0.l3 mo:L) of d:Lothyla~Lno-othanol and 15 ml
(0v1~ Mol) of' pyri.d:ino in 50 ml of chlorororrn was ad-lod, and tho
m.Lxturo was stirred ror 3 hou:rs at room tonlporature. The so-
lutlorl ~/as di:Lutod with eh:lorof`orlll ancl wcashod throo timos wLth
wator. Tho so:lvont WQ~ o.LLminato~ :ln vacuo, tho r~:Lcluo wai
d:lssolved in tolueno and agaln eoncentratod ln vaeuo. T}le re-
isinous crude baso was dii~so:Lved in 100 m:L of ch:loroform and
ethanolie hydrochloric acid was added unti~t a pII of 1 was
reaehed. Tho solvent was eliminated in vacuo, and the residue
wa~ digested thrao times with acotono and concentrated. The
precipitate va9 thon suction-filtered and washed wlth aeetono.
.
.
.. . . . . . . .
.
: . ., :, '
: . , , ~ : ' ". .;
.:, . . , . ' '.:
~1;37~739
Yie:Ld: 21 g (52 ~ of:' thc theor~t:ical yia:lcl) of colorless
cryst~ls, 11l.p. 162 - 163C.
The substltu-ted 2-chloro-:indolc 3-carboxylic ac-id estors
of tho E~amplos lis-t~d in Tablo 3 and the pharmacologically
usef`u~ salts -thcreof were preparad ~9 :~1 EXaTllpl~ 31 rrom -the
:indole carboxylic acid chlorido ancl thc corrcspondlng basic
est~r of -thereor.
T A ~ I, E '3:
Cl
C6115
l~xamplo No R m. pO C C; sa:L t (m. p . C )
3~ 0C112Cll2~(aEl3)2 ro,~ y~ ocllL-):r.l.cl~ (171-173)
33o(a;~ N(c~l3)2 127~13o; hyclrooh.Lo.r:Lclo (228-229)
31~-OC'I-I2C~lz ~ resin; hydroch:Lor:ido (248)
35C~l2 ~2 ~ rosin; hydrochloridc (250-251 )
36OCH~CH2 ~ :r~s:Ln; hyclroch:Loriclo (230 - 232)
37-0 ~ C}13 amorphous, hydrochlorido
clocomp. ~250
38 -0 ~ amoI p~lVUS; hyclrochloridv
~ ~ docomp. >265 .
C~13
39 . amorphous; hydrochloride
-0 ~ dQcomp. ~230
N
- 26 _
.
' , ,. . ~ ~ ' . : ' . '
;..
.. ..
' ' ' : ' : .,
' ,,
.
., i ' ,
~ 7~739
F Y A ~l P 1 ~ ~0 :
2-ChLoro-1-pheny.l :indol~ 3-carbo~ylic acid 2-cyclo:hoxy:Lamlno-
~y~ e t~r hyclrochLor:ide
CTC1 eoUs llydrog~n ch.Lor:icle Wl~ introducecl:Ln-to .a solution
of 30 g (0.2l mo:L) o:f 2-cyc.lohexyLa~ o-ethano:L in 300 ml of
~thyl aceta~c unt:il the so:Lutlc,n roached a p~l of 1. The so-
obta:ine~ su~peris:iorl of`-the am1rla hydrochLorids was then added
to 0.2 mol of 2-chloro 1-ptleny.L .indol.e 3-carboxy.Lic ac:id
chlor:ido which hcld been l3r~pared from 5ll.2 g of the correspon-
d:ing acid accorclirlg to Iixamp:Le 5, .,tld the ~ hlro W<l5 hocltec
-to the boil ~or 17 hours ~hil.e sti:rring. I~.ftor cooLi.ng, -tho
precipitate ~/as suction-fL.Lterod and w~shed w.i.-th ethyl aceta-te.
~lolti.ng t)oint~ 212 - 2-l5C. .~:t`tor .recrysta.l.L.i.~.at.l.on :from
eth.lr1o.l., tllo mo:ltlrlg t)o:Lrlti wa~g 21~ - ~l7C.
Y.l.o.L~l5 ~ r (~0 ~J~ ~.)t` i~ lo~roii.lc~~.1. y.Lo.~cl)~
f~ M P J I~
The sub~-titu-ted 2-chLoro-~in~o:l.e 3-ca:rboxyLic acid cster~
of formula I listocl in Table 4 were prep~recl ~ccording to
~Xalllp1e ]10 f`l'Oltl 2-ch:loro-i.rlclole 3-carbo~yl.ic acid e.hlorides
ancl the hydrochlor.ides of the corre3ponding ba~ic am:ino
a.Lcohols.
