Note: Descriptions are shown in the official language in which they were submitted.
1078376
The present invention relates to a pen-
tacyclic derivative of the general formula:
(I)
O
~ .
in which:
R represents a hydrogen atom or a hydroxymethyl
radical,
Rl represents a hydrogen atom, -
R and Rl being in the trans position in
relation to one another, or alternatively together
forming a double bond, and R2 and R3, which may be
the same or different, represent a hydrogen atom or
a halogen atom or an alkyl radical containing 1 to
4 carbon atoms or alkyloxyl radical whose alkyl part
contains 1 to 4 carbon atoms, or else R2 and R3 to-
- gether form a dioxymethylene radical, its optically
active forms, its addition salts with acids, its
quaternary ammonium salts and its N-oxides.
The novel products of the present inven-
tion have noteworthy therapeutical properties, and
are particularly interesting as cerebral protectors
and vasodilators. The invention provides a pharma-
; ceutical composition comprising the compounds of
this invention.
In another aspect of this invention there
is provided a process for the preparation of pent-
-- 30 acyclic derivatives of the general formula:
.,
~ ` 1078376 , -
R3 / ~ I
R
in which:
R represents a hydrogen atom or hydroxymethyl radical
Rl represents a hydrogen atom;
R and Rl being in the trans position in relation to one another
or alternatively together forming a double bond;
and R2 and R3, which may be the same or different, represent a
hydrogen atom or a halogen atom or an alkyl radical containing
1 to 4 carbon atoms or alkloxyl radical whose alkyl part contains
1 to 4 carbon atoms or alternatively R2 and R3 together form a
dioxmethylene radical, its optically active forms, its pharmaceuti- :
cally acceptable addition salts with acids, its pharmaceutically
acceptable quaternary ammonium salts and its N-oxides;
which comprises reducing, in an acid medium an immonium salt of
the general formula:
:i
~ ~ N + X II
0~
~:~ R
~ 2
:, ~
1078376
in which R, R2 and R3 are as defined above and X represents an
anion from an organic or inorganic acid; -
or which comprises deprotonising, in an alkaline medium, a pro-
duct of the general formula
X~ '
R3 ~ ~ + X II
~ O ;,, '
in which R2, R3 and X are as defined above,
According to the present invention, the products of the
general formula tI) in which R represents a hydrogen atom or a
hydroxymethyl radical, the symbols R and Rl being in the trans
position in relation to one another, and the symbols R2 and R3
are defined as above, may be obtained by the reduction in an
~: acid medium of an immonium salt of the general formula:
_ l ~ (II)
.~
in which R, R2 and R3 are defined as above and X represents an
anion such as the perchlorate ion (C104).
Generally, the reduction is carried outby meansof an
alkali borohydride suchas sodiumborohydride at a pHin thevicinity
- of 6 ina hydro-alcoholicmedium. It is notnecessary to isolate the
product of the general formula (II) in order tocarry out thereduc-
tion andit isparticularly advantageousto use the immoniumsalt of
the generalformula (II) prepared in situ.
Other reducing agents are particularly suitable and
among these one may mention: hydrogen in the presence of platinum
~ - 3 -
1078376 ;
oxide or carbon containing palladium.
The immoniumsalt of the generalformula (II) may be obtain-
ed by theaction of formaldehydeon anenamine ofthe generalformula:
2 - ~
R3 ~ N ~ N ~ (III)
H
in which R2 and R3 are as defined above, followed by the salti-
fication of the product obtained.
Generally speaking,the condensation of the formaldehyde
with the enamineof the generalformula (III) is carried out in a
hydro-alcoholic mediumsuch asa mixtureof water/ethanolat a tempera-
ture of between20C andthe boiling pointof the reactionmixture.
The saltformation iscarried outby theaddition of an acidsuch as
perchloric acid, to the reaction medium.
The condensation ofthe formaldehydewith theenamine ofthe
general formula (III) may lead,according tothe relative proportions
of formaldehyde andenamine, thetemperature andduration ofthe reac-
tion, either toan immoniumsalt ofthe generalformula (II) in which' 20
R represents ahydrogen atom,or toan immoniumsalt ofthe general
formula (II) in which Rrepresents a hydroxymethylradical, or to
a mixture thereof. In the lattercase, the subsequent reduction
leads to a mixture of products of the general formula (I), the
,,
constituents of which may be isolated by the application of
physicochemical methods such as fractional crystallisation or
:;~
chromatography.
The immonium salt of the general formula (II) in which
R represents a hydroxymethyl radical may also-be obtained by the
action of formaldehyde on an immonium salt of the general
formula (II) in which R represents a hydroqen atom.
-- 4
~1
1078376
The enamine of the general formula (III) may be
prepared by the deprotonation in an alkaline medium of an --
immonium salt of the general formula: ~
. . .
X~3 (IV)
H ~
in which R2 and R3 are as defined above and X represents an
anion such as the perchlorate ion or the chloride ion.
The deprotonation is generally carried out by the
addition of an aqueous solution of soda.
The immonium salt of the general formula (IV) may be
obtained by the action of phosphorus oxychloride followed by
the possible addition of an alkali perchlorate such as sodium
perchlorate on to a derivative of a tryptamine of the general
formula:
R
i
".,
~' in which R2 and R3 are as defined above.
The cyclisation with phosphorus oxychloride is
.:"
carried out in an organic solvent such as benzene, toluene,
dichloroethane at a temperature between 20C and the reflux
temperature of the reaction mixture.
The derivative of tryptamine of the general formula
(V) may be obtained by one of the following methods:
1) by the action of ethyl 5-bromo valerianate on a
tryptamine of the general formula:
~ 5
- 1078376
R3 ~ ~H2 (VI~
in which R2 and R3 are as defined above; ~-
- 2) by the action of 1-(4,~-diethoxy-butyl)-2-piper-
idone on a hydrazine of the general formula:
~,
2 ~
3 ~NH2 (VII)
'
in which R2 and R3 are as defined above.
Generally one operates in the presence of zinc chloride
at a temperature in the vicinity of 180C or in dilute
hydrochloric acid at a temperature in the vicinity of 80C.
The 1-(4,4-diethoxy-butyl)-2-piperidone may be
~` obtained by the action of ethyl 5-bromo valerianate on 4,4-
diethoxy butylamine.
The enamine of the general formula (III) may also be
i prepared by the method of E. WENKERT and B. WICKBERG, J. Amer.
Chem. Soc., 84, 4914 (1962) and J. Amer. Chem. Soc., 87, 1580
` (1965) or according to the method of R.N. SCHUT and T.J. LEIPZIG,
J. Het. Chem., 43, 101 (1966) or G.C. MOINISSON, W. CETENKO, -
J. SHAVEL, J. Org. Chem., 2771 (1964).
According to the invention, the products of the
general formula (I) in which R and Rl together form a double
bond may be obtained by the treatment in alkaline medium of an
immonium salt of the general formula (II) in which R represents
a hydrogen atom.
Generally speaking, th~ deprotonation is carried out
by means of a mineral base such as soda.
-- 6 --
1078376
The products of the general formula (I) may be
separated into their optical isomers by the application of the
usual methods. More particularly, one prepares an optically
active salt of a product of the general formula (I) which is
then separated by fractional crystallisation. The optically
active base is regenerated from its salt by using the usual ;-
methods. Preferably the splitting is carried out by means of
optically active O,O'-di-paratoluoyltartaric acids.
The new products according to the invention may
possibly be purified by physical methods (crystallisation,
chromatography) or chemical methods (salt formation,
crystallisation of the latter and then decomposition in an ~- -
alkaline medium).
They may be converted if desired into addition salts
with acids, into quaternary ammonium salts or into N-oxides.
The salts may be obtained by the action of the new derivatives
on acids or reactive esters such as an alkyl halide in
suitable solvents. As organic solvents one uses for example
alcohols, ethers or chlorinated solvents. The salt formed is
precipitated after the concentration of the solution and it is
separated by filtration or decantation.
The new products according to the present invention
and their salts present noteworthy therapeutical properties.
They are particularly interesting as cerebral protectors and
vasodilators.
They have been found active in the animal at doses of
between 0.1 and 5 mg/kg by intravenous route and at doses of
between 5 and 50 mg/kg by oral route.
