Note: Descriptions are shown in the official language in which they were submitted.
~2383Z6
-- 1 --
"PYRROLO[3,2,1-hi]INDOLE DERIVATIVES, THEIR PREPARATION
AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
The present invention relates to pyrroloindole
derivatives, their preparation and pharmaceutical
compositions containing them.
The invention provides pyrrolo[3,2,1-hi]indole
derivatives, in the form of racemates or optically active
isomers, of the formula (I)
N
~ ~ NH
1 N
~ (I)
R2
in which R is hydrogen or a linear or branched Cl 4 alkyl
group, and Rl and R2 which may be the same or different, are
hydrogen, halogen or Cl 4 alkyl, and their pharmaceutically
acceptable acid addition salts.
According to the invention, the compounds (I) can be
prepared by following the reaction scheme given in the
Appendix.
The starting ester (II), in which R' is an alkyl group,
in particular ethyl, can be obtained from N-aminoindole
according to the method described by H. Rapoport et al.
(J.A.C.S. [1958], _ , 5574-5), the N-aminoindole itself being
prepared according to the method described by A.N. ~ost et
30 al. (C.A. 54, 1964).
According to the invention, the starting ester (II) is
$l~
3Z~;
-- 2
hydrogenated by means of hydrochloric acid in the presence of
tin at ambient temperature to provide a compound (III).
Then
- either the compound (III) is reacted with ethylenediamine
in the presence of trimethylaluminium to obtain a compound
(I) in which R is hydrogen,
or the compound (III) is alkylated by reaction with an
alkyl halide ~X, in which R is Cl-C4 alkyl and X is halogen
(preferably iodine), for example in the presence Gf
diisopropylamine and butyllithium in a solvent, and the
alkylated compound (IV) thus obtained is reacted with
ethylenediamine in the presence of trimethylaluminium to
obtain a compound (I) in which R is a Cl-C4 alkyl group. The
compound (I) thus obtained can be converted into an acid
addition salt by any known method.
The Examples which follow illustrate the invention. The
structure of the compounds obtained was confirmed by analysis
and IR and NMR spectra.
Example 1 2-(4,5-Dihydro-l_-imidazol-2-yl)-1,2,3,4,5-
tetrahydropyrrolo[3,2,1-hi]indole and its fumarate.
1. In a l,000-ml three-necked flask equipped with a
magnetic stirrer, hydrogen chloride gas inlet, air-cooled
condenser with calcium chloride guard tube and thermometer,
placed in a bath of dry ice and isopropyl alcohol, 15.8 g
(0.073 mol) of ethyl 4,5-dihydropyrrolo[3,2,1-hi]indole-2-
carboxylate are introduced with 150 ml of ethanol.
The mixture is cooled to -20C and hydrogen chloride gas
is condensed in at this temperature until a solution is
obtained. 26.1 g (0.22 gram-atom) of granulated tin are then
added in a single portion, the cold bath is removed and
stirring is maintained for 20 hours at room temperature.
A yellow suspension is obtained, and this is
~2i;;~3;2~
-- 3
concentrated on the water bath and taken up in 550 ml of
absolute ethanol. The mixture is cooled, ammonia is
bubbled in until the pH equals 9 to 10 to precipitate the
tin salts, the latter are drained while being washed with
5 iced ethanol and the filtrate obtained is evaporated to
dryness. The residue is subjected to chromatography on
a silica column, eluting with methylene chloride. 11.65 9
of an oily yelLow product are finally collected.
2. In a 100-ml Keller flask equipped ~ith a mag-
1n netic stirrer, reflux condenser with calcium chlorideguard tube, thermometer, argon inlet, dropping funnel and
Dean-Stark apparatus, there are successively introduced,
under argon, 16 ml of toluene, 10.3 ml (0.025 mol) of tri-
methylaluminium at 25.2% strength in hexane and, while
15 cooling, 1.6 ml (equivalent to 1.43 9 or 0.024 mol) of
ethylenediamine dissolved in 4.5 ml of toluene.
The mixture is stirred for 5 minutes and then
heated to 50C, and at this temperature there are added
3.3 9 (0.015 mol) of the product previously obtained,
20 dissolved in 15 ml of toluene. The mixture is then heated
under reflux for 6 hours and then allowed to cool. After
the mixture has been cooled to between -10 and -15C, it
is hydrolysed with 10.2 ml of water while stirring, and
is then extracted ~ith ethyl acetate. The organic frac-
25 tions are combined, washed with sodium chloride solution,dried, filtered and evaporated. There remain approxi-
mately 3 g of a fatty yellow solid from which the fumarate
~23~
-- 4
is prepared directly~ For this purpose, the solid is
taken up in 50 ml of ethanol and the solution is filtered,
and a filtered solution of 1.5 9 (O.û13 mol) of fumaric
acid in 1ûO ml of ethanol is added to it. The solution
5 obtained is stirred and concentrated to dryness, and the
residue is taken up in acetone, filtered, dried under
vacuum and recrystallised in ethanol. 1.65 9 of the fuma-
rate is collected which melts at 184.5 - 186C.
