BENZOCYCLOHEPTENE DERIVATIVES AS PSYCHOSTIMULANTS

DERIVES DE BENZOCYCLOHEPTENE COMME PSYCHOSTIMULANTS

English Abstract

Abstract of the Disclosure:
The invention provides compounds of formula
<IMG>
wherein R1 is hydrogen, alkyl, alkoxy or halogen,
R2 is hydrogen or, when R1 is alkoxy, also
alkoxy, or R1 and R2 when bonded to
adjacent carbon atoms are methylenedioxy,
R3 is hydrogen or alkyl,
R4 may, for example, be alkyl, cycloalkyl-
alkyl of cycloalkyl, or R3 and R4 together
with the nitrogen atom to which they are
bound may be pyrrolidine,
and Z may, for example, be substituted or unsub-
stituted phenyl,
which posses pharmacological, e.g. psychostimulant,
activity.

Claims

WHAT IS CLAIMED IS:
1. A process for the production of a compound
of formula I,
I
<IMG>
wherein R1 is hydrogen, alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms or
halogen of atomic number from 9 to 35,
R2 is hydrogen or, when R1 is alkoxy of 1
to 4 carbon atoms, also alkoxy of 1 to
4 carbon atoms,
or R1 and R2 when bonded to adjacent carbon atoms
together form a methylenedioxy group,
R3 is hydrogen or alkyl of 1 to 4 carbon
atoms,
R4 is alkyl of 1 to 4 carbon atoms, cycloalkyl-
alkyl of 4 to 10 carbon atoms, cycloalkyl
- 21 -

of 3 to 7 carbon atoms or, when R3 is
alkyl of 1 to 4 carbon atoms, also
benzyl or benzyl monosubstituted in the
phenyl residue by chlorine, bromine,
alkyl of 1 to 4 carbon atoms or alkoxy
of 1 to 4 carbon atoms,
or R3 and R4 together with the nitrogen atom to
which they are bound form a pyrrolidine,
piperidine or morpholine ring; or a
piperazine ring, the nitrogen atom of
which is substituted by alkyl of 1 to
4 carbon atoms,
and Z is <IMG> <IMG> or <IMG>
II III IV
wherein,
either R5 is hydrogen, alkyl of 1 to 4
carbon atoms, alkoxy of 1 to
4 carbon atoms, alkylthio of 1
to 4 carbon atoms, trifluoro-
methyl or halogen of atomic
number from 9 to 35,
- 22 -

and R6 is hydrogen, alkoxy of 1 to
4 carbon atoms or halogen of
atomic number from 9 to 35,
or R5 and R6 when bonded to adjacent
carbon atoms together form a
methylenedloxy group,
R7 is hydrogen, alkyl of 1 to 4
carbon atoms or halogen of
atomic number from 9 to 35,
or a pharmaceutically acceptable acid addition salt
thereof, comprising
a) producing a compound of formula Ia,
<IMG> Ia
wherein R1, R2, R4 and Z are as previously defined
and R3 is alkyl of 1 to 4 carbon atoms or with
R4 and the nitrogen atom to which they are
bound forms a pyrrolidine, piperidine or morpho-
line ring; or a piperazine ring, the nitrogen
atom of which is substituted by alkyl of 1 to 4
carbon atoms,
by reacting a compound of formula V,
- 23 -

<IMG> V
wherein R1, R2, R? and R4 are as previously defined,
with a compound of formula VI,
Z-Mg-X VI
wherein Z is as previously defined
and X is chlorine, bromine or iodine,
or
b) producing a compound of formula Ib,
<IMG> Ib
wherein R1, R2 and Z are as previously defined
and R? is alkyl of 1 to 4 carbon atoms, cyclo-
alkylalkyl of 4 to 10 carbon atoms or
cycloalkyl of 3 to 7 carbon atoms,
by removing the benzyl group from a compound of
- 24 -

formula VII,
<IMG> VII
wherein R1, R2, R? and Z are as previously defined, and where
desired, forming a pharmaceutically acceptable acid addition salt
of said compound of formula I.
2. A compound of formula I, as defined in Claim 1, or
a pharmaceutically acceptable acid addition salt of said
compound, when prepared by the process of claim 1 or by an
obvious chemical equivalent thereof.
3. A process for the production of 5,6,8,9-tetrahydro-7-
methylamino-7-phenyl-7H-benzocycloheptene which comprises
subjecting 7-(N-benzyl-N-methyl-amino)-5,6,8,9-tetrahydro-7-
phenyl-7H-benzocycloheptene to hydrogenolysis, and if desired,
forming a pharmaceutically acceptable acid addition salt of the
compound produced thereby.
4. 5,6,8,9-tetrahydro-7-methylamino-7-phenyl-7H-
benzocycloheptene, or a pharmaceutically acceptable acid addition
salt thereof, when prepared by the process of claim 3 or by an
obvious chemical equivalent thereof.
-25-