~ore particularly:
They increase significantly the survival time of mice
placed in a confined atmosphere or at an imaginary altitude.
-- 7 --
~C~78376
They reduce the time of reappearance of corticular
electrogenesis in the rat subjected to a momentaneous cerebral
hypoxia as a result of ischaemia.
and theY increase the femoral and coronary arterial output
in the anaesthetised dog.
They also have a low toxicity. The 50~ lethal dose
(DL50) is generally greater than 200 mg/kg by oral route in the
mouse.
For medicinal use, the new compounds are used either
10 in the state of the base, or in the state of acceptable ~`~
pharmaceutical salts, that is to say ones which are non-toxic
at the doses at which they are used.
The following examples, which are given without being
.restrictive, show how the invention may be put into practice.
'~jIn the following, the structure of the products and
in particular that of 1,12b trans-1,2,3,4,6,7,12,12b-octahydro-
1,1-methanooxymethano(2,3-a) indoloquinolizine, was determined
by X-ray analysis and the structure of the other products for
which R and Rl each represent a hydrogen atom, was confirmed by
~20 the comparison of the spectral data.
., .:, ~ .
EXAMPLE 1
1 g of 2,3,4,6,7,12-hexahydro-(2,3-a) indoloquinolizine
is dissolved in 50 mls of ethanol and then one adds 5 mls of a
40% aqueous solution of formaldehyde.
The reaction medium is heated with agitation for 10
minutes at 70C. One adds 2 mls of perchloric acid and then one
adds, in small portions, 2 g of sodium borohydride over 30
minutes.
After the addition of 200 mls of water saturated with
sodium chloride, one extracts with 200 mls of chloroform. After
1078376
drying the organic solution over sodium sulphate and evaporating
the solvent, one isolates a residue which is filtered in
chloroform solution over a column of 80 g of silica.
The elution of the first chloroform fractions
(approximately 1 litre) supplies 1.1 g of 1,12b-trans-1,2,3,4,-
4,7,12,12b-octahydro-1,12-methanooxymethano-(2,3-a)-indolo-
quinolizine which, after crystallisation from ethyl acetate mels
at 150C and also possesses the following properties:
Infra-red spectrum: (determination in solution in chloroform).
Bands at 2860-28Q0 and 2755 cm 1 characterising the
trans-quinolizidine chain (Bohlmann's bands).
Mass spectrum: peaks at m/e 268 (M 100%), 267, 237.
NMR spectrum: (CDC13):
4H aromatics between 7.6 and 6.9 ppm; 2H (Na-CH2-O):
` 2 doublets centred at 5.7~ and 4.85 ppm JAB = 12Hz; 2H (OCH2-C_):
.1
2 quadruplets centred at 3.92 and 3.3 ppm (JAB = 12Hz, JAX = 4Hz,
BX lOHz).
, The corresponding tartrate is prepared by dissolving
1.1 g of the above base in 40 mls of methanol and then adding
0.3 g of tartaric acid dissolved in 30 mls of methanol. After
concentrating the methanol the salt is precipitated; it is dried
and one obtains 1.1 g of 1,12b-trans-1,2,3,4,6,7,12,12b-octa-
hydro-1,12-methanooxymethano-(2,3-a)-indolo-quinolizine tartrate
melting at 222C (yield: 79%).
EXAMPLE 2
To a solution of 0.1 g of 2,3,4,6,7,12-hexahydro(2,3-a)-
indoloquinolizine in 20 mls of ethanol one adds 2 mls of a 40
aqueous solution of formaldehyde.
The reaction mixture is heated, with agitation, at
_ 9 _
~078376
60C for 15 minutes. After concentrating the hydroalcoholic
solution one adds 0.1 ml of perchloric acid. The precipitate
which is formed is filtered and then washed with water. In this
way one obtains 85 mg of perchlorate which, after alkalisation
by a drop of concentrated soda provides 35 mg of 1,12-methano-
oxymethano-2,3,4,6,7,12-hexahydro(2,3-a) indoloquinolizine
which possesses the following characteristics: `
Mass spectrum: Peaks m/e : 266 (M 100~
NMR spectrum (CDC13): 4H aromatics between 7.6 and 6.9 ppm;
2H (Na-CH2-O):
1 singlet at 5.8 ppm; 2H(O-CH2): 1 singlet widened at 4.45 ppm.
EXAMPLE 3
a) To 1 g of 1,2,3,4,6,7,12H-hexahydro-(2,3-a)-indolo-quinoli-
zinium perchlorate dissolved in 100 mls of ethanol one adds
' 0.3 g of sodium carbonate and then 25 mls of a 40% aqueous
solution of formaldehyde. The reaction mixture is heated for
30 minutes at 60 C. One then adds, after cooling, 200 mls of
water and then one extracts with 200 mls of chloroform.
After drying the chloroform solution over sodium
sulphate and evaporating the solvent, the residue is dissolved
in 100 mls of methanol. One adds over a period of 10 minutes
1 g of sodium borohydride. The state of advancement of the
reaction is followed by thin layer chromatography. After the
usual treatment one obtains 0.45 g of 1-hydroxymethyl-1,2,3,4,-
6,7,12,12b octahydro-1,12 methanooxymethano-(2,3-a) indolo-
quinolizine which melts at 148C and has the following physical
properties:
Mass spectrum: peaks at m/e : 298 (M 100%).
NMR spectrum (CDCl ): 4E~ aromatics between 7.55 and 7 ppm;
-- 10 --
- ~078376
2H (Na-CH20) : 2 doublets centred at 5.88 and 4.99 ppm (JAB =
12HZ) ; 4H (-O-CH2-C-CH2-OH) : massif centred at 3.6 ppm.
b) The hydrochloride is obtained by dissolving the above ~ r
compound in the minimum of methanol and adding a few drops of
concentrated hydrochloric acid (12N).
; The hydrochloride obtained is recrystallised from a
mixture of ethyl acetate/methanol (50/50) and melts at 218-219C.
c) l-hydroxymethyl-1,2,3,4,6,7,12,12b octahydro-1,12 methano-
oxymethano-(2,3-a) indolo-quinolizine may also be obtained from
2,3,4,6,7,12 hexahydro-(2,3-a) indolo-quinolizine :
- To 1 g of 2,3,4,6,7,12 hexahydro-(2,3-a) indolo-
quinolizine dissolved in 1 ml of ethanol one adds 40 mls of a
40% aqueous solution of formaldehyde. It is agitated for 30
minutes at a temperature of 60C. It is diluted with 50 mls of
methanol and then reduced with 6 g of sodium borohydride. One
adds 200 mls of a saturated aqueous solution of sodium chloride
and then extracts twice with 200 mls of chloroform.
After the usual treatment one obtains 0.3 g of
l-hydroxymethyl-1,2,3,4,6,7,12,12b-octahydro-1,12 methanooxy-
methano-(2,3-a) indolo-quinolizine which is identical to the
product obtained in Example 3a.
EXAMPLE 4
One heats to 60C a solution of 4.6 g of 10-methoxy-
2,3,4,6,7,12-hexahydro-(2,3-a) indolo-quinolizine in 460 mls of
ethanol and then one adds over a period of 1 minute under an
atmosphere of nitrogen 9 mls of a 30~ aqueous solution of
formaldehyde. It is left for exactly 10 minutes in contact at
65C, and then one adds 2.39 mls of 70~ perchloric acid and it
is cooled to 20C in a bath of iced water. One then adds in
:1078376
small portions 3.15 g of sodium borohydride and it is left with
agitation for 45 minutes. After diluting with 180 mls of a
saturated solution of sodium chloride and 800 mls of water, one
; extracts three times with 250 mls of dichloromethane, the organic ~'
. phase is washed twice with 100 mls of water, dried over sodium
sulphate, filtered and concentrated to dryness under reduced
pressure (20 mm of mercury) at 20C. The residue is taken up
in three times 200 mls of boiling isopropyl oxide; the solution
obtained after elimination of a brown residue by filtration
is concentrated to a volume of 150 mls. After cooling for 1
hour to +4C the crystals are filtered and dried under reduced
;~ pressure (20 mm of mercury) at 20C. In this way one obtains
3.5 g of 1,12b trans-10-methoxy-1,2,3,4,6,7,12,12b-octahydro-
1,12 methanooxymethano- (2,3-a) indolo-quinolizine melting at
136C.