~ 2-Methyl-2-(4,5-dihydro-1H-imidazol-2-yl)-
10 1,2,4,5-tetrahydropyrrolo~3,2,1-hi]indole and its fumarate.
2 1. Ethyl 2-methyl-1,2,4,5-tetrahydropyrrolo¦3,2,1~hil-
.
indole-2-carboxylate.
In a 25û-ml Keller flask equipped with a magnetic
stirrer, thermometer, argon inlet and dropping funnel and
15 placed in a cold bath, there are introduced, under argon,
5.6 ml ~0.04 mol~ of diisopropylamine and 35 ml of tetra-
hydrofuran (THF). The reaction mixture is cooled to bet-
ween -70 and -75C and there are then introduced, in the
course of 20 minutes, 25 ml (O.û4 mol) of butyllithium in
20 1.6 molar solution in hexane.
The temperature is maintained at be~ween -70 and
-75C for 1 hour, and a solution of 7 9 (0.0322 mol~ of
ethyl 1,2,4~5-tetrahydropyrrolo~3,2,1-hi]indole-2-car~oxy-
late in 25 ml of THF is added in the course of 15 minutes.
The temperature is still maintained at between
-70 and -75C for 1 hour and a solution of 12.4 ml
(0.2 mol) of methyl iodide in 20 ml of THF is then added
~2~33'~6
in the course of 20 minutes.
The reaction mixture is maintained at between -70
and -75C for 1 hour, and then left at room temperature
for 3 hours 30 minutes. The reaction mixture is poured
into iced ~ater. It is extracted with diethyl ether in
the presence of saturated sodium chloride solutionO The
extract is washed ~ith water and dried over NA2S04.
The organic phase is separated. It is evaporated to
dryness under vacuum on the ~ater bath. An oil is
obtained which is purified by passage through a silica
column with methylene chloride as eluent.
2.2. ~ -~4,5-d~y~ 1H-imidazol-2-yl)-1~2~4
tetrahydropyrrolo~3,2,1-hi]indole and its fumarate.
In a 50-ml Keller flask equipped ~ith a magnetic
stirrer, reflux condenser, thermometer, argon inlet, drop-
ping funnel and Dean-Stark apparatus, there are introduced
successively, under argon, 10 ml of toluene, 5.4 ml
(0.013 mol) of trimethylaluminium at 25.2X strength in
hexane and, ~hile cooling to 0C, 0~9 ml ~equivalent to
0.013 mol) of ethylenediamine dissolved in 3 ml of toluene.
The mixture is stirred for 10 minutes and then
heated to 50C, and at this temperature there ~s added
1.9 9 (0.0082 mol) of the product previously obtained,
dissolved in 10 ml of toluene. The mixture is then heated
under reflux for 6 hours and then allowed to cool. After
the mixture has been cooled to between -10 and -15c, it
is hydrolysed with 5.4 ml of water, while being stirred,
~2~ 2S
~,
and is then extracted with ethyl acetate. The organic
fractions are combined, washed with sodium chloride solu-
tion, dried, filtered and evaporated. There remains a
yellow solid from ~hich the fumarate is prepared directly.
For this purpose the solid is taken up in 25 ml
of ethanol and the solution is filtered, and a filtered
solution of 0.7 9 (0.006 mol) of fumaric acid in 50 ml of
ethanol is added to it. The solution obtained is stirred
and concentrated to dryness, and the residue is taken up
in acetone, filtered, dried under vacuum and recrystal-
lised in ethanol. The fumarate is collected which melts
at 192 - 194C.
Example 3 2-n-Propyl-2-~4,5-dihydro-1H-imidazol-2-yl)-
7-methyl-1~2,4,5-tetrahydropyrroloC3,2,1-hi]indole and
its fumarate.
3.1. 5-Methyl-1-nitroso-2,3-dihydro-1H-indole
In a 500-ml three-necked flask equipped with a
magnetic stirring system, there are introduced 5-methyl-
2-indoline ~prepared according to G.W. Gribble and J.H.
Hoffman, Synthesis, 1977, 859-860 from indole, described
by J.E. Nordlander et al. J. Org. Shem. 46, 778-782,
C1981]) to the extent of 18 9 ~0.14 mol) and 300 ml of
20X sulphuric acid.
The solution is cooled to C and sodium nitrite
(9.7 9; 0.14 mol) dissolved in water (30 ml) is added.
