Note: Descriptions are shown in the official language in which they were submitted.
\ ~
~3~3`~i~
100-5214 ~ -
INDOLINE DERIVATIVES, THEIR PRODUCTIO~ AND P.~ ~A-
CEUTICAL COMPOSITIO~S CO~fTAINING THEM
This invention relates to indoline derivati-
ves, their production and pharmaceutical compositions
containing them.
~ .S.P. 4,080/330 discloses a class of 2-
unsubstituted-3-ohenylindolines ~Iherein the indoline
nucleus may be substituted in the phenyl ring in
the 5, 6 or 7 position. The ~henyl ring of the in- ~
10 doline nucleus and the exocyclic phenyl ring in the '!;
3 uosition may be monosubs~ituted by halogen,
I lower alkoxy or lower alkyl~ The indoline nitrogen
; atom may be unsubstituted or substituted hy a wide
. variety of substituents, including acyl and ootio-
nally substituted aminoalkyl radicals. Some of thecompounds are indicated to have local anesthetic
activity, platelet aggregation inhibiting activity
~nd hvDoglycemic activity. Some of the compounds,
_ although it is not clearly s~ecified in the patent
which,are said to have central nervous system
activity, e.g. anti-depressant activityO
, A ,,~, .
3~37~ -
: - 2 - lO0-52
. All the examples of aminoalkyl comnounds
specifically named in this U.S.Patent are characte-
rised by a substituted amino group and~or a propy- ~-
lene or tetramethvlene al~yl chain. The only example
fully characterised has a 2-piperidinoethyl side
chain~ and this is indicated to be an anti-de-
pressant. The substituted amino and~or prooylene
or tetramethylene alkyl_c ain compounds do not
~ _ _ _ _ _ _ _ _ _ _ _ _ _ _
- ~ossess in *act a satisfactor~ ~harmacolo-
gical profile of a well tolerated antidepressant,
e.g. they exhibit weak activity in at least one of
~he standard anti-depressant animal tests, e.g.
,the tetrabenazine ca~ale~sy and ptosis test, and/or
are not very active noradrenaline, dopamine or
5-hydro~ytryptam_ne uptake inhibitors. hTe have now
found that unsubstituted amino ethylene phenyl-
indolines which are nowhere specifically disclosed
or suggest~d in the above U.S. Patent have parti-
cularly desirable properties as well tolerated
.. 20 anti-depressant agents.
In particular the presen~ invention pro-
vides a compound of formula I
.~
~, ~
.
.,
;.
- , "~. .. , -
: .
:, . . .
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~3~3`7~1
- 3 ~ 100-5214
Rl ¦ R~
C~2CH;~ 2
wherein
Rl and R2 independently are hydrogen, halogen of
atomic number from 9 to 35, (Cl_4)alkyll (Cl_4)
alkoxy, hydroxy, or trifluoromethyl,
Rl' and R2' independently are hydrogen, halogen
of atomic number from 9 to 35, (Cl_4)alkyl,
~ (Cl 4)alkoxy, or hydroxy,
R2" is hydro~en or (Cl ~)alkoxy, with the proviso
that, when R2" is alkoxy, then R2 and R2' are
alkoxy, and
; R3 is hydrogen or (Cl 4)alkyl,
and pharmaceutically acceptable acid a~.ition sal.ts
thereof.
In formula I, alkvl and alkoxy contain pre-
ferably 1 or ~, and especially 1, carbon atom.
Halogen is preferably chlorine or 1uorine, espe-
cially chl.orine~ R3 is preferably hy~rogen~ Rl is ..
preferably in the 5 or 6 position of the in~oline
'~ :
~ "
- .
.: . . - , ~ : . . j . .;: : :
::. :: . : : : . .:
~3~3~
- 4 ~ 100-5~14
nucleus. Rl and Rl' are conveniently other than
chlorine in the 5 position of the indoline nucleus.
R2 is preferably in ~he meta or ~ara position~
The present invention provides additionally
5 a process for the production of a compound ~ for-
mula I -w-h~c_ comD~r1ses~r ~ nd of fo~r-
~ula II
R2
n Il
C~12CH2NH2
wherein
Rl, Rl', R2, R2', R2" and R3 are as defined above,
and where necessary converting the re~ulting comp-
ound of foxmula I lnto a pharmaceutically acceptable
acid additlon salt thereof.