After recrystallisation from a mixture of acetone and `
water (1/2 by volume), the product melts at 1~0C,
Analysis % Calc.: C 72.46 H 7.43 N 9.39 O 10.72
Found: 71.6 7.25 9.15 11.5
10-methoxy-2,3,4,6,7,12-hexahydro-(2,3-a) indolo-
quinolizine may be prepared in the following manner:
To a solution of 5.44 g of 1-~ (6-methoxy-3-indolyl)
ethy~ -2-piperidone in 300 mls of 1,2-dichloroethane one adds,
under an atmosphere of nitrogen and accompanied by agitation,
over a period of 10 minutes 5 mls of phosphorus oxychloride. It
is then heated under reflux for 3 hours and then allowed to
return to a temperature of 50C. One then adds 150 mls of
distilled water and heats it again under reflux for 45 minutes.
After cooling to 50C, the reaction mixture is decanted. The
organic phase is extracted with twice 20 mls of water at
approximately 50 C. To the aqueous phase one adds 6 g of sodium
-- 12 --
~ o7s376
perchlorate.
After cooling for 1 hour to 4C, the precipitate is
separated by filtration and then dried under reduced pressure
(0.5 mm of mercury), at 20C.
In this way one obtains 6.5 g of 10-methoxy-1~2,3,4,6,~
7,12H-hexahydro-(2,3-a)-indolo-quinolizinium perchlorate in the
form of a light green crystalline solid.
This product is dissolved in 400 mls of boiling
methanol. One adds 400 mls of distilled water and leaves it to
cool to 20C. One then adds drop by drop, accompanied by
agitation, 2 mls of 10N soda so as to obtain a pH in the vicinity
of 10. The mixture is cooled in an ice bath. After cooling for
1 hour, the product obtained is separated by filtration and then
dried under reduced pressure (0.55 mm of mercury) at 20C. In
this way one obtains 4.6 g of 10-methoxy-2,3,4,6,7,12-hexahydro-
(2,3-a)-indolo-quinolizine melting at 166C.
1-[2(6-methoxy-3-indolyl)-ethy~ -2-piperidone may be
prepared in the following manner:
One heats under a reflux, under an atmosphere of
20 nitro~en, a suspension of 9.5 g of 6-methoxy tryptamine and 5.32
g of sodium carbonate in 124 mls of methoxyethanol and then one
adds over a period of 30 hours accompanied by agitation a
solution of 10.4 g of ethyl bromovalerianate in 82 mls of
methoxyethanol. The agitation and the reflux are continued for
1 hour and 30 minutes after the end of the addition and the
mixture is concentrated under reduced pressure (0.5 mm of
mercury) down to a volume of 50 mls. After dilution with 500
mls of distilled water, one extracts with three times 200 mls of
dichloromethane. The organic phase is washed with two times
100 mls of a normal solution by hydrochloric acid and two times
1078376
100 mls of a saturated solution of sodium chloride. After drying
~' over magnesium sulphate, treatment with animal charcoal and
filtration, it is concentrated to dryness under reduced
pressure (20 mm of mercury) at 20C. One obtains in this way
11.2 g of a light yellow solid which is purified by chromato-
graphy on a column of 150 g of silica gel (neutral p~ 0.05-0.2)
contained in a column 1.6 cm in diameter. It is eluted
successively with 300 mls of a mixture of cyclohexane/ethyl
acetate (50:50 by volume), 300 mls of a mixture of cyclohexane/
10 ethyl acetate (25:75 by volume), 600 mls of ethyl acetate and
1200 mls of a mixture of ethyl acetate/methanol (98:2 by volume),
collecting fractions of 100 mls. Fractions 7 to 25 are combined
and concentrated to dryness under reduced pressure (20 mm of
mercury) at 20C. One obtains in this way 7.5 g of
l-C2(6-methoxy-3-indolyl)ethyl~-2-piperidone melting at 146C.
6-methoxytryptamine may be prepared according to
N.N. SUVOROV and co-workers, Zh. Obshch. Khim., 30, No. 9, 3118
(1960).
EXA PLE 5
One dissolves 18.5 g of 10-fluoro-2,3,4,6,7,12-hexa-
hydro-(2,3-a)-indolo-quinolizine in 2 litres of ethanol at
60C. One adds in one go 49.2 mls of formaldehyde in a 30%
aqueous solution. The reaction mixture is agitated for 10
minutes at 60C. One adds 12.9 mls of 65% perchloric acid and
the reaction mixture is cooled to 20C. One then adds 15.9 g of
sodium ~orohydride and it is left with agitation for 1 hour
and 20 minutes. One then pours the reaction mixture into 800
mls of a saturated aqueous solution of sodium chloride. It is
agitated for 45 minutes with 800 mls of methylene chloride and
then the organic phase is separated. The aqueous phase is
- 14 -
1078376 ~ ~
extracted three times with 800 mls of methylene chloride. The
organic extracts are combined, washed with 500 mls of distilled
water and dried over sodium sulphate in the presence of 5 g of
bleaching carbon. After filtration and concentration to dryness
under reduced pressure (20 mm of mercury~ one obtains 21.2 g
of a residue which is dissolved in 80 mls of methylene chloride
and filtered over 70 g of silica contained in a column 2.5 cm
in diameter. The silica is washed with 1.7 litres of methylene
chloride. The methylene chloride is concentrated under reduced
pressure (20 m~ of mercury): one obtains 15.9 g of a crystalline
residue which is purified by recrystallisation from 930 mls of
isopropyl oxide. One obtains in this way 8.5 g of 1,12b-trans-
l-fluoro-1,2,4,6,7,12,12b-octahydro-1,12-methanoxymethano-
(2,3-a)-indolo-quinolizine melting at 158-159 C.
Analysis Calculated % C 71.31 H 6.69 F 6.63 N 9.78
Found: 71.40 6.65 6.75 9.60
10-fluoro-2,3,4,6,7,12-hexahydro-(2,3-a)-indolo-
quinolizine may be prepared in the following manner:
To a suspension of 24 g of 1- [2(6-fluoro-3-indolyl)-
ethyl~-piperidone in 1 litre of toluene one adds over a period
of 30 minutes 24 mls of phosphorus oxychloride dissolved in
100 mls of toluenen It is then heated to 80C for 3 hours. It
is then left to cool and one adds, accompanied by agitation,
550 mls of distilled water. It is heated again to 80C for
45 minutes. It is allowed to cool to 50C and the aqueous
phase is separated by decantation. One extracts the organic
phase with twice 100 mls of water. One adds, accompanied by
agitation, 24 g of sodium perchlorate dissolved in 240 mls of
distilled water, to the combined aqueous extracts. A product is
precipitated. After 1 hour and a half of cooling to 4C, the
1078376
crystals are separated by filtration. In this way one obtains
30.4 g of 10-fluoro-1,2,3,4,6,7,12H-hexahydro-(2,3-a)-indolo~
- quinolizinium perchlorate melting at 223C.
30.3 g of the perchlorate thus obtained is dissolved
in 2.1 litres of boiling methanol and then one adds 2.1 litres
, .
of distilled water and one cools to a temperature in the vicinity
of 20C. One then adds 100 mls of normal soda. A product is
precipitated, which is separated by filtration, washed with
500 mls of distilled water.
In this way one obtains 17.2 g of 10-fluoro-2,3,4,6,7,-
12-hexahydro-~2,3-a)-indolo-quinolizine melting at 134 C.
l-t2(6-fluoro-3-indolyl)ethy~ piperidone may be
prepared in the following manner:
To 22.7 g of 6-fluoro tryptamine dissolved in 600 mls
of methoxyethanol one adds 13.3 g of anhydrous sodium carbonate
and one heats under reflux under an atmosphere of nitrogen.
