Note: Descriptions are shown in the official language in which they were submitted.
~ Case 100- a 7 3 2
1, 2, 3, 4, 4a, 10b ~ HE~AHYDRO-BENZ [f] ISOQUINOLINE COMPOUNDS
The present invention relates to 1,2,3,4,4a,10b-
hexahydro-benz~f]isoquinolines.
More particularly, the present invention
provides compounds of formula I,
¦1 3N-R3
wherein Rl is hydrogen, halogen of atomic number
from 9 to 35, alkyl of 1 to 4 carbon
atoms or alkoxy of 1 to 4 carbon atoms,
R2 is hydrogen, alkyl of 1 to 4 carbon
atoms, phenyl or phenyl mono- or di-
substituted with halogen of atomic
number from 9 to 35, alkyl of 1 to 4 car-
bon atoms or alkoxy of 1 to 4 carbon atoms,
and R3 is hydrogen; alkyl of 1 to 4 carbon
lS atoms; alkenyl of 3 to 6 carbon atoms or
61~
. .
alkynyl of 3 to 6 carbon atoms, the
multiple bond of which is not adjacent
to the tricyclic ring system; cycloalXyl-
alkyl of 4 to 10 carbon atoms; cyclo-
alkyl of 3 to 7 carbon atoms; phenyl-
alkyl of 7 to 10 carbon atoms, the
phenyl ring of which may be mono- or di-
substituted with halogen of atomic
numbex from ~ to 35, alkyl of 1 to 4
carbon atoms, or alkoxy of 1 to 4 carbon
atoms; a ~ noylalkyl of 3 to 5 carbon atoms,
- the oYygen atom of which is separated by
at least 2 carbon atoms from the nitro-
gen atom in the tricyclic system; and
pharmaceutically acceptable acid addition salts thereof.
. ~ ... . .. ... .
Insofar as the compounds of formula I are
substituted by an alkyl or alkoxy group as previously
defined, these groups preferably contain 1 or 2 carbon
atoms and especially signify methyl or methoxy.
When a substituent signifies halogen, this is
preferably chlorine.
Rl is pre~erably hydrogen. When Rl is halogen,
alkyl or alkoxy, this is preferably in position 8.
-- 3 --
., ~,
....
~5~ 100-4732
R2 is preferably hydrogen, methyl or phenyl.
R2 may also be phenyl mono- or di-substituted wi~h halo-
gen of atomic number from 9 to 35~ In a further group
of compounds, R2 is phenyl mono- or di-substituted with
alkyl of l to 4 carbon atoms or alkoxy of 1 to 4 carbon
atoms.
R3 can be alkyl of 1 to a carbon atoms and is
preferably methyl. R3 may also be hydrogen. When R3 is
alkenyl or alkynyl of 3 to 6 carbon atoms, these prefer-
ably contain 3 or 4 carbon atoms. R3 may be cycloalkyl-
alkyl of 4 to 10 carbon atoms, for example, cycloalkyl-
alkyl of 4 to 6 carbon atoms. R3 may also be cycloalkyl
of 3 to 7 carbon atoms, for example, cyclohexyl. When
R3 is phenylalkyl of 7 to 10 carbon atoms, this is pref-
erably phenethyl. The phenylalkyl group may be mono- or
di-substituted in the phenyl ring with halogen of atomic
number from 9 to 35. Additionally, the phenylalkyl
group may be mono- or di-substituted in the phenyl ring
with alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4
carbon atoms. When R3 is alkanoylalkyl of 3 to 5 carbon
atoms, this preferably contains an acetyl residue and is
especially acetonyl.
The invention further provides a process for
~.
., .
. .
~ ~,5 ~ ~ ~ 100-~732
the production of a compound of formula I, eomprising
a) producing a compound of formula Ia,
N-R3
R~ ~ Ia
wherein Rl and R2 are as previously defined, and
R3 is alkyl of 1 to 4 carbon ate~s; alkenyl
of 3 to 6 carbon atoms, the multiple
bond of whlch is not adjacent to the
tricyclic ring system; eyeloalkylalkyl of
4 to 10 carbon atoms; cycloalkyl of 3
to 7 earbon atoms; phenylalkyl of 7 to
10 earbon atoms, wherein the phenyl
ring may be mono- or di-substituted
with halogen of atomic number from 9 to
35; alkyl of 1 to 4 carbon atoms or
alkoxy of 1 to 4 earbon atoms; or,
lS when R2 is hydrogen, R3 can also be
hydrogen,
by removing water from a compound of formula II,
100-~732
~ N-R3
Rl ~ ~ II
HO R2
wherein Rl, R2 and R3 are as previously defined,
- b) producing a compound of formula Ib,
~ N-H
1 ~ Ib
. wherein Rl and R2 are as previously defined,
by removing the group R3 from a compound of
formula Ic,
~ N-RII
1 ~ ~ Ic
R2
wherein Rl and R2 are as previously defined and
R3 is methyl or benzyl,
or
c) producing a compound of formula Id,
N-R3
Id
R2
wherein Rl and R2 are as previously defined and
R3II has the same si.gnificance as R3
; with the exception of hydrogen,
by introducing a group R3 in a compound of
formula I_ as previously defined; and where
desired, forming a pharmaceutically acceptable acid
addition salt of said compound of formula 1.
