Note: Descriptions are shown in the official language in which they were submitted.
~ :~ 6 ~ 7
Heterocyclic compounds, their preparation and_~harma-
ceutical com~ositions containing them
This is a divisional of application Serial
No. 380,614 filed June 25, 1981.
The present invention relates to phenanthrene
derivatives, their preparation and pharmaceutical
compositions containing them~
Belgian patent n 877 169 describes a class
of 4,5~/5a,6-tetrahydro-dibenz[cd,f]indole derivatives
havin~ stimulant activity on central dopaminergic
receptors. All the compounds sp~cif:ically exemplified
which have alkyl groups attached to positions 4 and 5,
contain as one alkyl group a methyl group. It has
been now surprisingly found that a group of (4R*r5aS*)
-4,5,5a,6-etrahyd~o dibenæ[cd,f]indole derivatives
having ethyl and n-propyl groups in the 4 and 5
positions, which are nowhere specifically described
or suggested in this patent, possess a particularly
interesting pharmacological profile, inter alia, lvng
-duration of action and/or notable potency as central
dopaminergic agents and good tolerability.
'~.
2 7
- 2 - 100-5~10
In accordallce with the inventioll there
are provided compounds of formula I,
w~erein
P~l and R2 independently, are ethyl or nrpr~yl radicals,
and
the R3 substituents are the same and are hydroxy or
acyloxy radicals,
in racemic form having the relative configuration
4~*,5aS*, or in optically active isomer form having
the absolute configuration 4S,5aR.
Tne acyloxy radicals are conveniently
radieals of formula
Ra ~ CO - (i)
in which Ra is an alkyl radical, (C3 7)cycloalkyl,
a ~henyl xadical or a 5- or 6-membered heterocyclic
ring.
When Ra is an alkyl radi.cal,this may
conveniently contain 1~17 carbon atoms, preferably 1
to 7 carbon atoms, and may be straight chain or
branched chain.
,~ t
' ' ~ - ' ' ' ' - ' . . :
'.
~ lG2~7
3 --
( Ra may be a substituted alkyl radical, con-
taining .in -the alkyl chain conveni.ently 1-5 carbon
atoms. Conveniently it is a monosubstituted alkyl
radical. The substituents may be, e.g. carboxy,
hydroxy, amino, (Cl 4)alkylamino, (C1 4)alko~y,
di-(Cl 4)alkylamino, halogen, (Cl_4)alkylthio,
phenoxy, a phenyl radical, l~pyrrolidinyl, piperidino
or morpholino, and conveniently a phenyl radical
Ra may also be e.g. an alkyl radical containing in the
alkyl chain 1-4 carbon atoms and substituted by
(C3 7)cycloalkyl.
~ en Ra is a phenyl radical or alkyl substi-
tuted by a phenyl radical, the phenyl radical may be
unsubstituted or contain 1, 2 or 3 identical or diffe-
rent substituents, selected, for example, from halogen,trifluoromethyl, (Cl_4)alkyl, (Cl ~)alkoxy,
(Cl_4)alkylthio and di-(Cl 4)alky1aminot or a methylene-
dioxy group. Preferably the phen.yl ring is mono- or
disubsti~u~ed.
When Ra is an alkyl substituted by a phenyl
radical, Ra is preferab7y a benzyl radical. The
phenyl ring may bear substituents selected, for example,
from halogen~ (Cl_4)alkyl, (Cl_4)alkoxy or (Cl 4)alkyl-
thio.
~1
2~
When Ra is a heterocyclic ring, this is
suitably a heterocycle containing oxygen, nitrogen
or sulfur as sole heteroatom, e.g. pyridine, thiophene
or furan.
Preferably Ra is (cl_7)alkyl; (C3_6)cyclo
alkyl; unsu~stituted phenyl; phenyl mono- or disubsti-
tuted by chlorine, fluorine, trifluoromethyl,
(Cl 4)alkyl or (Cl 4)alkoxy; unsubstituted benzyl;
or benzyl mono- or disubstituted by chlorine, fluorine,
(Cl_4)alkyl or (Cl_4)alkoxy.
Halogen may signify chlorine, bromine or
fluorine, preferably chlorine or fluorine.