One adds, over a period of 3 days, 26.5 g of ethyl 5-bromo
valerianate in 50 mls of methoxyethanol. The reflux is continued
: i
for 5 hours. After the end of the addition one concentrates to
.
dryness under reduced pressure (20 mm of mercury). The residue
; is taken up in 300 mls of water. It is extracted 4 times with
450 mls of methylene chloride. The organic extracts are combined
and are washed with 100 mls of N hydrochloric acid and then with
twice 100 mls of water, dried over sodium sulphate in the
presence of 0.2 g of bleaching carbon. After filtration and
concentration to dryness under reduced pressure (20 mm of
mercury), one obtains 27.7 g of a crystalline residue which is
purified by chromatography over 125 g of silica contained in a
column with a diameter of 3 cm, by eluting with 3.5 litres of
ethyl acetate. After the concentration of the eluates one
- 16 -
~078376
.
obtains 24 g of 1- L2(6-fluoro-3-indolyl)ethy~ piperidone
melting at 146C. 6-fluoro tryptamine may be prepared
according to the process described in British Patent 846.675.
EXAMPLE 6
One heats to 60 C a suspension of 8.6 g of 9-methyl-
2,3,4,6,7,12-hexahydro-(2,3-a)-indolo-quinolizine in 750 mls
of ethanol. One obtains a solution to which one adds, over a
period of 2 minutes, 20.6 mls of a 30% aqueous solution of
formaldehyde. The reaction mixture is maintained at 60C for
10 minutes. One adds 5.4 mls of 70% perchloric acid over a
period of 1 minute and the reaction medium is then cooled to
20C. One then adds in small portions and accompanied with -~
agitation 7.1 g of sodium borohydride over a period of 15
minutes, it is allowed to continue with agitation for a further
30 minutes and then the mixture is poured into 375 mls of a
saturated solution of sodium chloride, it is left for 5 minutes
with agitation and extracted twice with 400 mls of chloroform.
The organic phase is dried, filtered over bleaching carbon and
evaporated to dryness under reduced pressure (20 mm of mercury).
In this way one obtains 9.8 g of crude product which is
chromatographed over 500 g of basic alumina contained in a
column with a diameter of 43 cm, eluting with methylene chloride
and collecting fractions of 120 mls. Fractions 2 to 14, after
concentration, provide 5 g of a product which is recrystallised
from 50 mls of acetone. One obtains in this way 3.3 g of
1,12b-trans-9-methyl-1,2,3,4,6,7,12,12b-octahydro-1,12-methan~-
~! oxymethano-(2,3-a)-indolo-quinolizine, melting at 183C.
Analysis: Calculated % C 76.56 H 7.85 N 9.92
Found 76.5 7.6 9.7
9-methyl-2,3,4,6,7,12-hexahydro-(2,3-a)-indolo-
quinolizine may be prepared in the following manner:
- 17 -
1078376
To a solution of 16 g of 1- C2t5-methyl- 3-indolyl)-
ethyl~-2-piperidone in 450 mls of toluene one adds 15 mls of
phosphorus oxychloride and heats the mixture at 85 C for 3 hours.
It is cooled to 20C and then one adds 200 mls of water and
heats it again to 90 C for 40 minutes accompanied by agitation.
The mixture is cooled. ~fter decantation, the organic phase
is washed with 200 mls of water. The aqueous phases are
combined and heated to 40C. One then adds over a period of 3
minutes a solution of 15 g of sodium perchlorate in 100 mls of
water. An oil is salted out. After cooling, the water is
decanted; one adds 500 mls of water to the residue and hçats
under a reflux. After cooling, the crystallised yellow product
is separated by filtration and dried. One obtains in this way
13.1 g of 9-methyl-1,2,3,4,6,7,12H-hexahydro-(2,3-a)indolo-
quinolizinium perchlorate in the form of yellow crystals.
This perchlorate obtained in this way is dissolved
at 50C in a mixture of 750 mls of water and 750 mls of methanol
and one adds 4~1 soda to it to bring the pH to 20. An emulsion
is formed which crystallises when cooled. After leaving it for
20 1 hour at 5C, it is filtered. One obtains in this way 8.6 g !~
of 9-methyl-2,3,4,6,7,12 hexahydro-(2,3-a)indolo-quinolizine
melting at 167C.
2(5-methyl-3-indolyl)-ethyl~ -2-piperidone may be
prepared in the following manner:
To a suspension of 14 g of 5-methyl tryptamine
hydrochloride and 7.2 g of sodium carbonate in 250 mls of
methoxyethanol heated under a reflux, one adds over a period of
8 hours a solution of 15 g of ethyl 5-bromo valerianate in 45 mls
of methoxyethanol. The heating under a reflux is maintained for
a further 16 hours. After cooling, the mineral salts in
- 18 -
1078376
suspension are separated by filtration and the filtrate is
evaporated to dryness under reduced pressure (20 mm of mercury).
The residue is taken up in a mixture of 250 mls of water and
500 mls of methylene chloride. After decanting, the aqueous
phase is extracted again with 250 mls of methylene chloride.
The combined organic phases are washed 3 times with 500 mls of
dilute hydrochloric acid, dried over sodium sulphate, filtered
over bleaching carbon and evaporated to dryness under reduced
pressure. In this way one obtains 16 g of 1- [2(5-methyl-3-
indolyl) ethy~-2-piperidone in a form which can be used without
subsequent purification.
5-methyl tryptamine hydrochloride may be prepared
according to M. PROTIVA and co-workers, Czech. Chem. Comm.,
25, 784 (1960).
EXAMPLE 7
One heats to 60C a solution of 8.4 g of 9-methoxy-
2,3,4,6,7,12-hexahydro(2,3-a) indolo-quinolizine in 840 mls of
ethanol and one rapidly adds 22.2 mls of a 30% aqueous solution
of formaldehyde. The temperature is maintained for 10 minutes
at 60C and then one rapidly adds 5.6 mls of 70% perchloric
acid. The reaction medium is cooled to 20C and becomes
heterogeneous. One adds in small portions over a period of 4
minutes 7.20 g of sodium borohydride and then one leaves it for
45 minutes with agitation, one adds 300 mls of a saturated
solution of sodium chloride and agitates for 10 minutes. One
then adds 1000 mls of water and 1000 mls-of methylene chloride
and continues the agitation for a further 10 minutes. After
decanting, the aqueous phase is extracted again with 1000 mls of
methylene chloride. These organic phases are combined, washed
with 500 mls of water and 750 mls of a saturated solution of
-- 19 --
1078376
sodium bicarbonate and dried over sodium sulphate, filtered
over bleaching charcoal. In this way one obtains, after
evaporation to dryness under reduced pressure (20 mm of mercury)
11 g of crude product which is chromatographed over 200 g of
basic alumina contained in a column with a diameter of 30 cm,
eluting with methylene chloride and collecting fractions of 60
mls. Fractions 2 to 24 after concentration provide 7.7 g of
a product which is recrystallised from 150 mls of a mixture of
ethyl acetate and isopropyl oxide (1:1 by volume). One obtains -
in this way 5 g of 1,12b-trans-9-methoxy-1,2,3,4,6,7,12,12b
octahydro-1,12 methanoxymethano(2,3-a) indolo-quinolizine
melting at 130C.
Analysis Calculated: C 72.46 H 7.43 N 9.39
Found: 72.4 7.4 9.2
9-methoxy-2,3,4,6,7,12-hexahydro (2,3-a) indolo-
quinolizine may be prepared in the following manner:
To a suspension of 17 g of 1- C2(9-methoxy-3-indolyl) - '
ethy~-2-piperidone in 500 mls of toluene one adds over a period
of 2 minutes 17.2 mls of phosphorus oxychloride and then one
heats to 80C for 3 hours accompanied by agitation. It is cooled
to 50C and then one adds 400 mls of water and heats the
mixture again to 85C for 30 minutes. After cooling, one adds
1000 mls of water, decants and eliminates the organic phase.
To the aqueous phase, heated to 50C, one adds a solution of
17 g of sodium perchlorate in 180 mls of water. A precipitate
; is formed which, after cooling to 20C, is separated by
filtration. In this way one obtains 18 g of 1,2,3,4,6,7,12H
hexahydro-(2,3-a) indolo quinolizinium perchlorate in the form
of pale yellow crystals. One dissolves 16.5 g of the perchlorate
so obtained in a mixture of 1300 mls of methanol and 1500 mls
.