The removal of water according to process
variant a) can be effected in known manner, for example,
by treating the compound of formula II with an appro-
priate spiitting agent, conveniently in the presence of
an inert organic solvent. Suitable materials for
removing water include strong acids, acid anhydrides
and acyl halides~
~ 1hen R3 in the compounds of formula II is
alkenyl, the reaccion is preferably effected in the
presence of an acyl halide.
-- 7 --
r ~
~ 5~ 100-4732
The removal of the group RII from the compounds
of formula Ic according to process variant b) can be
effected in known manner. The reaction is pxeferahly
carried out by reacting the appropriate compound of
formula Ic with a chloroformic acid ester and convertins
the urethane so obtained by acid or alkaline hydrolysis
to a compound of formula Ib.
The introduction of the group R3II into com-
pounds of formula Ib according to process variant c) can
be effected by known methods for the alkylation of
secondary amines, for example, by reaction with a com-
pound of formula III,
RIII X
wherein R3II is as previously defined and
X i9 the acid residue of a reactive
ester.
X is preferably halogen or an organic sulph-
onic acid residue.
The resulting compounds of formula I may be
isolated and purified using conventional techniques.
Free base forms of the compounds of formula I
may be converted into acid addition salt forms and vlce
:~ - 8 -
~ 100-~732
versa in conventional manner. Suitable acids for pro-
ducing acid addition salt forms include hydrochloric and
maleic acids.
The compounds of formula I possess two asym-
metric carbon atoms in the tricyclic system at positions4a and 10b. Accordingly, two isomer groups may exist,
namely compounds wherein rings B and C are linked in the
cis configuration and cornpounds wherein rin~s B and C
are linked in the trans configuration. The configura-
tion of the tricyclic system of ~he starting materials
remains unchanged by the process variants of the inven-
tion.
The starting materials can be prepared as
follows:
a') The compounds of formula II can be produced by
kno~n methods from compounds of formula IV,
~ N-R3
1 ~ OH IV
wherein Rl is as previously defined and R3V is
lower alkyl. The compounds of formula II wherein
_ g _
.
S~6~1 l00-~732
R2 is as previously defined with the exception
of hydrogen may, for example, be produced in the
manner hereafter described in Example la) to le)
whereby, after cyclisation, the 3-methyl group may be
substituted by the desired group R3 according to
known methods. The compounds of formula II wherein
R2 is hydrogen may, for example, be produced in the
manner hereinafter described in Exampl~ la) to ld)
and then as described in Example 15 (production of
the starting materials).
b') The compounds of formula IV may, for example, be
produced by reducing a compound of formula V,
I~ N-RIV
Rl ~3/I~R4 V
wherein Rl and R3 are as previously defined and
R~ is lower alkyl. The reduction can, for example,
be effected with a complex metal hydride, such as
lithium aluminium hydride, according to known
methods.
- 10
~ 100-4732
:
c') The compounds of formula V can, for example, be
produced by reacting a compound of formula VI,
COOR4
VI
'IV
R3
wherein R3 and R4 are as previously defined, with
a Grignard compound of formula VII,
Mg-X
VII
~Rl
wherein Rl is as previously defined and XI is
- chlorine, bromine or iodine. The reaction can, for
example, be effected according to the methods
described in J. Org. Chem. 22, 261 ~1957).
Insofar as the production of the starting
materials has not been described herein, these compounds
are either known or can be produced by known methods or
by methods analogous to those described herein or by
methods analogous to known methods.