Description

~ 23~ case 100-4806
BENZOCYCLOHEPTENE DERIVATI~S AS PSYCHOSTIrlULANTS
This invention relates to 5,6,8,9-tetrahydro-
7H-benzocycloheptenes.
More particularly, this invention provides
5compounds of formula I,
R1 N / R3
2 \ R4
~'
: wherein Rl is hydrogen, alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms or
~ halogen of atomic number from 9 to 35,
- R2 is hydrogen or, when Rl is alkoxy of 1
10to 4 carbon atoms, also alkoxy of 1 to
:~ 4 carbon atoms,
or Rl and R2 when bonded to adjacent carbon atoms
together form a methylenedioxy group,
R3 is hydrogen or alkyl of 1 to 4 carbon
15atoms,
R4 is alkyl of 1 to 4 carhon atoms,cycloalkyl-
alkyl of ~ to 10 carbon atom6, cycloalk~l
.
;~
.

23~
100-4806
of 3 to 7 carbo.n atoms or, when R3 is
alkyl of 1 to 4 carbon atoms, also
benzyl or benzyl monosubstltuted ln the
phenyl residu~ by chlorlne, bromine,
alkyl of 1 to 4 carbon atoms or alkoxy
of 1 to 4 ca~:bon atoms,
or R3 and R4 together wlth the nltro~en atom to
which they are bound orm a pyrrolidine,
plper~dlne or morphollne ring; or a
;~ 10 piperazine ring, the nltrogen atom of
~ whlch is substituted by alkyl of 1 to
.
4 carbon atoms,
; ~na z iB ~ ~R~ or ~ ~
. II III IV
wherein,
either R5 i~ hydrogen, alkyl of 1 to 4
carbon atoms, alkoxy of 1 to
4 carbon atoms, alkylthio of 1
to 4 carbon atom~, trlfluoro-
methyl or halogen of atomlc
number from 9 to 35,
3 -
: 1
- ~ :
. - .

~O~SZ3~
and R6 is hyd~ogen, alk~xy of 1 to
4 carbon atoms or halogen of
atomic number from 9 to 35,
or R5 and R6 when bonded to adjacent
carbon atoms together form a
methylenedioxy group,
and R7 is hydrogen, alkyl of 1 to 4
carbon atoms or halogen of
atomic number from 9 to 35~
and pharmaceutically acceptable acid addition salts of said
compound of formula I.
When a substltuent in the compounds of for-
` mula I ls alkyl, alkoxy or alkylthio, these preferably
contain 1 or 2 carbon atoms and especially signlfy methyl,
methoxy or methylthio. When a substltuent is halogen,
this is preferably chlorine.
Rl and R2 are each preferably hydrogen. When
Rl and R2 are other than hydrogen, these are preferably
in the 2- or 3- position of the benzocycloheptane
resldue.
`When bonded to adjacent carbon atoms, Rl and
;jR2 can form a methylenedioxy group.
When R4 is cycloalkyl, this preferably con-
talns 5 or 6 carbon atoms. When R4 is cycloalkylalkyl,
.,
- 4 -
.- ..,;~

2 31
100-4806
the cycloalkyl residue preferably contains ~rom 3 ~o 6
carbon atoms and 1 or 2 carhon atoms in the al~ylene
~hain. R4 can also signify benzyl or benzyl monosubsti-
tuted in the phenyl residue by chlorine, bromine, alkyl
of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
When R3 and R4 together wlth the nitrogen atom to which
they are bound form a heterocycllc ring, this is prefer-
ably a pyrrolidine or morpholine ring.
Z i6 preferably unsubstltuted phenyl or unsub-
stituted 2-thienyl. When Z i8 substituted phenyl, R~
can be al~yl of 1 to 4 carbon atoms, alkoxy of 1 to 4
carbon a~oms, alkylthio of 1 ~o 4 carbon atoms, ~ri-
'A fluoromethyl or halogen of atomic number from 9 to 35
and R6 can be hydrogen, alkoxy o~ 1 to 4 carbon atoms or
halogen of atomic number from 9 to 35. When bonded to
adjacent carbon atoms, R~ and R6 ~ogether can also be
methylenedioxy.
When Z is the residue III t R7 can be alkyl of
l-to 4 carbon atoms or halogen of atomic nwnber from 3
~o 35.
In one group of compounds, Z ls the residue IV.
The invention also provides a process for the
,~ .
, .