- 20 -
1078376
of water at 55C. It is cooled to 40C and one adds over a
period of 10 minutes 100 mls of 4N soda. After 30 minutes of
cooling to 10C, the crystals obtained are separated by filtra-
tion. One obtains in this way 8.5 g of 9-methoxy-2,3,4,6,7,12-
hexahydro (2,3-a) indolo-quinolizine in the form of yellow
crystals melting at about 130C.
l-C2(5-methoxy-3-indolyl)-ethyl~-2-piperidone may be
prepared in the following manner:
One heats to 80C a solution consisting of 140 mls of
water, 60 mls of acetic acid and 40 mls of normal hydrochloric
acid. One then adds 5.52 g of p-methoxyphenylhydrazine followed
by 9.7 g of 1-(4,4-diethoxybutyl)-2-piperidone. The solution
is maintained at 80C for 2 hours. It is then cooled to 5 C
and then one adds 200 mls of water and 150 mls of methylene
chloride. After decanting, the aqueous phase is extracted again
with 200 mls of methylene chloride. The organic phases are
combined, washed with 100 mls of water and then with a saturated
solution of sodium bicarbonate, dried over sodium sulphate,
filtered over bleaching charcoal and then evaporated to dryness
under reduced pressure (20 mm of mercury). The residue (10 g)
is chromatographed over 75 g of silica gel contained in a column
with a diameter of 2.7 cm and eluting with ethyl acetate,
collecting fractions of 120 mls. Fractions 4 to 12 are
evaporated. In this way one obtains 7.5 g of 1- ~1(5-methoxy-3-
, indolyl)-ethy~-2-piperidone melting at 150 C.
1-(4,4-diethoxy-butyl)-2-piperidone may be prepared
in the following manner:
To a solution of 97 g of 4,4-diethoxybutylamine in
1800 mls of methoxy-ethanol heated under a reflux one adds over
a period of 19 hours a solution of 130 g of ethyl 5-bromo
- 21 -
1078376
,
valerianate in 160 mls of methoxyethanol. The mixture is heated
under a reflux for a further hour after the end of the addition.
After cooling, the mineral salts are separated by filtration and
the filtrate is evaporated to dryness under reduced pressure
(20 mm of mercury). The residue is dissolved in 1000 mls of
methylene chloride, washed twice with 500 mls of water and then
with 500 mls of a 4% solution of citric acid. The organic
phase is dried over sodium sulphate, filtered over bleaching
charcoal and evaporated to dryness. In this way one obtains
122.5 g of crude 1-(4,4-diethoxy-butyl)-2-piperidone which is
used without subsequent purification.
EXAMPLE 8
To a solution of 17.5 g of 9-chloro-2,3,4,6,7,12- ; !
hexahydro(2,3-a)-indolo-quinolizine in 1700 mls of ethanol at
60C one rapidly adds 45.4 mls of a 30% aqueous solution of
formaldehyde. It is maintained at 60C for 10 minutes and then
one rapidly adds 11.5 mls of 70% perchloric acid. After cooling
the mixture to 20~, one adds, over a period of 3 minutes in
small portions, 14.7 g of sodium borohydride accompanied by
agitation. The agitation is continued for a further 30 minutes
and then one adds 350 mls of a saturated solution of sodium
chloride and 500 mls of water. The agitation is continued for
a further 20 minutes and then it is extracted with 800 mls of
methylene chloride. The organic layer is washed with 1000 mls
of water, dried over sodium sulphate, filtered over bleaching
charcoal and evaporated to dryness. One obtains 20 g of a crude
product which is recrystallised from 150 mls of ethyl acetate.
One obtains in this way 11 g of 1,12b trans-9-chloro-1,2,3,4,6,- -
7,12,12b octahydro-1,12 methanoxymethano-2,3-a) indolo-quino-
lizine in the form of white crystals melting at 154C.
~078376
Analysis Calculated % C 67.43 H 6.33 Cl 11.71 N 9.25
Found 67.6 6.3 11.8 9.0
9-chloro-2,3,4,6,7,12 hexahydro (2,3-a) indolo-
quinolizine may be prepared in the following manner:
To a suspension of 1~.5 g of 1- ~2(5-chloro-3-indolyl)-
ethyl~-2-piperidone in 375 mls of toluene one adds 16.5 mls of
phosphorus oxychlori~e and then one heats this mixture for 3
hours at 80C. After cooling to 30C one adds 750 mls of water
and then one heats again at 85C for one hour. After cooling
and decanting, the organic phase is extracted with 100 mls of
water. The aqueous phases are combined and heated to 55C,
one then adds a solution of 16.5 g of sodium perchlorate in 180
mls of water. The suspension formed is cooled to 15C and then
filtered. One obtains in this way 21g of 9-chloro-1,2,3,4,6,7,-
12-H hexahydro(2,3-a) indolo-quinolizinium perchlorate in the
form of orange crystals melting at about 300C with decomposi-
tion.
One dissolves 28 g of the perchlorate thus obtained in
a mixture brought to reflux of 850 mls of methanol and 500 mls
~,20 of water. One then adds 35 mls of 4N soda whilst slowly cooling
to 5C. The crystals formed are separated by filtration and ~`
dried. One obtains in this way 17.5 g of 9-chloro-2,3,4,6,7,12
hexahydro(2,3-a) indolo-quinolizine in the form of yellow
crystals melting at 147C.
l- [2(5-chloro-3-indolyl ethy~ -2-piperidone may be
prepared in the following manner:
One gradually heats a mixture of 31 g of anhydrous
zinc chloride, 31 g of p-chlorophenylhydrazine and 52.5 g of
l-(4,4-diethoxy-butyl)-2-piperidone to 115C. The ethanol
formed is eliminated by distillation. One continues heating,
- 23 -
1078376
and at 170C an exothermic reaction is formed which brings the
mixture to 240C. The mixture is then maintained at 180C for
4 hours.
After cooling the mixture, one adds 150 mls of a 2N
solution of acetic acid and then heats under a reflux for 5
minutes. After cooling, one adds 150 mls of methylene chloride.
After decanting, the aqueous phase is extracted again with 200
mls of methylene chloride. The organic phases are combined,
washed with 200 mls of water, 300 mls of a saturated solution ~ -
of sodium bicarbonate, dried over sodium sulphate and evaporated
to dryness under reduced pressure (20 mm of mercury). The
residue (56 g) is chromatographed over 500 g of silica gel
contained in a column 5 cm in diameter and eluting with ethyl
acetate, collecting fractions of 400 mls. Fractions 8 to 15
are evaporated to dryness. One obtains in this way 32 g of
l-C2(5-chloro-3-indolyl) ethyl~-2-piperidone, melting at 158C.
EXAMPLE 9
; To a solution heated to 60C of 19 g of 9-fluoro-
2,3,4,6,7,12 hexahydro-(2,3-a) indolo-quinolizine in 1900 mls of
ethanol one adds, over a period of 1 minute, 40.5 mls of a 30%
aqueous solution of formaldehyde. It is left at 60 for 10
minutes whilst agitating and then one adds, over a period of
1 minute, 10.8 mls of a 70% perchloric acid solution. It is
cooled to 20 and then one adds in small fractions 14.3 g of
sodium borohydride, and it is then left for a further 30 minutes
accompanied by agitation. One then adds 600 mls of a saturated
solution of sodium chloride and then extracts it with twice
1000 mls of chloroform. The combined extracts are washed with
1000 mls of water, dried over sodium sulphate, filtered and
evaporated to dryness under reduced pressure (20 mm of mercury).
24
, . ..
1078376
The residue (22.5 g) is recrystallised twice from acetone. One
obtains in this way 7.3 g of 1,12b-trans-9-fluoro-1,2,3,4,6,7,-
12,12b octahydro-1,12 rnethanoxymethano-(2,3-a) indolo-quinolizine
in the form of pale yellow crystals melting at about 155 C.
Analysis Calculated ~ C 71.31 H 6.69 F 6.63 N 9.78
Found 70.3 6.5 6.9 9.8
9-fluoro-2,3,4,6,7,12-hexahydro (2,3-a) indolo-
quinolizine may be prepared in the following manner:
To a suspension of 30 g of 1- ~2(5-fluoro-3-indolyl)
ethy~-2-piperidone in 1500 mls of toluene, one adds 28 mls of
phosphorus oxychloride and heats to 80C, accompanied by
agitation, for 3 hours. It is then cooled to about 50C and
then one adds 750 mls of water and heats to 85C for 45 minutes.