The process may be effected in conventional
manner or the reduction of an indole to an indoline.
For example the process may be effected with nascent
hydrogen, e.g. with lithium, sodium, or potassium,
in liquid ammorlia. Rreferably for halogen-containing
compounds an alternative reduction using diborane or
a complex borohydride, e~ g. NaBH4~BF3 or a borane/
dimethylsulphide com~lex ls effected.
. . . _ . .
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,
,
~L3~L3~7~
~ 5 ~ 100-5214
The reduction in liquid ammonia may be ef ec-
ted in the presence of an inert or~anic solvent
such as an ethert e.g. tetrahydrofuran. Suitable
temperatures may be fxom about -70~ C to about
30 C, preferably -40 to -30 C0 The reduction
with boron compounds is conveniently effected like-
wise in an organic solvent. Suitable reaction tem-
peratures may be from about 0 C to the reflux
temperature of the reac~ion mixture. Any resul~ant
boron complex may be conveniently decomposed with
acidt e.g. 4N-5N HCl.
The compounds may be isolated fxom the
,l ~reaction mixture and purified in conventional manner.
,) The compounds of fGr~la ~L~_~ may exist in the form
of optical isomers or racemates. t~en R3 is alkyl,
~he compounds may exist ln diastereoisomeric forms.
~ The individual optical isomers and diastereoisomers
; may be obtained in conv~ntional manner, e.g. by
fractional crystallization of salt forms with appro-
; 20 priate acids.
Free base forms of the comDounds of =
ormula I may be converted into acid addition salt
forms in conventional manner~ and vice versa. Sui-
table acids for salt formation irclude the hydro
.
,
- -. -
3~3 ~ ;
- 6 - ~00-5~14
chloric, maleic, f~aric, cyclohexylsul~nic, an~
naphthalen-1,5-disulphonic acids.
The starting material of foxmula II may be
produced in conventional manner, e.g. from ~he
S compound of formula III,
~2
H
wherein - ---
R~, Rl', R2, R2', R2~ and R3 are as defined above~
~y introducing the ~roup--CH2CONH2 or -CH2C~.~ into
a compound of formula III (e.g. with Hal-CH2CO~H2
or Hal-CH2CN) and reducing the resultant amide or
nitrile to the amineO
Insofar as the production of any startin~
material is not particularly describea these are
known or may be produced in analogous manner to
known compounds or to processes described herein.
In the following examples all temperatures
;are in degrees Centigrade and are uncorrected.
In the tables the mel~ing 2oin~ refers to
the hydrogen maleate salt form exceDt wnen _ther-
-wl-se s~ated, e.g~
, ~ . .. . _ . ..
l.,~, '
,,, . - I .
~. .
- ~3~7~
_ 7 _ 1oo-s2l4 ~ -
~ ' .
1) hydrogen fumarate
2) bis [base~ fumarate
3~ base
4) hydrochlorlde
; Other ab~reviations:~
5) Decomposi~ion point starting at a~out temperature
gi~en
Diastereoisomeric isomer
',
~
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-:: : : : ,
~3~3~ I
~ ~ ~ 100-5214
EXAMPLE 1: 1--(2-aminoe~hvl~-3-ohenYlindolil~e
A solution of 34.7 g 1-(2-~minoethyl)-3-
phenylindole in 300 ml ~etrahydrofuran is dropDed
into a solution of 17 g sodium in li~ui2 am~onia.
After a further 30 minutes the sodium excess is
decomposed by the addition of solid ammonium chlo-
rideO The ammonia is e~a~orat~d off to give the
title com~ound. M.pt. (hydrogen maleate) 169 170,
(from ethanolj.
. The starting material is produced as follows:-
a~ A solution of 100 g 3-ohenylindole in 350 ml
dimethylfonmamide is dropPed into a suspension
of 22.7 g sodium hydride (55 ~ hy weight in oil)
in 350 ml dimethylformami2e. After hydrogen for-
mation has finished, 73 g solid chloroacetamide
are added. The mixtuxe is stirred for 17 hours
at room temDerature, and poured onto ice-water
causing 3-Phenylindolyl-l-acetamide t~ preci-
pita~e (M.pt. 20~202 from CH2C12).