In a group of compounds, Rl is n~propyl and
R2 is ethyl. In another group of compounds, Rl and R2
are the same and signify ethyl or n-propyl. Preferabl~
in the compounds of formula.I the R3 substituents
are hydroxy. The preferred compounds are the
(4S,5aR) optical isomers.
More particularly, the invention provifles
a process for the production of compounds of formula I,
which comprises
a) producing a compound of formula Ia
~ ~2~
HO~
wherein Rl and R2 are as defined above, by splitting
the ether groups Z of a compound of formula II
~ -R2 II
wherein ~1 and R2 are defined above and Z is a
splittable ether group, in racemic form having the
relative configuration 4R*, 5aS*, or in optically active
isomer form having the absolute configuration 4S, 5aR, or
b) producing a compound of formula Ib
2 Ib
.
wherein Rl and R2 are defined above and the radicals
R3 are identical acyloxy radicals, by acylating a
compound of formula Ia in racemic form having the
relative con~iguration 4R*, ~aS* or in optically
a¢tive isomer form having the absolute configuration 4S,5aR~
~!
9 ~ 7
The ether splitting process according to process
a) may be effected in conventional manner for splitting
ether groups. For example the reaction may be
carried out by treatment of the starting materials
with a strong mineral acid, e.g. hydrobromic or
hydroiodic acid, at a temperature of at least 100C,
preerably from 100C to the boiling point of the
reaction mixture, especially at about 130C. The ether
group Z is prefarably a methoxy radical.
The acylation process according to process b),
may be effected in conventional manner for the selective
acylation of phenolic groups in the presence of an
amine function. For example there may be used, as
acylating agent, a functional derivative of an acid
such as acid chloride, acid bromide or the acid
anhydride. Conveniently the reaction is carried out
by reacting an acid chloride in the presence of tri-
~luoroacetic acid at temperatures from 20C to the
boiling point of the reaction mixture or in the pre-
sence of pyridine at temperature from 0C to roomtemperature.
Th~ resulting compounds o~ formula I may be
isolated from the reaction mixture and purified in
known manner. The free base forms of compounds of
formula I may be converted into acid addition salt
~`i
,I~f~ ~"
l 3, ~ Vl
- 7 - ~00-5410
forms in conventional manner and vice versa. Suitable
acids for salt formation are, for example, hydrochloric
acid~tartaric a~id, di-0,0-p-toluoyl-D-or L-tartaric
acid, and hydrobromic acid.
Racemic compounds of formula I may be
obtained from racemic starting materials. Optically
active isomers of formula I may be obtained from
optically active precursors with the configuration
(4S,5aR) or from the racemate. The 4S,5a~ enantiomer
may be obtained from racemate by known methods, or
example by fractional crystallization of ~iastereo-
isomeric salts, e.g. their salts with (+)-di-0,0-p-
toluoyl-D-tartaric acid or (-)~di-0,0-p-toluoyl-L-
tartaric acid. Racemic resolution into the optically
active isomers may be effected preferably at an
early stage in ~he synthesis, e.g. before splitting
of the ether ~roups.
The starting materials of formula II may
be prepare~ by reducing compounds of formula III
Z ~ ~ III
; ~ 7
, . i,
3'~ 7
- ~ 100-5410
wherein Rl, R2 and R3 are as defined above.
The reduction may be effected convenierltly
under acidic condi-tions suitable for the acidic
reduction of enamines or imines, for example with
zinc in an aqueous mineral acid, preferably hydrochlo-
ric acid, conveniently in the presence of a mercury (II)
salt, for example mercury(II) chloxide. The reaction
may suitably be effected for example in ethanol, and
at temperatures from 50C to the boiling point of
the reaction mixture.
Starting materials of formula III may
be prepared, fox example, accoxding the follo~ing
reaction scheme:
A;
~ 9 ~ I00-5410
( II I )
~ Rl-MgBr or
ter t . -butyl~1 \ R -Li
lithium
~0-R ~ ~ (VI)
R:2
1` ' I C2
I }~al-C0-R
_R2 ~ ~-\i
butyl li thium
z ~ (YIII)
~-R2
l~iborane
~U-CO-~2 (~X)
~ 1~ COOU~ ~hl
~ ~629~
-- 10 --
(
In the reaction scheme the radicals Rl, R~
and Z are as deflned above and R2 is methyl or ethyl.