The reaction mixture is maintained at C during the
addition.
-- 7
After 30 minutes of stirring at 0C, the aqueous
phase is extracted with ether (500 ml). The ether phase
is washed with water and then with saturated NaCl solution
and dried over magnesium sulphate. The solvents are
evaporated under vacuum. The compound obtained is used,
as it is, in the following stage.
3.2. 5-~ethyl-2,3-dihydro-lH-indol-l-amine
In a 2-1 three-necked flask equipped with a mechan-
ical stirring system, condenser, dropping funnel and
thermometer, and under argon, there are introduced lithium
aluminium hydride (6.08 g; 0.16 mol) and tetrahydrofuran
(THF) (300 ml). The compound obtained above (22 g;
0.14 mol?, dissolved in THF (300 ml) is added to the
suspension. The temperature is maintained at 35C.
The reaction mixture is stirred for 4 hours at
20C and then hydrolysed (H20, 10 ml). 10 ml of lN
NaOH solution are then added, followed by 20 ml of water.
The suspension is stirred at 20C for 30 minutes,
then filtered and the residue rinsed with ether. The
organic phase is dried over sodium sulphate. The solvents
are evaporated under vacuum. The compound obtained is
used, as it is, in the following stage.
3.3.Ethyl 2~(~5-methyl-2,3-dihydro-lH-indol-l-yl]imino-
propanoate
In a 500-ml single-necked flask equipped with a
magnetic stirring system and condenser, and under argon~
~3~ 6
there are introduced the above compound (20 9; 0.13 mol),
ethyl pyruvate (16.24 g; 0.14 mol~, ethanol ~200 ml) and
acetic acid (0.5 ml).
The reaction mixture is stirred at 80C for 5
5 hours. The ethanol is evaporated under vacuum and the
residue is purified by column chromatography (SiO2; elu-
ent, cyclohexane/ether 2:1). The compound obtained is
used, as it is, in the following stage.
3.4. ~ 7-methyl-4,5-dihydropyrroloC3,2,1-hi]indole-
10 2-carboxylate.
In a 25-ml three-necked flask equipped with a mag-
netic stirring system and condenser, and under argon,
there are introduced the compound obtained above (7 g;
0.028 mol) and acetic acid (8 ml), and ~F3 etherate
15 (3.42 ml; 0.028 mol) is added. The reaction mixture is
stirred at 90C for 50 minutes. It is cooled and hydro-
lysed (H20, 40 ml). The aqueous phase is extracted with
ether (3 x 200 ml). The organic phase is washed with
sodium bicarbonate, and with saturated sodium chloride
20 solution, and then dried over sodium sulphate.
The solvents are evaporated under vacuum and the
residue is purified by column chromatography ~SiO2; elu-
ent, cyclohexane/ether 2:1). The ester (II) obtained is
used in the follo~ing stage.
25 3.5. Ethyl 7-methyl-1,2,4,5-tetrahydro yrroloC3,2,1-hi~-
indole-2-carboxylate.
In a 50-ml three-necked flask equipped with a
~$~,326
_ 9 _
magnetic stirring system and condenser, ethanol (21 ml)
is introduced. The ethanol is saturated with hydrochloric
acid at -10C. The ester obtained above (2.4 9;
0.011 mol) is added, followed by tin (3~8 9; 0.032 9-
S atom). The reaction mixture is stirred at +20C for
8 hours~ The solvent is evaporated under vacuum and the
residue is dissolved in ethanol (50 ml). The mixture is
saturated with ammonia until the pH equals 9. The sus-
pension is filtered and the ethanol is evaporated under
vacuum. The residue is dissolved in water and the aque-
ous phase is extracted with ether (300 ml); the ether
phase is washed with saturated sodium chloride solution
and then dried over sodium sulphate.
The ester (III) is obtained.
3.6. Ethyl 2-n-propyl-7-methyl-1,2,4,5-te~rahydropyrrolo-
[3,2,1-hi]indole-2-carboxylate.
In a 500-ml three-necked flask equipped with a
magnetic stirring system and under argon, there are intro-
duced diisopropylamine (0.600 9; 0.006 mol) and THF (5 ml).
The solution is cooled to -78C and n-butyllithium is
added in hexane (3.75 ml; 0.006 mol). The solution is
stirred at -78C for 30 minutes, and the ester obtained
above (III) (1.15 9; O.Oû5 mol) is then added in THF
(10 ml). The reaction mixture is stirred at -78C for
1 hour (bro~n coloration). 1-Iodopropane (1.02 9;
0.006 mol) in THF (5 ml) is added.