~0 b) A solution of 1~.4 ml conc. H2SO~ in 200 ml
ketrahydrofuran is added dropwise to 5d~ 6 g
lithium aluminium hydride in 1 litre tetra-
hydrofuran at -30. The mixture is allo~e2 to
warm to 0, then treated drop~lise with a sus-
" ~
, 'L, . .
... . , . _ . . . _ . , . ... . . _ . . _ . . _ _ _ . _ _ : : -- _ _ _ _ _, . _
;. ' ' . ' :
t ' ` - : . ' : : ~:
. ,' ' ' '
~L~3~3~
9 - 100~5214
pension of 90.2 g 3-phenylindolyl-1-acetamide in
700 ml tetrahydrofuran and s~irred thereafter for
2 hours at room tem~era~ure. The resultant 1-(2-
aminoethyl) 3-phenylindole melts at 268 ~o 270~
'~~- t~ydrochloride~salt for~m)~ -
In analogous manner compounds wherein Rl' ~ :
~2' = R2~ = P3 = H may bs made as folLows:-
;-
,
.
;~
~ .
.:
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- 10 - 1S~5214 -~
TABLE 1
,
.
. - .. , _.... . ,.............. ~_ ~ .. .... - -
Ex Rl R2 M~pt
No .. .~ __~
~ ' 5~F ~ 1~3--144
- . . , 7-F H 180-183~
. ~, 7-Cl ~ 177-180
. 7-CH3 ~ 188--190
6 H o-Cl 172--176 ~
7, H m-Cl 175-178~
10 E ' H - p-Cl 1~ 8-170
~: ~ ~ 4-Cl H 171 173
6--Cl H - ~ 6 2--16 4
1i 1 H Jn-CF3 172--177
. . .. .. .. _~... . . .
.12, R o-F ~ 5g--163
15 13 ~ m-F 154-157
p_~ ~54-159
1,5, 5-C~1 ~ 154-156
16 ~ S-OCH3 H 156--158
17 , 6-F ~ 1 30-134
;!018 4~F H . 170--172
19 S-OH }I 16 B-170
2~ 6 Cl m-Cl 155-158
21 6-Cl p-F 28004 ~ 5)
. ~ 2 2 6-F p-F 16 6--16 7 ~
25 23 5_07~ m-Cl 182-185
2 ~ S-OH p--F lg 3--19 7
. J`~
... .... . .
. . . :; ; ~,
:: : . -
3~3`~0
~ 11 -- - 10C)--5214
. .
. __ .. _ _ , _ .
Ex R R2 M . pk .
- ~CI 1
:25 G-F m-Cl . 208-210'' ~ J
. 26 ' ~-O~I ~ . 172-1753)
2J, H m-OH .135-139
2 . ~I p-OH 182--185
. , . ~ p-CF3 16 4--16 7
: 30 . 6--CF3 H . 176-179
31, 4 -t^F H . ~ .19 5 _ 19 8 4 )
. 32 1 5-Br H 168-170
' 33 ~ ~ 3 ~1 ~60-1~54)
3~. . ~ p~OCH3 7 ~ 0 3 )
35 t ~ m OC~3 '~75-177
36, 5-OCH3 p-F 130-13~ -
7: m-C I _ ~_ ~ 4
- ... ,
;.
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- 12 - 100-5214 _ - :
.q'ABLE 2
_
In analogous rnanner t:he ~ollowing com~oun~s
wherein R ' and R " = H may be maaeO
: ~ ~
Ex Rl R2 R2 ' R3 M . ~t .
3 8 H . H CH3 19 4 -19 7 )
39 H E~ H CH3 17~-181
- . . 40 _ _ ~Cl p-Cl - H 12 B- 132
-
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~3~3~7~
~ 13 - 100-5214
The compounds o~ f~rmula I exhibit pharma-
cological activity in animals, in particular an-ti-
depressant activity, as indicated by an inhibition
of ptosis and catalepsy induced by tetrabenazine
in rats o~ i.p. administration of 1 to 50 mg/kg of
the compounds.