The reactions may be carried out in conventional manner
and the products of the above reactions may be isolated
and puri~ied in known manner.
In the above intermediates the ether groups
Z are conveniently methoxy.
Insofar the preparation or any particular
starting material is not particularly described, this
may be effected in con'ventional manner.
For example the phenanthrene derivatives which are
staxting materials of formula XI, are descrihed in the
Elsevier's Encyclopaedia of Organic Chemistry, vol. 13,
Tricyclic compounds, Elsevier Publishing Company Inc.
New York (1946).
In the following Examples all tempera~ures
are ~iven in degrees Celsius ancl are uncorrected.
EXAMPLE 1:
a) 9-(N-ethyl-N butyryl-amino)--3-bromo-3,4-dimethoxy-
phenanthrene [compound of formula IVJ
A solution of 50 g 5138 mM) 9-ethylamino-8-
bromo-3,4-dimethoxy-phenanthrene in 57.5 ml 5333 mM)
N-ethyl-diisopropylamine and 420 ml methylene chloride
is added dropwise, with stirring, under a nitrogen
\,
~ ~2~7
(
atmosphere over a period of 20 minutes to a solution
o~ 28.8 ml (276 m~1) butyryl chloride in 420 ml
methylene chloride. During the addition the reaction
mixture i5 maintai~ed at room temperature by cooling
in a water bath. The resultant yellow-red solution
is then worked up in known manner to afford 9-(N-ethyl-
N-butyryl-amino)-8-bromo-3,4 dimethoxy-phenanthrene;
M.pt 102-104.
b) (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9,10-dimethoxy-
. .
4~n-propyl-dibenz[cd,f]indole [compound of formula III]
25 g (58.14 mM) of 9-N-ethyl-N-butyryl
amino)-8-bromo-3,4-dimethoxy phenanthrene are
dissolved with stirring in 450 ml anhydrous
tetrahydrofuran and the solution obtained is cooled
to -25 with a bath of methylena chloride and dry
ice. 73 ml tll6.28 mM) of a 1.7 molar solution of
tert.~butyl-lithium in pentane are then added
dropwise over 4 minutes. Then the temperature
of the reaction mixt~re is allowed to increase to ~5
over a period of 30 minutes, the reaction mixture
is poured ontG 500 ml of a mixture water and ice,
extracted three times with, each time, 500 ml
methylene chloride, and the organic phases are washed
with water, dried and evaporated. After the product
is dried in high vacuum, the~e is obtained
~,~
1 ~;2~ ~
- 12
(4RS)-5-ethyl-4,5~dihydro-4-hydroxy-9, 10-dimethoxy-
4-n-propyl-dibenz[cd,f]indole in the form of a yellow
green foam.
c) (~ (4R*,saS*)-5-ethyl-4,5,5a,6-tetrahydro-9,10-
dimethoxy-4-n-propyl~dibenz[cd,f]indole [compound of for-
mula II]
A suspension of 40.6 g (116 mM) of (4RS)-5-
ethyl-4,5 dihydro-4~hydroxy-9,10-dimethoxy-4-n-propyl-
dibenæ~cd,f]indole in 1060 ml ethanol is added with
stirring to a suspension o 140 g of zinc dust
and 31.6 g ~116 mM) of mercury tII) chloride in
1060 ml distilled water (alternatively the zinc dust/
mercury chloride may be added to the dibenz-indole).
The re~ction mixture is refluxed, 360 ml of 18~
hydrochloric acid are added dropwise over a period
of 15 to 20 minutes and the mixture is refluxed overnight
with stirring. The reaction mixture is cooled to
room temperature, filtered and the zinc amalgam is
washed with 500 ml methylene chloride. The filtrate
is made alkaLine with 1 litre of concentrated NH40H
and the alkaline phase is extracted o~ce with 1 litre
methylene chloride and twice with, each time, 500 ml
methylene chloride. ~he combined organic phases are
washed with water, dried and
2 7
- 13 -
evaporated. The resultant oil is chromatographled
on silicagel using methylene chloride with 2~ methanol
as eluant to give (~)-(4R*,5aS*)-5--ethyl-4,5,5a,6-
tetrahydro-9,10-dimethoxy-4-n-propyl-dibenzLcd,f]
S indole in form of an oil.