In the following Examples, all temperatures
are in degrees Celsius~
-- 11 --
~ 5~ 0-4732
,
EXAMPI.E 1: Trans-1,2,3,4,4a,10b-hexahydro-3,6-
dime ~ n~[f]iso~uinoline
A mixture of 1~.6 g of trans-1,2,3,4,4a,5,6,10b-
octahydro-3,6-dimethylbenz[f]isoquinoline-6-ol in 20 ml
of isopropanol and 30 ml of 5 N isopropanolic hydro-
chloric acid solution is heated to boiling under nitro-
gen for 30 minutes~ The resulting suspension is cooled
to 10 and the hydrochloride of the title compound which
crystallises out is filtered, washed with ether and
recrystallised from ethanol/isopropanol. M.P. 302-303 (deccmp.)
The starting material may be produced as
follows:
a) A solution of 39 g of thionyl chloride in 300 ml of
anhydrous chloroform is slowly added dropwise at
lS 0-5 to a solution of 82 g of 1-methyl-4-phenyl~
piperidine-3-ylmethanol in 1500 ml of anhydrous
chloroform. The reaction mixture is stirred for one
hour at room temperature, one hour at 40 and sub-
sequently for 3 hours a~ the boiling temperature.
After evaporating to dryness, the residue is tri-
turated with a large amount of ether. The solid
3-chloromethyl-1-methyl-4-phenylpiperidine hydro-
- 12 -
- 100-4732
chloride is filtered by suction and dried ln vacuo.
M.P. 203-211~
b) The above product is converted with caustic soda
solution to the base, which is extracted with
methylene chloride. After drying over sodium
sulphate, the organic phase is evaporatsd to dry-
ness. 51 g of the evaporated residue and 13.4 g of
sodium cyanide are suspended in 40 ml o dimethyl
formamide and are heated to boiling for 2 hours
with vigorous stirring. On cooling to room temper-
ature, the reaction mi.xture is diluted with 200 ml
of water, extracted with chloroform and the chloro-
form phase is washed with water, dried over sodium
sulphate and concentrated. The l-methyl-4-phenyl-
piperidin-3-ylacetonitrile (M.P. of the naphthalene-
l,S-disulphonic acid salt form: 292-296, decomp.)
remaining as a viscous oil is used without further
purification.
c) A solution of 85 g of the above product in 150 ml
of absolute ethanol is saturated at 10 with hydro-
gen ~hloride. The dar~ reaction solution is then
stirred for 24 hours at the boiling temperature~
100-4732
thoroughly concentrated by evaporation, 200 ml of
anhydrous benzene are added and the solution is
evaporated to dryness. The res.idue is taken up in
290 ml of absolute ethanol, 7.2 ml of water added
and the residue is hea~ed to the boil for 2 hours.
On concentration by evaporation, the residue is
dissolved in chloroform, water is added and the
; residue is made alkaline with sodium bicarbonate.
After separating the chloroform solution, the
aqueous solution is ayain shaken out with chloro-
form, the extracts are washed with 10% sodium bicar-
bonate and with water, dried over sodium sulphate
and evaporated to dryness. The residue is distilled
under high vacuum to yield l-methyl~4-phenylpiper-
idin-3-ylacetic acid ethyl ester. B.P. 118-123/
0.08 Torr. n20: 1.5220.
d~ A solution of 16.8 g of 1-methyl-4-phenylpiperidin-
3-ylaGetic acid ethyl ester in 10 ml of anhydrous
xylene is added dropwise over a period of 15 min-
20 . utes to a mixture of 85 g o polyphosphoric acid and
25 ml of anhydrous xylene, preheated to 90, with
vigorous stirring. The reaction mixture is stirred
- ~4 -
.':
100-~73~
~ ' .
for a further 2 hours at 120-125, cooled to approx~
imately 80 and poured onto 300 ml of water. The
resulting aqueous solution is washed with ether,
made alkaline with 20~ caustic soda solution and
extracted with chloroform. The ch]oroform solution
is washed neutral with water, dried over sodium
sulphate, evaporated, the residue is dissolved in a
mixture of methylene chloride/methanol 9:1 (v/v),
filtered through aluminium oxide and evaporated to
dryness. The 1,2,3,4,4a,10b-hexahydro-3-methyl-
benz[f]iso~uinoline-6-(5H)-one (isomeric mixture)
remainin~ as an oil distills at 106-110/0.08-0.1 Torr.
Isomer separation: The trans-form crystallises
from the isomeric mixture from ether/petroleum
ether. M.P. 84-85 (ether/petroleum ether).