After cooling and decanting, the organic phase is extracted
twice with 100 mls of water, the aqueous phases are combined
and heated to 50C. One then adds a hot solution of 30 g of
sodium perchlorate in 200 mls of water. A precipitate is formed.
The suspension is agitated for 30 minutes in an ice bath. The
precipitate is separated by filtration. In this way one obtains
40 g of 9-fluoro-1,2,3,4,6,7,12-H hexahydro(2,3-a) indolo-
quinolizinium perchlorate in the form of orange crystals.
This perchlorate is dissolved at 20C in a mixture of
2500 mls of methanol and 2500 mls of water. One adds, with
agitation, to this solution 10N soda so as to bring the pH to
10. A precipitate is formed. The mixture is agitated for 30
minutes in an ice bath. The precipitate is separated by
filtration and dried and one obtains in this way 19 g of
9-fluoro-2,3,4,6,7,12-hexahydro(2,3-a) indolo-quinolizine in
the form of orange crystals melting at about 108C.
1- ~2(5-fluoro-3-indolyl) ethy~-2-piperidone can be
prepared in the following manner:
- 25 -
~078376
One gradually heats a mixture of 16.3 g of anhydrous
zinc chloride, 14.5 g of p-fluorophenylhydrazine and 28 g of
1-(4,4-diethoxy-butyl)-2-piperidone. At 110C one eliminates
by distillation the ethanol formed and then one continues to heat.
From 150C, an exothermic reaction is produced and the tempera-
ture of the reaction mixture rises to a temperature of 210C.
The temperature is then maintained at 180C for 4 hours. After
cooling to about 100C, it is extracted twice under a reflux
with 100 mls of a water/ethanol mixture (1:1 by volume). To
these extracts one adds 10 mls of acetic acid and then one
extracts three times with 200 mls of methylene chloride. The
combined organic extracts are washed with 200 mls of a saturated
solution of sodium bicarbonate, dried over sodium sulphate,
filtered over a bleaching charcoal and evaporated to dryness,
(20 mm of mercury). One obtains 38 g of a brown gum which is
chromatographed over 500 g of silica gel contained in a column
with a diameter of 5 cm, collecting fractions of 500 mls and
eluting with ethyl acetate. Fractions 20 to 36 are combined
:.
and evaporated to dryness. In this way one obtains 22 g of
1- ~2(5-fluoro-3-indolyl) ethyl~ -2-piperidone in the form of
pale yellow crystals melting at 152C.
EXAMPLE 10
One heats to 65C under an atmosphere of nitrogen a
solution of 17.8 g of 9,10-dioxymethylene-2,3,4,6,7,12 hexahydro
(2,3-a) indolo-quinolizine in 1700 mls of ethanol, and then in
a period of 1 minute one adds 37.6 mls of a 30% aqueous solution
of formaldehyde. A precipitate is formed. It is maintained at
65C for 10 minutes and then in a period of 1 minute one adds
9.9 mls of 70% perchloric acid and then leaves it to cool with
agitation to 25C. One then adds over a period of 15 minutes,
- 26 -
- , ,, ~
1078376
in small portions, 13.2 g of sodium borohydride and then
continues the agitation for 30 minutes. One adds to the
mixture 700 mls of a saturated solution of sodium chloride, ~-
1000 mls of chloroform and 400 mls of water. After decanting,
the aqueous phase is extracted again with 600 mls of chloroform.
The organic fractions are combined, washed twice with 1500 mls
of water, dried over sodium sulphate and concentrated to dryness.
The residue (16.8 g) is chromatographed over 400 g of silica
gel contained in a column with a diameter of 5 cm, collecting
10 fractions of 600 mls and eluting with a mixture of methylene ~`
chloride/ethyl acetate (85:15 by volume). Fractions 5 to 15 are
combined and evaporated. The residue, ~.9 g, is recrystallised
successively from a mixture of ethyl acetate and acetone. In
this way one obtains 3.5 g of 1,12b-trans-9,10-methylenedioxy-
1,12-methanoxymethano-1,2,3,4,6,7,12,12b octahydro(2,3-a) indolo-
quinolizine in the form of white crystals melting at 234C.
Analysis Calculated % C 69.21 H 6.45 N 8.97 O 15.37
Found 69.4 6.5 8.8 15.3
9,10-methylenedioxy-2,3,4,6,7,12-hexahydro(2,3-a)
indolo-quinolizine may be prepared in the following manner:
One heats under a reflux under an atmosphere of
' nitrogen a solution of 10.25 g of C2(5,6-methylenedioxy-3-indolyl)
! ethylJ-2-piperidone in 475 mls of 1,2-dichloroethane and one
adds over a period of 10 minutes a solution of 10.5 mls of
~ phosphorus oxychloride in 25 mls of 1,2-dichloroethane.
`~ It is maintained for a further 3 hours under reflux.
After cooling to about 50C, one adds 250 mls of water and then
one heats it again under a reflux for 45 minutes. After cooling
:.
and decanting one extracts the organic phase with 50 mls of
water; the aqueous phases are combined and heated to 50C. One
.:
- 27 -
:- .
:
1078376
then adds a solution of 10.25 g of sodium perchlorate in 50 mls
of distilled water. A precipitate is formed. After cooling
for 30 minutes the precipitate is separated by filtration and
dried. It is filtered and in this way one obtains 12.2 g of
methylene-9,10-dioxy-1,2,3,4,6,7,12H-hexahydro(2,3~a) indolo-
i quinolizinium perchlorate in the form of dark green crystals.
This perchlorate is dissolved under an atmosphere
of nitrogen under a reflux in a mixture of 750 mls of methanol
and 500 mls of water. It is cooled to 45C and then one adds
10 25 mls of 4N soda. A precipitate is formed. This mixture is
cooled in an ice bath for 2 hours. The precipitate is separated
by filtration and then dried. In this way one obtains 8.5 g of
methylene-9,10-dioxy-2,3,4,6,7,12-hexahydro(2,3-a) indolo-
; quinolizine in the form of a green solid melting at about 180C.
l-C2(methylene-5,6-dioxy-3-indolyl) ethyl~-2-
piperidone may be prepared in the following manner:
One heats under a reflux a solution of 22 g of
~ methylene-3,4-dioxyphenylhydrazine hydrochloride in 880 mls of
i -
a mixture of ethanol and water (50:50 by volume) and 200 mls of
j 20 5N hydrochloric acid. One then adds over a period of 5 minutes r
~i a solution of 28.4 g of 1-(4,4-diethoxybutyl)-2-piperidone in
¦ 140 mls of ethanol, heats it again under a reflux for 5 minutes.
~j After cooling, the solution is neutralised by the addition of
100 mls of a saturated solution of potassium bicarbonate. It is
then extracted successively with 500, 350 and 350 mls of
` methylene chloride. The organic phases are combined, washed with
200 mls of water, dried over sodium sulphate, filtered over
; bleaching charcoal and evaporated to dryness under reduced
pressure (20 mm of mercury). The residue (34 g) is chromato-
graphed over 500 g of silica contained in a column with a
- 28 -
1078376
'.~.
diameter of 5 cm, collecting fractions of 500 mls and eluting
with ethyl acetate. Fractions 11 to 18 are combined and
evaporated. In this way one obtains 11.75 g of 1- C2(methylene-
5,6-dioxy-3-indolyl)ethy~ -2-piperidone melting at 180C.
EXAMPLE 11
One heats to 65C a solution of 7.3 g of 9,lQ-dimethoxy-
2,3,4,6,7,12-hexahydro (2,3-a) indolo-quinolizine in 730 mls of -
ethanol. One adds, over a period of 1 minute, 14.4 mls of a
30~ aqueous solution of formaldehyde. It is then left at 65C
for 10 minutes and then one adds in a single go 3.8 mls of
70~ perchloric acid. After cooling to 20C, one adds in small
portions 4.9 g of sodium borohydride and then leaves it with
agitation for 30 minutes. One adds 300 mls of a saturated
solution of sodium chloride and 600 mls of methylene chloride.
After decanting, the aqueous phase is extracted with 300 mls of
methylene chloride. The organic phases are combined, washed
twice with 500 mls of water, dried over magnesium sulphate and
:
evaporated to dryness under reduced pressure (20 mm of mercury).
;~ The residue (8.3 g) is chromatographed over 350 g of basic
alumina contained in a column of 3.8 cm diameter, collecting
::
~ fractions of 300 mls and eluting with methylene chloride.