EXAMPLE 2:
The (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9,
10-dimethoxy~4-n-propyldibenz[cd,f]indole obtained
in the Example lb), may also be prepared as foliows:
0 a) 9-amino-3,4-dimethoxy-phenanthrene [compound of
formula X~
A mixture of 430 ml (3.08 moles) trifluoro-
acetic anhydride and 430 ml (5.62 moles3 trifluoro-
acetic acid is added at room temperature under a
nitrogen atmosphere to 53.6 g (0.19 mole~ 3,4-
dimethoxy-phenanthrene~9-car~oxylic acid and the
mixture is stirred for 10 minutes. ~fter the mixture is
cooled to -5, 15.2 g (0.234 mole) sodium azide are care-
fully added in solid form, the mixture is stirred for
3 hours at 2, poured onto ice and the resulting
suspension worked up in known manner to give
9-amino-3,4-dimethoxy-phenanthrene as a solid. The
hydrochloride melts at over 215 with decomposition.
b) 9-acetylamino-3,4-dimethoxy-phenanthrene [compound
of formula IX]
; `~,
~ 3.623'~7
- 14 -
(~
55 ml (0.319 mole) N-ethyldiisopropylamine
are added to a solution of 38.2 g (0.151 mole) 9-amino-
3,4-dimethoxy-phenanthrene in 200 ml methylene
chloride. To the resulting mixture is added dropwise
over 20 minutes a solution o~ ~0.8 ml (0.292 mole)
acetyl chloride in 250 ml methylene chloride. During
the addition, the temperature of the reaction mixture
is maintained at 20 by cooling with an iCP bath.
The reaction mixture is stirred for 14 hours at
room temperature and worked up in known manner
to afford 9-acetylamino-3,4-dimethoxy-phenanthrene;
M.pt. 190-195 after recrystallisation from ethex.
c) 9-ethylamino-3,4-dimethoxy-phenanthrene [compound
of formula VIII]
34 g (0.124 mole) 9-acetylamino-3,4-
dimethoxy-phenanthrene in suspension in 450 ml anhydrous
tetrahydrofuran are reduced with 500 ml (0.5 mole) of a
molar solution of diborane in anhydrous tetrahydro~uran
and worked up in known manner to give 9-ethylamino-3,4-
dimethoxy-phenanthrene; M.pt. 94-95.
1 lB292 7
- 15 -
d) 4,5-dihydro-9, 10-dimethoxy-5-ethy_-4-oxo-dibenz-
[cd,f]indole [compound of Eormula VI~
122 ml (0.2 mole) oE a 15~ solution of
n-butyl-lithium in hexane are added at 0, under a
nitrogen atmosphere, to a solution of 28.1 g (0.1 mole)
of 9-ethylamino-3 r 4-dimethoxy-phenanthrene in 300 ml
anhydrous tetrahydrofuran; the reaction mixture
becomes bright red. Dxy ice is then added until the
colouration disappears : the formation of a solution
with yellow-green fluorescence is observed. After
the temperature o~ the reaction mixture is allowed
to reach room temperature, the mixture is poured
onto water/ice, extracted three times with methylene
chloride and the organic phase dried over sodium
~ulfate and evaporated. There is thus obtained
4,5-dihydro-9, 10-dime~hoxy-5-ethyl-4-oxo-dibenz~cd,f]-
indole which melts at 125-126 (with decomposition)
after crystallisation from ether/petxoleum ether.
e) ~4RS3-5-ethyl-4,5-dihydro-4-h~droxy-9, 10-dimethoxy-
4-n-propyl-dibenzlcd,f3indole [compound of formula III]
2.1 ml (33mM) of a solution of _-propyl-
magnesium bromide in ether are added dropwise at room
temperature to a solution o 10 g (33mM~ of 4,5-dihydro-
9, 10-dimethoxy-5-ethyl-4-oxo-dibenz~cd,f]indole in
300 ml anhydrous ~etrahydrofuran. After 30 minutes,
.. ~
.~
23~
- 16 -
f
a solution of ammonium chloride is added, the mixture
extracted with methylene chloride and the organic
phase dried and evaporated to give (4RS)-5-ethyl-
4,5-dihydro-4-hydroxy-9,10-dimethoxy-4-n-propyl-dibenz
[cd,f]indole in the form of a yellow green foam.