(Hydrochloride form, M.P. 300-302 decomp., from
methanol.) The c1s-form is isolated as ~the hydro~
~en fumarate form from the mother liquor. M.P. 175-
177, sint. 172 (from ethanol/ether).
e) To a solution of 115 ml of 2 M methyllithium in
ether and ~00 ml of anhydrous ether, there is added
dropwise, in a nitro~en atmosphere and with
- 15 -
5~ oo 4732
stirring, a solution of 20.0 g of trans-1,2,3,4,4a,10b-
hexahydro-3-methylbenz[f]isoquinoline-6(5H)-one in
400 ml of anhydrous benzene over a period of 45 min-
utes at room temperature. The reaction mixture is
stirred for 2 hours at room temperature, poured onto
1 litre of 20~ ammonium chloride solution, the
organic phase separated and the aqueous solution
extracted with methylene chloride. The separate
organic solutions are washed with wa~er, dried over
sodium sulphate, combined and evaporated. The
remaining trans-1,2,3,4,4a,5,6,10b-octahydro-3,6-
dimethylbenz[flisoquinoline-6-ol is recrystallised
from benæene/hexane. Sint. 130, M.P. 148-153.
The following compounds can be obtained in a
manner analogous to that described in Example 1, employ-
ing appropriate starting materials in approximately
equivalent amounts~
- 16 -
54~6~ 100-4732
._ . oo~ ooooOoO oLn^
L~ O ~I Ln 0~ 0~~D 0~Ct)
~Dr` CO O ~ N ~
Nt'`l t~l O O t~ 1 0
4 N I I ~ Ll ~ ~ N n~ a
. ~ ~ a ~ Q
t~J N N '-- N t~l N N ` NN ~_1 N
__ ~ , . . . _____ _ . _
.,
O
~ O
`'~ h 3 ~ o
_ . ._ . . . . .
.~
H r~) U - U ~ U
. .. __ _ _ _
P;~ ~ 3 0 ~
_ _ _ ___ ~.. __ _ . _ __ . . .
U~ U U U
P~ ~
- . - . . - - ~ -
~ h ~ h ¦
~1 Z; (~ ~ ~ Ln ~ o 'I
---~
-- 17 --
~ 100-4732
EX~1P1E 15: Trans~1,2,3 r 4 r 4a,10b-hexahydro-3-methyl-
benz~f]isoquinoline
In a manner analogous to Example 1, the title
compound is produced from 10.0 g of trans-1,2,3,4,4a,5,
S 6,10b-octahydro-3-methylbenz[f]isoquinoline-6-ol in
25 ml of isopropanol and 30 ml of 5 N isopropanolic
hydrochloric acid solution after boiling for 2 hours.
The title compound is isolated as the hydrochloride salt
form. M.P. from 285 (decomp.).
The starting material is produced as follows:
To a suspension of 1~.0 g of lithium aluminium
hydride in 800 ml of anhydrous ether, is added dropwise
at 0-5, a solution of 15.0 g of trans-1,2,3,4,4a,10b-
hexahydro-3-methylbenz[f]iso~uinolin-6(5H)-one in 300 ml
of anhydrous ether over a period of 30 minutes. The
resulting suspension is stirred for one hour a~ room
temperature, 100 ml of water are added dropwlse at 0-5
and the insoluble material filtered off and washed
several times ~ith methylene chloride. The organic
phase is separated from the filtrate, washed with water,
dried over sodium sulphate and concentrated by evapoxa-
tion. The solid residue is recrystallised from ether/
- 18 -
. ..~ ;.
'54~ 0 0--G 732
petroleum ether. i~l.P. 118-128.
The following compounds can be obtained in a
manner analogous ~o that described in Exam~le 15, using
appropriate starting materials in approximately equiv-
5alent amounts.
_ _ _ . .
Ex Confn. Rl R2 R3 Form M.P.
_ _ _ __
16 cis H H -CH3 Hydro- 225-226
chloride
17 trans 8-Cl H -CH ll > 265
3 (Decc~p.)
18 ll 8-CH3 H -CH3 ~ 224-225
19 . H H -CH2 ~ ll 252-253 .