Furthermore the comoounds lnhibit the in
vitro uptake of noradrenaline and serotonin into rat
cortical slices and of dopamine into rat striatal
lC slices, as indicated in standard tests. These tests
have been carried out according to the princi~les
of A~ I o Salama et al., JO Pharmacol. Exp. Ther. 178,
474-481, 1971. The in vitro noradrenaline and sero-
~onin uptake was tested as follows:
~lale ra~s were killed by decapitation and
the brains quickly removed. The cortices were re-
moved and 0~4 mm slices were cut from the parietal
~ area. These were the~ placed in incubation flasks,
; wi~h slices from one hal~ of a brain as control
and slices from the other half being used ~or
treatment. Both flasks contained 2.975 ml oxycarb-
,~ saturated Krebs-~Eenseleit solution pH 7.4, with
the test drug (initially 5 ~g/mlj bëing
added to one. Arter pre-incubation for 10 minutes
at 37 C--25 ~l_of a solution~of_3~-noradrenaline or
,.
.
, ~
,.; - . ~
.~. :;:. : :.:
~iO 3~370!
14 - 1~0-5214
25 ~1 of 3H-serotonin was added to ~ive a fina~
concentration of 3H-noradrenaline of 11.3 nMI or
; - 6.6 nM 3H-serotonin. After incubation for a further
lS minutes the solutions were replaced with fresh
Rrebs-Henseleit solution and post~incubation con~
tinued for a further 10 minutes. After centrifuga ;~
~tion the slices were washed with 1 ml 0~9 ~ sodium
chloride, dissolved in 1 ml ~5 % formic a~id at
60 C and the retained 3H-noradrenaline or 3H-
serotonin estimated by scintillation counting.
The in vitro dopamine uptake into rat stria-
tum was examîned as follo~s:-
Male rats were killed by decapitation andthe striata guickly dissected out on an ice-cold
surface. The two striata were chopped into 0~4 ~m
slices. ~Xe sllces ~~x-o-m~each~s-t~rlatum ~ere then i~mer-
sed in 2.975 ml oxycarbsaturated Krebs-Henseleit
solution. The test subs~ance(initially 10 ~s~ml)
was added to one incubation tube, the other served
as control~ After pre-incubation for 10 minutes at
37 ~5 ~1 of 3H dopamine were then added to give a
final 3H dopamine concentration of 1.68 nM. After
incubation for a further 15 minutes the excess
dopamine was removed with fresh Krebs-Henseleit
solution and ~he mixture pos~-incubated ~or a fux
~, .. .
, . .: :
..
~L3~3~
- 15 - 100~5214
ther 10 minutes. After centrifugation the super-
nates were discarded~ the residual slices washed
with 1 ml 0.9 % sodium chloride and then dissolved
in 1 ml ~5 ~ formic acid. The retained radioactivity
was determined by scintillation counting.
The compounds of formula I inhibit noradre-
naline, serotonin and dopamine u~take at rom about
5 to about 20,000 nM.
The compounds are therefore indicated for use
as anti-depressant agents. For this indication an
indicated daily dose is from 1 to 300 mg, convenien~
tly administered in divided doses 2 to 4 times a day
in unit dosage form containing from 0.25 to 150 mg
; (e.y. 1.5 to 75 mg), or in susta~ned release form.
I'he compounds of formula I may be administered
in pharmaceutically acceptable acid addition salt
Eorm. Such acid addition salt forms exhibit the same
; order of activity as the free base forms and are
readily prepared in conventional manner. The present
invention also provides a pharmaceutical composition
comprising a compound of formula I, in free base form
or in pharmaceutically acceptable acid addition salt
form, in association with a pharmaceutical carrier or
diluent.
The compound of Examples 1 and 2q exhibits part- ;
icularly interestina properties.
::
~3~3'~
- 16 - - 100-5214
In one group o compounds of formula I R2
is hydrogen, halogen, alko~y, hydroxy or trifluoro-
- methyl, Rl' and ~2" are each hydrogen, and R2' is
hydrogen ox halogen.
In another gxoup of compounds o formula I
~2' and R2 n are each hydrogen~
.
.
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