lOS~Z31
100-4806
production of compounds of formula I comprising
a) produc~ng a compound of formula Ia,
Rl
~ Z RI la
; R2 4
wherein Rl, ~2~ R4 and Z are as previously defin~d
and R3 is alkyl of 1 to 4 carbol ~toms or with
R4 and the nitrogen atom to which they are
bound ~orms a pyrrolidine, piperidine or morpho-
llne ring; or a piperazine ring, the nitrogen
i atom of which is substituted by alkyl of l to 4
: carbon atoms,
by reacting a compound of formula V,
~ R3
- R R4
wherein Rl, R2, R3 and R4 are as previously defined,
wlth a compound of formula VI,
Z-Mg~X VI
., ~

10S~23~
100-4806
where~n Z is as previously defined
and X is chlorine, bromine or ~odine,
;~ . or .
~ . b) producing a compound of formula Ib,
~CX NHR4 lb
R2 .:
wherein Rl, R2 and Z are as previously deflned
and R4 is alkyl of 1 to 4 carbon atoms, cyclo-
alkylalkyl of 4 to 10 carbon atoms or
~, cycloalkyl of 3 to 7 carbon atoms,
by removing the benzyl group from a compound of
formula VII,
R~ N- C~2 ~ VII
R2 II
.' ,
wherein Rl, R2, R4 and Z are as previously de~ined.
and where desired, forming a pharmaceutically acceptable
acid addition salt of said compound of formula I.
The reaction of the a~,~inonitrile compound of
,,
~`~, .. .

lV~231
10~-4806
formula V with the Grignard compound of formula VI
accordlng to process variant a) can be effected accord-
ing to known methods. For example, the reaction can be
effected in a suitable solvent for Grlgnard reactions,
e.g. in the presence of an open chain or cyclic ether
such as diethyl ether or tetrahydrofuran.
The removal of the benzyl group from the
compounds of formula VII according to process variant
b) can be effected by known methods. The benzyl group
; 10 is preferably removed hydrogenolytically, especially
employing a palladium catalyst ln a solvent which ls
lnert under the reaction conditions, e.g. ln a lower
alcohol or dimethyl formamide. The hydrogenation may
advantageo~sl~ be ~fected at room temperature and at
norm~l pressu~e,
The resulting compounds of formula I may be
isolated and purlfied using conventlonal techni~ues.
Where re~uired, free base forms thereof may be con-
verted into acid addition salt forms ln conventlonal
manner and vice versa. Suitable aclds for salt forma-
tion are hydrochloric, sulphuric, fumaric, maleic and
naphthalene-1,5-disulphonic acid.
- 8 - ~
.
'''

~ Z31 100-4806
The ~tarting materials of formula V can be
obtained according to the following reactlon scheme:
; A compound of formula VIII,
~\
R2 ~ CHO VIII
CHO
: wherein Rl and R2 are as previously defined,
. 5 is reacted with 3-oxo-glutaric acld diethyl ester
to produce a compound of formula IX,
1 ~ C2N5 IX
R2 COOC2E~5 .`
.,
wherein Rl and R2 are as previously defined,
the compound of formula IX is reduced and decarboxylated
according to known methods to yield a compound of
formula X,
~0 X
R
.. .
_ g _
.
, :- - .

2 31
100-4806
wherein Rl and R2 are as previously defined,
and the compound of formula X is reacted ln known manner
with an alkali metal cyanide and an acld additlon salt
of a c~mpound of formula XI,
~ I
HN XI
'
S whereln R3 and R4 are as previously deflned,
to yield a compound of formula V.
The starting materlals of formula VII can be
produced by reacting a compound of formula XII,
, Rl
~9 XII
wherein Rl, R2 and R4 are as previously
deflned,
wlth a Grignard compound of formula VI, according to
known methods, for example as for process varlant a).
The compounds of formula XII can be produced
from compounds of formula VIII ln manner analogous to
~ .
- 10 - ~
,
.
i - :: ~ .
`' ~

1~3~ Z31
100-4806
that prevlously descrt bed for the preparation of com-
pounds of formula V.
Insofar as the production of the startlng
materials has not been described, these are either
known or may be produced in conven~lonal manner from
available materials, or by methods analogous to those
described hereln.
In the following Examples, all temperatures
are ln degrees Cels~us.
`.