[IR Spectrum (CH2C12) : 3540 cm (OEI)]. The crude
product is directly used ~or the next step.
EXAMPLE 3: (+)-~4R*,5aS*)-5-ethyl-4 ! 5,5a,6-tetrahydro-
9,1~-dihydroxy-4-n-propyl-dibenz[cd,f]indole
20g (27.66 mM) (~)-(4R*,5aS*)-5-ethyl-
4,5,5a,6-tetrahydro-9,10-dimethoxy-4-n-propyl~dibenz
[cd,f]indole in 200 ml of a 47% aqueous solution of
hydrobromic acid are warmed for ~ hours at reflux,
at a bath temperature of 150. After evaporation
of the reaction mixture to dryness, the crystalline
residue is stirred in acetone and filtered under
suction. The precipitate is washed with acetone then
with ether and dried under high vacuum. There is
thus obtained ~ (4R*/5aS*)-5-ethyl-4,5,5a,6-tetra-
hydro-9,10-dihydroxy-4-n-propyl-dibenz[cd~f]indole
hydrobromide whi~h melts at 200 with decomposition.
The following compounds may be prepared
in analogous manner from the appropriate starting
materials :
.~
9 ~ 7
- 17 -
a) (+)-(4R*,5aS*)-4,5-diethyl-4,5,5a,6-tetrahydro-9,10-
dihydroxy-dibenz[cd,f]indole (hydrobromide,
M.pt >175 with decompo 5 ition);
b) (+)-(4R*,5aS*)-4,5,5a,6-tetrahydro-9,10 dihydroxy-
4/5-di-n-propyl-dibenz[cd~f]indole(hydrobromide~
M.pt > 190 with decomposition).
c) (+)-(4R*,5aS*)-4-ethyl-4,S,5a,6-tetrahydro-9,10-
dihydroxy-5-n-propyl-dibenz[cd,f]indole.
EXAMPLE 4: (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-
9,lO-dihydroxy-4-n-propyl-dibe-z[cd~f]indole
a) (-)~(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-
dimethoxy-4-n-propyl-dibenz[cd,f]i~dole
30 g (89 mM) of (+)-~4R*,5aS*)-5-ethyl-
4,5,5a,6-tetrahydro-9,10-dimethoxy-4-n-propyl-dibenz
[cd,f~indole are dissolved in 300 ml ether and a
solution of 35.95 g of (-)-di-0,0-p-toluoyl-L-
tartaric acid monohydrate in 300 ml ether is added
with stirring. The mixture is further stirred for
one hour at room temperatura, a total of l litre ether
being added in portions during this period. The
resultant precipitate is filtered off under suction,
washed wi~h ethyl acetate until it remains light
yellow, and dxied.
,1; ~
~,. ~
.
'2~
- 18 -
(
61.88 g of the crystals obtained from the first
crystallisation are dissolved in 1 litre acetone and 300 ml
methanol at reflux and the solution is filtered and
concentrated until a major part of the product crystallizes
out. The mixture is stirred for about 15 minutes, the
product is filtered off under suction, washed with
ethyl acetate until it remains colourless and dried.
The resulting product is recrystallis~d in
the same manner by using 1.7 litres acetone and 35 ml
methanol to give colourless crystals.
The resulting crystals are recrystallised
in the same manner, by using 1~2 litres acetone and 60 ml
methanol. There is thus obtained ~ t4S,5aR)-5-çthyl 4,
5,5a,6-tetrahydro-9, 10-dimethoxy-4-n-propyl-dibenz
lcd,f]indole (~)-di-0,0-p-toluoyl-L-taxtrate in
form of colourless crystals which melt at 178-179;
~a]D =-138 (c = 0.29 in methanol).
The following compounds may be prepared
in analogous manner from the appropriate starting
materials:
- (-)-(4S,5aR)-4,5-diethyl 4~5,5a,6~tetrahydro-
9, 10-dimethoxy-dibenz[cd,f]indole (-)-di-0,0 p-
toluoyl-L-tartrate, M.pt 187-189; [a]D =-138
~c=0.5 in methanol); the racemic starting material
., .~
,
-- 19 --
(
is reacted first with (~)-di-0,0-p-toluoyl-D-
tartaric acid instead of the L-isomer and the mother
liquor obtained on crystallisation is treated with
NH40H to liberate the base. The base is reacted
with (-)-di-0,0-p-toluoyl-L-tartaric acid and the
crystals obtained from an ether solution.