~, L ~ 2 ~ ~ L
EXAMPLE 21: Trans-1,2,3,4,4a,10b-hexahydro~6-methyl-
__ _ _ ~
benzEf]isoquinoline
To a solution of 7.0 g of trans-1,2,3,4,4a,10b-
hexahydro-3,6-dimethylbenz[]isoquinoline in 70 ml of
anhydrous benzene is added dropwise a solution of 12.2 g
of chloroformic acid ethyl ester in S0 ml of benzene
at room temperature
-- 19 --
,1,
: _
100-4732
5fl~
over a period of one hour. The reaction mixture is
stirred for one hour at room temperature and for 3 hours
at the boiling temperature, cooled to room temperature
and washed with water, l N hydrochloric acid and again
with water, dried over magnesium sulphate and evaporated
; to dryness. The resulting crude trans-3-ethoxycarbonyl-
1,2,3,4,4a,10b-hexahydro-6-methylbenz[f]isoquinoline is
ta~en up in 34 ml of n-~utanol, 4.5 g of potassium
hydroxide are added and stirring is effected for 18
hours at 100. After cooling, the reac~ion mixture is
diluted with 300 ml of benzene, washed neutral with
water and extracted with 2 N tartaric aci.d. The tar-
taric acid extract is made alkaline with caustic soda
solution and shaken out with methylene chloride. The
lS methylene chloride solutions are washed with water,
dried over sodium sulphate and evaporated. The title
compound, remaining as an oily residue, is taken up in
ethanol and converted into the hydrogen maleate salt
form. M.P. 169-170 tfrom ethanol/ether).
EXAMPLE 22:
In a manner analogous to that of Example 21,
trans-1,2,3,4,4a,10b-hexahydro-8-methylbenz[f]isoquino-
- 20 -
100-473
~ 6 8
line can be produced using an equivalent quantity of
the appropriate starting material. M.P. of the hydro-
chloride salt form: over 310 (decomp.).
EXAMPLE 23: Trans-1,2,3,4,4a,10b-hexahydro-3-isopropyl-
_
6~methylbenz[f~isoquinoline
[Process variant c)]
A mixture of 7.0 g of trans-1,2,3,~,4a,10b-
hexahydro-6-methylbenz[f]isoquinoline and 8.0 g of
anhydrous sodium carbonate in 70 ml of dimethyl form-
amide is preheated to 50. At this temperature, a
solution of 6.5 g of isopropyl bromide in 20 ml of
dimethyl formamide is slowly added dropwise, the reac-
tion mixture is stirred for 6 hours at the same tempera-
ture, cooled to 20 and poured onto 300 ml of water and
200 ml of chloroform. The organic solution is separated
and the aqueous phase extracted with chloroform. The
combined organic solutions are washed with water, dried
over sodium sulphate and evaporated. The title compound
is isolated as the hydrochloride salt form from methanol/
ethanol. M.P. over 300 (decomp.).
The following compounds can be obtained in a
- 21 -
~ . .
~ `s~
100-4732
manner analogous to that of Example 23 using appropriate
starting materials in approximately equivalent amounts.
_ ~ _ ~ .. , _
Ex Confn. R1 R2 3 Salt Form M.P.
~ _
24 trans H -CH3 -CH2C--CH Hydrochloride 242-243
25 H -CH3 -CH2COC~3 L _ 215-216
- 22 -
~5~6~
100-4732
The compounds of formula I exhibit pharmaco-
logical ac~ivity. In particular, the compounds exhibit
anti-aggression activity, as indicated in standard tests,
for example, in the sedation of aggressive behaviour in
mice caused by isolation.
The compounds are therefore indicated for use
in the treatment of aggression.
For this use, an indicated daily dose is from
about 1 to about 100 mg, suitably from about 5 to about
50 mg, conveniently administered in divided doses 2 to
4 times a day in unit dosage form containing from about
0.25 to about 50 mg, suitably from about 1 to about
25 mg, or in sustained release form.
The compounds also exhibit sedative and
neuroleptic effects on the central nervous system as
indicated in standard tests, for example, in the climb-
ing test in mice.
The compounds are therefore indicated for use
as neuroleptics and sedatives.
For these uses, an indicated daily dose is from
about S to about 200 mg, conveniently from about 5 to
about 50 mg, and suitably from about 10 to about 50 mg,
conveniently administered in divided doses 2 to 4 times
5 ~ ~ ~
100-~732
a day in unit dosage form containing from about 1 to
about 100 m~, conveniently from about 1 to about 25 mg,
and suitably from about 2.5 to about 25 mg, or in sus-
tained release form.
The eompounds of formula I may be administered
in pharmaceutieally aeceptable acid addition salt form.
Sueh acid addition salt orms exhibit the same order of
aetivity as the free base forms and are readily prepared
in eonventional manner. Suitable acids for salt forma-
tion inelude inorganic acids such as hydroehlorie aeid
and organie aeids sueh as maleie acidO
The present invention also provides a pharma-
eeutical eomposition eomprising a eompound of formula I
in free base form or in pharmaeeutieally aceeptable aeid
addition salt form, in assoeiation with a pharmaeeuti-
eally aeceptable diluent or earrier. Sueh eompositions
may be formulated in eonventional manner and may, for
~xample, be a solution or a eapsule.
- 24 -