10~31 100-4~06
EXAMPL~ 1: 7-Dimethylamtno-s~6~8~9-tetrahydro-7-phen
_ . _
7H-benzocycloheptene
A solutlon of 10.0 g of 7-dimethylamino-
5,6,8,9-tetrahydro-7H-benzocyclohepten-7-carbonitrlle
in 150 ml of anhydrous ether is added dropwise to a
solutlon of phenyl magnesium bromide (prepared from
35.6 g of bromobenzene and 5.6 g of magnesium turnings)
ln 100 ml of anhydrous ether, over a period of one hour
and at room temperature. The reaction mixture is
stlrred for 30 minutes and thereafter 90 ml of 20%
ammonlum chloride solution are added dropw~se with
strong cooling. After ~eparating the organic phase, the
aqueous solution is shaken with ether and the combined
organic solutions washed with saturated brlne, dried
over potassium carbonate and evaporated. The title com-
; pound remains as an oily res$due and is converted to the
hydrochloride form in ethanol/acetone. M.P. 237-238
(from ethanol/acetone).
The starting material can be prepared as
follows:
t , To a solution of 14.2 g of potassium cyanide
in 80 ml of ethanol and 20 ml of water are first added
.
- 12 -
:

100-4806
1(3~231
17.8 g of dimethylamine hydrochlorlde followed by 35.0 g
of 5,6,8,9-tetrahydro-7H-benzocyclohepten-7-one in 50 ml
of ethanol over a period of 1.5 hours. The reaction
mixture is stlrred for 24 hours at room temperature,
considerably reduced in volume, diluted with ice/water
` and made slightly alkaline by the addition of potassium
hydroxide solution. The substance which precipitates is
extracted with ether, the ethereal extracts washed with
water, dried over potassium carbonate and reduced in
volume. The residue, 7-dimethylamino-5,6,8,9-tetrahydro-7H-
benzocyclohepten-7-carbonitrile, is recrystallized from
ether/petroleum ether. M.P. 110-112.
The following compounds can be produced in
manner analogous to that described in Example 1, employ-
lng appropriate starting materials in approximately
e~uivalent amounts.
, .
,
.. . .
.:
:,~
'
~ - 13 -
'` ,
. . .
.,
. ,, ~ ~, ~ .

10S~231
100-4806
Ex R3 _ _ _
No Rl R2 \R Z M . P .
,._._ . .. ~
2 H H - N~ ~ HCl*: 208-209
~:: 3 H H -N N-CH3 ~ Fu**: 194-195
4 H H -N (CH3) 2 CH HCl*: 214-215
H H n ~ 3 HCl*: 223 - 224
S H H n CH~ Cl HCl*: 205-207
, . 7 H H -N~ ~ HCl*: 230-232
~ 8 H H -N~ ~ HCl*: 230-231~
.~ 9 H H -N (CH3) 2 ~F HCl*: 2 41-242
CF 3
.~ . 10 H H n ~ F3 HCl*: 237-238
11 H H n~Cl HCl*: 232-234
12 H H -Nr--~0 HCl*: 219-220
- 14 -
.

1( ~231 100-4806
~Z I ~P
14 H H --N (CH3 ) 2 ~CH3 HCl*: 218-22 0
H H n ~SCH3 HCl*: 194--195
16 H H n ~3 98--100
17 ¦ ~ ¦ H¦ ~ J~H13 ~ I 99-1 0
I la I H 1 HI C~3 ¦ liPu~ ~: 125-12G~ ¦
9 ~i 1~ ~ ~ iiCl*:129-130
* HCl = Hydrochloride
** Fu = bistbase]fumarate
*** HFu = Hydrogenfumarate
- 15 - .
:

~ 231 100-4806
~XAMPLE 20: 5,6,0,9-Tetrah~dro-7-methYlamlno-7-~henxl-
7H-b- ~
~ ~olutlon of 25.0 g of 7-(N-benzyl-N-methyl-
am~no)-5,6,8~9-tetrahydro-7-phenyl-7H-benzocycloheptene
ln 500 ml of N,N-dimethyl ormam1de 18 hydroyenated ln
the presence of 2.5 g of 10% palladlum on charcoal at
; normal pres6ure and at room temperature. After take-up
of the theoretlcal quantlty of hydrogen, the cat~lyst 1
~lltered of, the filtrate evaporated to half it8 volume
, 10 and poured onto water. The entlre mlxture 18 shaken
- wlth ether ~3 appllcatlons), the extract~ washed wlth
water, drled over magne~ium sulphate and ev~porated.
The tltle compound remalns ~ an oll and 18 converted
to the hydrochlorlde form in ethanol. M.P. 275-276
lS (after recrystalllzatlon from ethanol).
The startlng material can be prepared a~
follows:
a) The starting matex~al ls prepared a~ de~crlbed ln
Example 1, uslng 37.5 g o benzylmethylamlne hydro-
chlorlde 1nstead of 17.8 ~ o~ dlmethylamine hydro-
chlorlde. 7-(N-b~nzyl-N-methylamlno)-5,6,8,9-t~tr~-
hydro-7~-benzocyclohepten-7-carbonltrile is obtalned.
M.P. 89-90.
- 16 -
:
~. .
. ' . - : ' ' ~ ' ~ ,