- (-)-(4S,5aR~-4,515a,6-tetrahydro-9,10-dimethoxy-
4,5-di-n-propyl-dibenz[cd,f]indole (-)-di-0,0-p-
toluoyl-L-tartxate, M.pt 165-166; [a]D =-123
(c = 0.27 in methanol).
b) (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-
dihydroxy-4-n-propyl-dibenz[cd,]îndole
Proceeding as described in Example 3,
(-) (4S,5aR)-5-ethyl-4,5/5a,6-tetrahydro-9,10-dihydroxy-
4-n-propyl-dibenz[cd,f]indole hydro~romide is
obtained from the tartrate obtained above under a). It
melts above 210; [a]20 = -64 (c = 0.245 in methanol).
The corresponding hydrochloride melts at
above 185 with decomposition; [a~20 = _750
(~ = 0.28 in methanol).
EXAMPLE 5-
The following compounds may be prepared inanalogous manner as described in Example 4b) from the
appropriate starting materials:
a) (-)-(4S,5aR)-4,5-diethyl-4,5,5a,6-tetrahydro-9,10-
i3 ~ 7
- 20 -
(
dihydroxy-dibenz[cd,f]indole hydrochloride, M.pt.200 with
decornposition; [a]20 = -72 (c = 0.25 in methanol);
b) (-)-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dihydroxy-4,5~di-
n-propyl-dibenz[cd,f]indole hydrochloride, M.pt > 187 with
decomposition; [a]20 = -58.5 (c = 0.35 in methanol).
c) ~-)-(4S,5aR)-4-ethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy-
5-n-propyl-dibenz[cd,f3indole.
EXAMPLE 6: (+)-(4S,5aR)-5-ethyl-9,10-dibenzoyloxy-
4,5,5a,6-tetrahydro-4-n-propyl-dibenz[cd,f]lndole
0.376 ml t3.23 mM) of benzoyl chloride are
added dropwise with stirring, over 5 minutes and at
a temperature of +5, to a solution of 600 mg
(1.54 mM~ of ~ )-(4S,5aR)-5 ethyl-4,5,5a,6-tetrahydro-9,
10-dihydroxy-4-n-propyl-dibenz[cd,f~indole hydro-
bxomide in 5 ml anhydrous pyridine and the reaction
mixture is further stirred for 14 hours at room
temperature. The mixture is then evaporated to
dryness, the residue is dissolved in methylene chloride
and the solution i~ washed first with a mixture of
ice and a saturated solution of potassium bicarbonate,
and then with water. ~rhe aqueous phases are extracted
twice with methylene chloride and the combined organic
.~
~ c) 2 3 2 7
- 21 -
(
phases are dried and evaporated. The residue is
dissolved in methylene chloride and the solution
evaporated under high vacuum. The procedure of
dissolving the residue in methylene chloride and
evaporating is repeated twice more. 550 mg of the
resulting product are dissolved in acetone and this
solution is added dropwise to a solution of 156 mg
L(+)-tartaric acid in acetone. The resultant preci-
pitate is filtered off and dr~ied to give
(+)-(4S,5aR)-5-ethyl-9,10-dibenzoyloxy-4,5,5a,6-
tetrahydro-4-n propyl-dibenz[cd,f]indole
L(~)tartrate; it melts at 161-162 after crystallisa-
tion in ethyl acetate/ether; [a]24 = +23.5 (c = 0.28 in
methanol).
The following compoumds may ba prepared in
analogous manner from the appropriate starting materials
- (-)-(4S,SaR)-9,10-diacetoxy-5-ethyl-4,5,5a,6-tetrahy-
dro-4-n-propyl-dibenz[cd,f]indole hydrochloride,
M.pt ~188 (with decomposition); [a]20 =-99
(c = 0.28 in methanol).
- (-)-~4S,5aR)~5-ethyl-4,5,5a,6-tetrahydro-4-n-propyl-
9,10-dipropionyloxy-dibenz[cd,f]indole hydro
chloride, M.pt > 175 ~with decomposition)
[a]D = 76 (c = 0.25 in methanol);
- (-)-(4S,5aR)~9,10-dibutyryloxy-5-ethyl-4,5,5a,6-
. ' . ' ~J ~
`
'.