The reaction mixture is stirred at -78OC for
1~3~26
- 10 -
1 hour and then at 20C for 1 hour. The mixture is
hydrolysed (H20, 10 ml). The aqueous phase is extrac-
ted with ether. The ether phase is washed with water and
with saturated sodium chloride solution, and is then dried
over sodium sulphate. The ester obtained (IV) is used
in the following stage.
3.7. 2-n-Propyl-2-(4,5-dihydro-1H-imidazol-2-yl)-7-methyl-
1 2 4 5-tetrahydropyrroloC3,2,1-hi]indole and its
fumarate.
a. In 3 5û-ml three-necked flask equipped with a
magnetic stirring system and condenser, and under argon,
there are introduced toluene (10 ml) and trimethylalumi-
nium at 25X strength in hexane (4.5 ml; 0.011 mol). The
solution is cooled to -1ûC and ethylenediamine (0.640 9;
0.011 mol) in toluene (S ml) is then added. The reaction
mixture is allowed to return to 20C and the ester (IV)
obtained in 3.6 (1.22 9; O.û044 mol) is added in toluene
(10 ml).
The reaction mixture is stirred at 110C for
20 4 hours. It is cooled to -10C and then hydrolysed (H20,
5 ml), and ethyl acetate (50 ml) is added. The mixture
is stirred for 30 minutes at 0C and then filtered. The
filtrate is dried over Na2S04. The solvents are evapo~
rated under vacuum. The fumarate is prepared directly.
b. In a 250-ml single-necked flask equipped with
a magnetic stirring system, the compound obtained in a.
is introduced in ethanol (20 ml), and fumaric acid
~2383:~6
(0.500 g; 0.0042 mol) in ethanol (30 ml) is added. The
solution is stirred for 30 minutes, and the ethanol is then
evaporated under vacuum. The residue is taken up in ether.
It is filtered, dried under vacuum and recrystallised in
ethanol. The fumarate is collected which melts at 178 -
180C
The Table which follows illustrates compounds prepared
according to the invention.
~s
- 12 -
Table
N
H
~ (I)
Compounc R1 R2 R Salt M.P-(C)
_ . ,
1 H H H fumarate 184-186
benzoate 146-148
2 H H CH3 fumarate 192-194
3 H H C2H5 fumarate 162-164
4 H H nC3H7 fumarate 202-204
H H nC4H9 fumarate 171-173
6 8-C1 H H fumarate 195-196
7 a C1 H CH3 fumarate 94- 99
a 8-C1 H nC3H7 fumarate 202-204
9 7-F H H fumarate 137-141
1û 7-F H CH3 fumarate 147-150
11 .~ ___ _ _ 3 7 fumarate 200-203
~3,B326i
~ '1 _ .~ ~
¦ 12 7-CH3 HH ¦ fumarate ¦ 168-172
13 7-CH3 HnC3H7 fumarate 178-180
14 6-CH3 8-CH3 H fum~rate 217-219
6-CH3 8-CH~CH3 fumarate 207-210
16 6-CH3 8-CH3nC3H7 fumarate 180-185
3~33~26
- 14 -
The compounds of the invention were subjected to
pharmacologicaL tests which showed their value as ~2-
antagonists.
To this end, the compounds were studied in the
test of potentiality and selectivity of antagonists
towards~ 2-receptors in vitro.
Determina~ion of the PA2 value in respect of the
inhibi~ory effects of clonidine, a well-knownr~2-agonist~
was carried out on rat vas deferens stimulated at a fre-
quency of 0.1 Hz in the presence of 30 nM prazosin and
1 ,uM cocaine, according to the method described by G.M.
Drew (European Journal of Pharmacology, 42, (1977)
123-130).
The PA2 of the compounds of ~he invention are
between 7 and 9.5.
The compounds of the invention are powerful ~2-
antagonists which can be used for the treatment of depres-
sion (either alone or in association with a product which
inhib;ts neuronal uptake mechanisms), hypotension, post-
operative paralytic ileum, asthma and obesity.
The pharraceutical compositions can be in a form
suitable for oral, rectal or parenteral administration,
for example in the form of capsules, tablets, pellets,
gelatine capsules or solutions, syrups or suspensions to
be taken orally, and can contain suitable excipients.
The daily dosage can range from 0.1 to 10 mg/kg
P . o .
~2~3~
- 15
Appendi~
N
r -r (I)
N
R~J
P`2
React;on scheme
C2R C2R ~r_C02R '
R l=~ r I r I
R2~ ~ Rl~h R
(III)
tII) (IV) I
H2N-(CH2)2 NH2 . H2N-(CX2)2--~H2
(CH3)3 Al . ~(CH3)3 Al
~ here R = H(I) ~here R = aL~yl
R' = alkyl, preferably ethyl
X 2 halogen, preferably I