~ Z31 100-4806
b) The reactlon i~ effected as descrlbed ln Example 1,
usln~ 13.6 g of 7-(N-benzyl-N-methylamlno)-5,6,8,9-
tetrahydro-7il-benzocyclohepten-7-carbonltrile
ln~tead of 10.0 g o 7-dlmethylamlno-5,6,8,9-tetra-
hydro-7H-benzocyclohepten-7-carbonitrile. 7-(N-
benzyl-N-methylamlno)-5,6,8,9-tetrahydro-7-phenyl-
7H-benzocycloheptene i~ o~tained~ M.P. 129-130
hydrochloride ~orm).
- 17 -

100-4806
lOg~ Z31
The compounds of formula I exhibit pharmaco-
logical activlty. In partlcular, the compounds exhibit
anti-depressant activlty, as lndicated in standard tests,
for example, in the tetrabenazlne antagonism test in
rats.
The compounds are therefore indicated for use
as antl-depressants.
Fox thls use, an indlcated dally dose is from
a~out 0.1 to about 100 mg, conveniently adminlstered in
divlded doses 2 to 4 times a day in unlt dosage form
containing from abou~ 0.025 to about 50 mg, or ln
sustained release form.
The compounds also exhlbit psychost~mulant
activity, as lndicated by standard tests. For example,
in one standard test, the compounds are administered
orally to m~ce and subcutaneously or lntraperitoneally
to rats and the effect on the excitability of both spe-
cies observed over a perlod of several hours.
The compounds are therefore indlcated for use
a~ psychostimulants.
Additionally, the compounds exhlbit vlgilance-
lncreasing activity, as indicated ln standard tests.
For example, in one test, the sleep-wakefulness cycle is
- 18 -

~ 31 100-4806
determined in ratQ in conventlonal manner, using an
electroencephalograph.
The compounds are therefore indicated for use
as vigllance-increasing agents.
Fo~ these uses, an lndicated daily dosage is
from about 1 to about 500 mg, convenlently administered
in divided doses 2 to 4 times a day in unlt dosage form
containing from about 0.25 to about 250 mg of the
. ,~ :
~ compound admixed with a solid or liquid pharmaceutical
carxler or dil~ent.
The ~ompounds of formula I may be adminlsterçd
lp pharmaceutically acceptable acid addltion salt Eorm.
Such acld addltlon salt forms exhlblt the same order of
activlty as the free base forms and are readlly pre-
pared in conventlonal manner. The present lnvention
also provides a pharmaceutical ¢omposltion comprising
a compound of formula I, in free base form or in pharma-
ceutlcally acceptable acid addition salt form, in
assoclation with a phaxmaceutically acceptable diluent
or carrier. Such compositions may be formulated in
conventional manner and may be, for example, a solution
or a capsule.

100-4806
~ 2 ~ -
Sultable acids for salt formatlon lnclude
hydrochlorlc and fumaric acids.
In one group of compounds, Rl, R2, R4 and Z
are as previously deflned. ~3 1~ alkyl of l to 4 carbon
atoms, or R3 and R4, togethex wlth the nitrogen atom
to whlch they are bound, form a pyrrolidlne, plper~dine
or morphollne ring; or a plperazlne rlng, the nltrogen
atom of which is substituted by alkyl of l to 4 carbon
; atoms.
In a second group of compounds, Rl and R2 are
- a~ previously defined, R3 1~ hydrogen, R4 18 alkyl of
. 1 to 4 carbon atom3, cycloalkylalkyl of 4 to lO carbon
: atoms or cycloalkyl of 3 to 7 carbon atoms and Z 18 a
group II, III or IV a~ herelnbefore deflned.
- 20 -
~ '.
'''`"`
,-: . , :; .~ '
.
,