;.~.i
Fractions 6 to 14 are combined and evaporated to dryness. The
residue (5 g) recrystallised from 100 mls of ethyl acetate. One
obtains in this way 3.5 g of 1,12b-trans-9,10-dimethoxy-1,12-
methanoxymethano-l,2,3,4,6,7,12,12b-octahydro(2,3-a) indolo-
quinolizine in the form of yellow crystals melting at 170C.
Analysis Calculated: C 69.49 H 7.37 N 8.53 O 14.61
Found: 69.0 6.8 8.4 14.9
9,10-dimethoxy-2,3,4,6,7,12-hexahydro (2,3-a) indolo-
quinolizine may be prepared in the following manner:
- 29 -
1 1078376
One heats under a reflux for 3 hours a solution of 14 g
of l-C2(5,6-dimethoxy-3-indolyl)ethyl~-2-piperidone and 11.7 mls
of phosphorus oxychloride in 700 mls of 1,2-dichloroethane.
After cooling to 50C, one adds 350 mls of water and
heats for 45 minutes under a reflux. After cooling and decanting,
the organic phase is extracted twice with 50 mls of water. The -
combined aqueous phases are heated to 50C; one then adds a
lukewarm solution of 14 g of sodium perchlorate in 70 mls of
water. A precipitate is formed. The suspension is cooled for
1 hour in an ice bath. The crystals are separated by filtration
and dried. One obtains 13.7 g of 9,10-dimethoxy-1,2,3,4,6,7,12H-
hexahydro (2,3-a) indolo-quinolizinium perchlorate in the form
of green crystals.
This perchlorate (13.5 g) is dissolved under a reflux
in a mixture of water and methanol (50:50 by volume). After
cooling to 50C one adds, drop by drop, 10N soda so as to bring
:.
the pH to 10. A precipitate is formed. The suspension is
maintained for 1 hour in an ice bath and then the precipitate is
separated by filtration and dried. One obtains in this way 7.4 g
of 9,10-dimethoxy-2,3,4,6,7,12-hexahydro (2,3-a) indolo-
`~ quinolizine in the form of a yellow solid melting at 122C.
1- ~2(5,6-dimethoxy-3-indolyl)ethy~ -2-piperidone may
be prepared in the following manner:
One dissolves 54 g of 3,4-dimethoxy phenylhydrazine
hydrochloride in a mixture of 750 mls of ethanol, 750 mls of
. .
water and 350 mls of 5% hydrochloric acid. It is heated under
a reflux, and then one adds over a period of 5 minutes a
solution of 63 g of 1-(4,4-diethoxybutyl)-2-piperidone in 250
mls of ethanol. After heating under a reflux for 2 hours and
then cooling, one eliminates the ethanol by distillation under
reduced pressure (20 mm of mercury) and then extracts
- 30 -
7~3376
successively with 500 mls, 300 mls and 200 mls of methylene
chloride. The combined organic phases are washed with 500 mls
of water and then 500 mls of a saturated solution of sodium
bicarbonate, dried over magnesium sulphate and evaporated to
dryness under reduced pressure (20 mm of mercury). The residue
(58 g) is chromatographed over 1 kg of silica gel contained in
a column with a diameter of 6 cm, collecting fractions of 500
mls and eluting with ethyl acetate containing 1.5~ of methanol.
Fractions 31 to 43 are combined and evaporatad to dryness.
In this way one obtains 17 g of 1- C2(5,6-dimethoxy-3-indolyl)
ethyl~-2-piperidone in the form of a thick yellow oil which
slowly crystallises.
:
EXAMPLE 12
, One heats 570 mls of ethanol to 60C and then one
'A~ adds 5.85 g of 10-chloro-2,3,4,6,7,12-hexahydro ~2,3-a)-indolo-
quinolizine.
One obtains a homogeneous solution to which one adds
in one go 15.2 mls of 30% aqueous formaldehyde solution.
The reaction mixture is maintained for 10 minutes at
60C and then one adds over a period of one minute 3.85 mls of
a 70~ aqueous solution of perchloric acid. After cooling to
20C, one adds with agitation, in small portions over a period
of 15 minutes, 4.9 g of sodium borohydride. The excess of
borohydride is destroyed by the addition of 290 mls of a 1.25 M
aqueous solution of sodium chloride. The agitation is continued
for 20 minutes and then one extracts twice with 500 mls of
dichloromethane.
The combined organic phases are washed with twice
200 mls of a 5 M sodium chloride solution and then dried over
magnesium sulphate in the presence of bleaching charcoal,
- 31 -
:
107837G
filtered, then concentrated to dryness under reduced pressure.
The product obtained (6.8 g) is agitated in a mixture
of 20 mls of methanol and 40 mls of di-isopropyl oxide at 20C.
By filtration one obtains 4.0 g of a pale yellow
crystalline powder melting at 207C, which is chromatographed
over a column of 30 g of silica gel contained in a column of
; 2 cms in diameter, collecting fractions of 30 mls and eluting
with a mixture of dichloromethane/methanol (97:3 by volume).
Fractions 3 to 8 are combined and evaporated.
The residue of 2.93 g is recrystallised from 600 mls
of di-isopropyl oxide.
One obtains in this way 1.9 g of 1,12b-trans-10-chloro-
1,12-methanoxymethano-1,2,3,4,6,7,12,12b-octahydro-(2,3-a)-
indolo-quinolizine in the form of fine white needles melting at
209C.
Analysis: Calculated: O% 67.43, H% 6.33; Cl~ 11.71; N% 9.25;
O% 5.28
Found: C% 66.4; H% 6.4; Cl~ 11.7; N% 9.5;
~ i . .
, O% 5.5.
. 1
10-chloro-2,3,4,6,7,12-hexahydro-(2,3-a)-indolo-
quinolizine may be prepared in the following manner:
One brings into suspension 15 g of 1-C2(6-chloro-3-
indolyl)-ethyl~-2-piperidone in 700 mls of toluene and over a
period of 5 minutes one adds a solution of 14 mls of phosphorus
1 oxychloride in 50 mls of toluene.
¦ The reaction mixtu~e is then heated for 3 hours at
80C. One adds 325 mls of distilled water and continues the
heating to 80C for a further one hour. After 16 hours at 4C,
the crystals are separated by filtration.
One obtains in this way 14 g of 10~-chloro-1,2,3,4,6,7,-
12H-hexahydro-(2,3-a)-indolo-quinolizinium chloride.
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10~37~
The chloride thus obtained is dissolved in 1000 mls
of distilled water at 35 C.
After cooling to 20C one adds, drop by drop, 60 mls
of lN soda.
The yellow precipitate obtained is separated by
filtration, washed with water until neutral and then dried.
One obtains in this way 11.2 g of 10-chloro-2,3,4,6,7,-
l~-hexahydro-(2,3-a)-indolo-quinolizine in the form of a yellow
amorphous powder, which is used without any subsequent
purification.
2~6-chloro-3-indolyl)-ethyl~ -2-piperidone may be
prepared in the following manner:
One heats under a reflux under an atmosphere of
''! nitrogen 22 g of 6-chloro-tryptamine in 500 mls of 2-methoxy-
ethanol containing in suspension 12 g of anhydrous sodium
carbonate.
Whilst maintaining the agitation and the heating under
a reflux one adds over a period of 48 hours a solution of 23.65 g
-',Jj of ethyl 5-bromovalerianate in 200 mls of 2-methoxy-ethanol.
When the addition is completed, one maintains the
'l
agitation and the heating under a reflux for a further 15 hours.
After cooling to 20C the mineral salts are separated
` by filtration and the filtrate is concentrated to dryness under
` reduced pressure (15 mm of mercury). One obtains a brown oil to
which one adds 500 mls of water. It is acidified to a pH of 1
by the addition of 4N hydrochloric acid and then one extracts
4 times with 500 mls of dichloromethane.
The combined organic phases are washed with twice 500
mls of N hydrochloric acid, 4 times 500 mls of distilled water,
and then dried over magnesium sulphate and finally concentrated
to dryness under reduced pressure.