' .~
`.
'
- 22 -
tetrahydro-4-n-propyl-dibenz[cd,f]indole hydrochloride,
M.pt > 105 (with decomposition); [a]D = -77 (c=0.28
in methanol)
- (-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro-9,10-
diisobutyryloxy-4-_-propyl-dibenz[cd,f~indole hydrochloride,
M.pt > 165 (with decomposition); [a]D = -96 (c=0.29
in methanol).
- t-)-(4S,5aR)-5-ethyl-4,5,5a,6-tetrahydro 4-_-propyl-
-9,10-divaleryloxy-dibenz[cd,f]indole hydrochloride;
- (-)-(4S,5a~)-5-ethyl-4,5,5a,6-tetrahydro 4-n-propyl-
9,10-dipivaloyloxy-dibenz[cd,f~indole hydrochloride;
- (-~-(4S,5aR)-4,5,5a,6-tetrahydro-9,10-dipropionyloxy-
4,5-di-n-propyl-dibenz[cd,f]indole, M.pt. 115,
[a]D = -67 (c = 0.51 in methanol).
~5 In analogous manner to Example 6, the
following compounds of formula I wherein Rl and R2 are
each independently ethyl or _-propyl and R3 is
- acetoxy
- propionyloxy
?0 ~ butyryloxy
- isobutyryloxy
- valeryloxy
- pivaloyloxy
may be prepared.
3 ~ ~
- 23 - 100-5410
The compounds of formula I possess pharmacolo-
gical activity. In particular, the compounds are
indicated ~or use as central dopaminergic stimulant
agents, as indicated by ~he following standard tests:
~`he dopaminergic activity of compounds of
formula I was studied in the rat according the method
descrihed by U. Ungerstedt in Acta Physiol. Scand.,
Suppl. 367, 69-93 (1971). 6-hydroxydopamine is unila-
terally injected in the substantia nigra which pro-
duces, after a week, unilateral degeneration of nigro-
striatal pathways. Administration of from about
0.03 to a~out 1 mg/kg i.p. of the compounds of formula
I to these rats leads to a notable turning behaviour of
long duration contralateral to ~he lesion~
The central dopaminergic activity of compounds
of formula I has been also confirmed according the
following test.
Rats, 180-222 g, are placed in perspex
cylinders of 30 cm diameter on a wire grid floor.
~o After 30 minutes to allow acclimatisation to the
cag~, the rats are injected with the compound under
invest~gation. The behaviour o~ the ra-ts is observed
for 2 minutes at 30 minutes inter~Tals or 2 hours and
then at 60 minutes intervals for total of up to 6
hours. The de~ree of stereotyped behaviou~ observed is
~...... S
,
,
- 2~ 2'.3 ~ ~ 100-5410
assessed using a scoring system based on that descri-
bed by Costall, Naylor and Olley [Euro J. Pharmac.
8, 83-9~ (19721.
The scores and criteria are as follows :
1. Intermittent sniffing
2. Persistent sniffing, occasional licking
3. Licking, occasional biting
4. Intense and persistent biting.
Administered i.p. from about 0.03 to about
30 mgfkg animal body weight, the compounds of formula
I induce stereotyped sniffing, licking and biting
behaviour in the rat.
The compounds are therefore indicated for use
as central dopaminergic stimulant agents, for
example for txeating Morbus Parkinson. For this indi-
cation, an indicated daily dose is from about o.l to
about 20 mg, conveniently administered in divided
doses 2 tc 4 times a day in unit dosage form contai-
nin~ from about 0.025 to about 10 mg, or in sustained
Ielease fo~m.
The compounds of the invention exhibit fur-
~hermore anti-depressant activity, as indicated by the
inhlbition of catalepsy induced by reserpine in mice
on s.c. administration of about 0.001 mg to about
1 mgfkg of the compounds and by the inhibition of
~ !
~ 25 - 100-5410
t
the catalepsy induced by tetrabenazine in rats on
i.p. administration of about 0.2 to about 2 mg/kg
of the compounds.
The compounds are therefore indicated
for use as anti-depressant agents.
An indicated daily dosage is in the range
from about 0.05 to about 2 mg, conveniently given
in divided doses 2 to 4 times a day in unit dosage
form containing from about o.01 mg to about 1 mg
- 10 of the compounds admixed with a solid or liquid
pharmaceutical carrier or diluent.