T A }I L E /l~
~;ou2
. - 27 -
, . .
, . .
:: . : - :
.
',~1 ~
739
R3 4 R2
____ _____ _~_
5-C~I30 C~3 -OCH2CH2N~
6-CH30 C6 5 -C~'2Cfl2
__,
5,6~DiCM30 C~3 ~OC~-I2CH2N~
6-C21150 C6H5 -OCII~CH2NIL-{~
II C6~5 -OC~T2C~I
~[ C6~ _OCf-I(6~l5)C~I2N~I
~t . a2l'l5 _OC~12Cl12~lla~l(a~l3)2
~I C6~I5 _o ~ NH
Fl C6~[5 -O-fH c~l2N~12
C~I~CL
X ~ ~I P L E l~24
-
2-Chloro-1-phony:L-Ln~oLo 3-oarboxyllc ac:Ld /~-(Z-(1,3 cl.Loxolan-
2-y:L)-ethylypiperazide
A tnixture 0~ 13.6 (40 mmols) of 2-chLoro-1-phenyl-indole
3-carboxylic acid piperazide (Example 2~, 17 g (0.125 mol) of
~-(2-chloroethyl)-1,3-dioxolane, 20 ml of trie-thylamine and
120 ml of toluene wera kep-t boiling for ~8 hours while s tir-
- 28 -
:,. ' , :
.. . . ..
. ~ ..
.
~/1? 3 3 o
'1~379739
ring. Tile coo.led IlliX ture was d:LLuted ~ith o-thyl acc-tate,
washf,~d throe -tinle~ ~JiLh wa-ter, and the resinous residtle of the
or~an:ic phase was cl-lromatographed us1ng s:Llica gel 60 (o.o6 -
~.2 mm, clf3act-i.vatf3cl by tO ',~ of wa-ter; co.lumrl s1zc: 3.5 x 100
cm) and ethy.l acetate. ~`ter a firs-t fract.ion o:f I l, the
above compouncl was f~lutecl a~ a res:Ln, T:l1c hydrochloride melted
a-t 230 - 23ZC,
Yielfl: 9.5 g o~ hydroc.ilLoricle (~0 ~h of tho theoretical yicld).
E X A ~I P I,E ~
2-Chloro-1-ph~nyl-:indol~ 3-car.i)o.xy.l.:Lc ac:;cl ~-(3,~ mf3-thylene-
c~ f~ )Z-~:L~f,~r~ le
_____________. __
~ mixt~ro o:i-` l2 ~; (35 mlllols) o:~' 2~ahLf).t~o-1-phf3rlyl-~irldolf3
3-~ L)oxy.l.;i.c .lc:Lcl p.l~)f~ Lcl~ (E`~ f).l.f3 2), 17 g (0.l Illo.l) of`
pl.~f)~o~ly.L ch.Lo.r.l.cle, l'7 nl.L o.i.' I;:rl.etlly:l.a~LIle arlcl l~0 Ill;L oE' l;o
lS Luf3rl0 we.re rf.~ Luxod f`or 2ll llou.r..c.~. The coo.l.ed so:Lut:Lon wa~ cll-
luted with f~tllyl aceta~,e, wQshed with water and the solven~
tras e~ Liminated in vacuo . The resirlous rcsidue was clissolved in
acotoJ1e, exccss othanolic hyclrochlorlc ac:id (40 nmlols) was
added, and tho prec:Lpitate :~o:rmeclt~as suc-tion-f:i.l.-tored and
~ashed w:Lth acotono.
Tl1o ylo.Ld of co.Lor.lo~ product was 15.2 g (85 $ o~` tho theo-
rot:Leal y:Lo.L~) nl.p. 24l - 2l~(~.
E X A M P ~ _F, 4l~
The compounds o~ Table 5 were prepared ~rom the carboxy-
lic acid piperazides and the corresponding alkyl halides
according to Examp:Lcs 42 and 43.
' ' ' , .
- _ 29 -
,'
' ~
1~973't3 llor 7~
T A B 1,
R3 ~'i ~Cl nlJr R3 ~V N~
R3 E~ R
~ _ __ ___
~1 C~15 ~C~12C:~12C~o_~
~1 C6~15 -C1~2C ~ Cfl
}I C6~15 -C~12 C:~l=C}12
6--C11 0 ~ C fl -~Cft2Cl~
5-Cfs30 C~S3 -C1~12CO-~3
5, 6 D1-C1130 C1~13 -CH2C6~I5
2 5 C6H5 -CH2CONHC}13
~ a2~lS -OH2'~ 'C-a'~l3
.'
H C6H5 - C}12C~S2N ( CZH5 ) 2 J"
. ::
': ~ : ,i :