The com~ounds of forrnula I exhibit furtner-
more prolactin secretion inhibition as indicated by the
lowering of serum levels of prolactin of the rat after
lS s.c. administration of from about 0.1 to about 1 mg/~g
o~ th2 compounds, using radio-immunolo~ical techniques,
e.g. described by Niswender, G.D. et al., siol. & Med.
130, 793 (196~ and Neil, J.J. et al., Endocrinology 88,
54~ (1971).
The compounds of formula I are therefore
- indicated ~or use as prolactin inhi~itors,e.g. in the
treatment of conditions involving hyperprolactinemia,
sucn as menstrual dysfunctions, e.g. ammenorrhea and ga-
lactorrhea, or hypertension of mammary carcinoma asso-
ciated with elevated serum prolactin levels, or in the
~ 1 t) ~
- 26 - 100-5410
treatment or co~ditions involving hypogonadis~, e.g.
infertility or impotence, or in the regulation of
post-partem lactation.
An indicated daily dosage is in the range
from about 5 to about 50 mg, conveniently given in
divided doses 2 to 4 times a day in unit dosage form
containing from about 1.25 mg to about 25 mg of the
compounds ad~ixed with a solid or liquid pharmaceu---
tical carrier or diluent.
The compounds of the invention exhibit further-
more antipsychotic activity as indicate by the inhibi-
tion of the locomotion in mice on s.c. administra~ion
of from about 0.001 mg to about 0~1 mg/kg of the
compounds and by the dopamine agonistic action on the
presynaptic receptors of the rat at doses of from about
1 mg to about 10 mg/~g of ~he compounds, accordîng the
ollowing test.
The dopamine agonistic action of the
compounds of formula I on the presynaptic receptors
was studied on the rat using the in vivo method des-
cribed by J.R. Walters and coll. in Maunyn Schmiede-
ber~'s Arch. Pharmacol. 296, 5-14 (1976). The dopami-
nergic L~e flo~ was inhibited pharmacologically
by ~-butyrolactone. The activity of the aromatic
amino acid decarboxylase was inhibited by hydroxy-
- ~7 - loO-5410
benzylhydrazine (I~SD 1015) and half an hour later
the rats were sacrificed. The resulting accumulation
of DOP~ during 30 minutes in striatal tissue was
taken as a ~asure of the in vivo activity of tyrosine
hydroxylase. Administration per os of the compounds
reversed the effects of ~-butyrolactone in a dose
dependent manner.
The compounds of formula I are therefore
indicated for use as antipsychotic agents, fox example
for the treatment of schizophrenia. An indicated
daily dosage is in the range from a~out 0.01 to about
1 mg, conveniently given in divided dc~es 2 or 4 times
a day in unit dosage form containing from about
0.0025 mg to about 0.5 mg of the compounds admixed
with a solid or liquid pharmaceutical carrier or
diluent.
The preferred indication is the anti-
parkinson indication.
The compounds (4S,5aR~-5-ethyl-4,5,5a,6-
tetrahydro-9,10-dihydroxy-4-n-propyl-dibenz[cd,f]
indole, (~S,SaR)-4-ethyl 4,5,5a,6-tetrahydro-9,10-
dihydroxy-5-n-propyl-9,10-dihydroxy-dibenz~cd,]indole,
~4S,5aR)~4,5-diethyl-4,5,5a,6-tetrahydro-9,10-dihydroxy-
dibenz~cd,f]indole and (4S,5aR) 4,5,5a,6-tetrahydro-
9,10-dihydroxy-4,5-di-n-propyl-dibenz~cd,f]indole
- 28 - 100-5410
and the corresponding di-n-propionyl-and di-isobutyryl-
ester-derivatives are the preferred compounds.
Tne compounds of formula I may be administered
in pharmaceutically acceptable acid addition salt
form. These salt forms exnibit the same order of
activity as the free base forms.
The present invention also provides a pharma-
c~utical composition comprising a compound of formula
I, in free base form or in pharmaceutically acceptable
acid addition salt ~orm~in association with a
phar~aceutically acceptable diluent or carrier.
These compositi~s may be formulated in con-
ventional manner so as to be, for example, a solution,
2 capsule or a tablet.