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107837~
One obtains 31.5 g of a brown oil which is chromato-
graphed over a column of 150 g of silica gel contained in a
column with a diameter of 3.5 cms, collecting fractions of 1000
mls and eluting with a mixture of ethyl acetate and cyclohexane
(35-65 by volume). Fractions 4 to 19 are combined and
concentrated to dryness.
The residue of 22.5 g is recrystallised from ethyl
acetate.
One obtains in this way 20.5 g of 1- ~2(6-chloro-3-
' 10 indolyl)-ethy~ -2-piperidone in the form of fine white needles ~
, which melt at 188C. '
6-chloro-tryptamine may be prepared according to
F. BENINGTON et al., J. Org. Chem., 25, 1542 (1960).
~ EXAMPLE 13
;' One heats 1800 mls of ethanol to 60C and then one
adds 18 g of 1~-methy1-2,3,4,6,7,12-hexahydro-(2,3-a)-indolo-
uinolizine.
' ,, One obtai,ns a homogeneous solution to which one adds
' 44.S mls of 30% aqueous formaldehyde solution.
:, .
~' -- 20 One maintains the reaction mixture agitated for 10
minutes at 60C and then one adds in a single go 11.2 mls of
'~ 70% perchloric acid and cools immediately by means of a water-
bath.
As soon as the temperature of the mixture reaches
21C one adds, in small portions, over a period of 15 minutes,
1~ g of sodium borohydride. The agitation is continued for
30 minutes and then one adds 800 mls of a 2.5 M sodium chloride
solution and one agitates for 45 minutes until gas ceases to
be evolved.
One then extracts with twice 400 mls of dichloromethane.
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~ 1078-37~; ,
The combined oxganic phases are washed with twice
200 mls of water and then dried over magnesium sulphate,
bleached over bleaching charcoal, filtered and finally concen-
trated to dryness. -
One obtains 19 g of brown powder which is taken up
again in 350 mls of acetone under a reflux.
It is allowed to crystallise by cooling to 0 C for one
hour.
One obtains 7.5 g of yellow crystals.
By concentrating the filtrate to a small volume one
obtains a second batch of 1.4 g under the same conditions.
The two batches are combined and chromatographed over
a column of 117 g of silica gel contained in a column with a
diameter of 3 cms, collecting fractions of 300 mls and eluting
with dichloromethane.
Fractions 3 to 11 are combined and evaporated.
The residue of 6.4 g is recrystallised from 240 mls of
acetone under a reflux.
One obtains in this way 6 g of 1,12b-trans-10-methyl-
1,12-methanoxymethano-1,2,3,4,6,7,12,12b-octahydro-(2,3-a)-
indolo-quinolizine in the form of fine white needles which melt
at 178C.
Analysis: Calculated: C% 76.56; H~ 7.85; N% 9.92; O% 5.67
Found: C% 75.6; H% 8.0; N% 9.9; O% 5.9
10-methyl-2,3,4,6,7,12-hexahydro-(2,3-a)-indolo-
quinolizine may be prepared in the following manner:
25 g of 1- r2(6-methyl-3-indolyl)-et~yl] -2-piperidone
are suspended in 1200 mls of toluene and over a period of 5
minutes one adds a solution of 25.3 mls of phosphorus oxychloride
in 50 mls of toluene.
- 35 -
~078376
The reaction mixture is heated at 80 C for 3 hours.
One adds 600 mls of distilled water and continues the
heating at 80C for a further one hour.
One cools to a temperature in the vicinity of 20C ~ -
and then one adds a solution of 21 g of sodium perchlorate
monohydrate in 270 mls of water.
After 16 hours at a temperature in the vicinity of
4C, the crystals are separated by filtration, washed with water
and dried.
One obtains in this way 44.8 g of wet product
containing 31 g of 10-methyl-1,2,3,4,6,7,12H-hexahydro-(2,3-a)-
indolo-quinolizinium perchlorate.
The wet perchlorate is dissolved in 2 litres of
methanol under a reflux. One adds 2 litres of distilled water
and maintains the heating under a reflux.
It is then allowed to return to a temperature in the
vicinity of 20C. One obtains a clear yellow solution to which
one adds 120 mls of 1 N soda, whilst agitating vigorously.
After 30 minutes' agitation the solid product is
separated by filtration and washed with water to neutrality.
After drying one obtains 18.8 g of 10-methyl-2,3,4,6,7-
12-hexahydro-(2,3-a)-indolo-quinolizine in the form of a light
yellow powder which is used without subse~uent purification.
1- [2(6-methyl-3-indolyl)-ethy~ -2-piperidone may be
prepared in the following manner:
One heats under a reflux under an atmosphere of
nitrogen 21 g of 6-methyl-tryptamine in 500 mls of methoxyethanol
containing 12.84 g of anhydrous sodium carbonate in suspension.
Whilst maintaining the agitation and the heating under
a reflux one adds over a period of 20 hours a solution of 25.3
- 36 -
?'11
.,',~
~'
j; 107837
!~,' !
g of ethyl 5-bromovalerianate in 130 mls of 2-methoxyethanol.
When the addition is completed, one maintains the agitation and
the heating under a reflux for 15 hours.
It is then flltered at 20C and the filtrate is
concentrated under reduced pressure (15 mm of mercury).
One obtains a brown oil to which one adds 400 mls of
water. It is acidified by the addition of 20 mls of 4 N
hydrochloric acid and extracted 4 times with 400 mls of dichloro-
methane. The combined organic phases are washed successively
with twice 500 mls of N hydrochloric acid and 4 times 500 mls
distilled water, then dried over magnesium sulphate and finally
concentrated to dryness under reduced pressure.
One obtains 28.8 g of a brown oil which is chromato-
graphed over 140 g of silica contained in a column with a
diameter of 3.5 cms, collecting fractions of 500 mls and eluting
with an ethyl acetate gradient in cyclohexane.
Fractions 14 to 50 eluted with a mixture of ethyl
acetate/cyclohexane (1:1 by volume) are combined and concen-
trated to dryness under reduced pressure.
In this way one obtains 24.7 g of a solid melting at
140C which is recrystallised from 400 mls of ethyl acetate.
One obtains 23 g of 1-~2(6-methyl-3-indolyl)-ethy~ -2-piperidone
in the form of fine silky needles melting at 154C and then
160C.
6-methyltryptamine may be prepared according to
J.H. GASSUM et al, Quat. J. Exp. Physiol., 40, 49 (1955).
EXAMPLE 14
One dissolves 1.5 g of the product obtained in
Example 1 in the form of a base in 200 mls of hot methanol.
One then adds 1.13 g of (l)-di-O,O'-paratoluoyl tartaric acid in
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i 1078376 ~ '
20 mls of hot methanol. After standing for 14 hours at a
temperature in the vicinity of 20C, the salt is separated by
filtration and then recrystallised from 400 mls of a mixture of
dioxan/methanol (75:25 by volume). After 14 hours standing at
a temperature in the vicinity of 20C one obtains 1.36 g of
salt which, after alkalisation and extraction provides 0.57 g
of base, which is purified by chromatography over 15 g of silica
in chloroform, eluting with a mixture of chloroform/methanol
t98:2 by volume).
One obtains in this way 0.47 g of (1)-1,12b-trans-
1,2,3,4,6,7,12,12b-octahydro-1,12-methanoxymethano-(2,3-a)-
indolo-quinolizine:
(~)D = -127 (c = 1, chloroform)
EXAMPLE 15
Operating as in Example 14 but starting off from 1.42 g
of base and 1.07 g of (d)-di-O,O'-paratoluoyl tartaric acid,
one obtains 0.355 g of (d)-1,12b-trans-1,2,3,4,6,7,12,12b-octa-
hydro-1,12-methanoxymethano-(2,3-a)-indolo-quinolizine:
(~)D = + 124 (c = 1, chloroform)
The pharmaceutical compositions containing a product
of the general formula (I) and/or one of its salts in the pure
state or in the presence of a diluent or of a casing constitute
another object of the present invention. These compositions may
be used per os, rectally or parenterally.
As solid compositions for oral administration one may
use tablets, pills, powders or granules. In these compositions,
the active product according to the invention is mixed with one
or more inert diluents such as saccharose, lactose or starch.
These compositions may also include substances other than
diluents, for example, wetting agents, swee~ening agents or
- 38 -
107837~i
flavourings.
The compositions according to the invention forparenteral administration may be aqueous or non-aqueous sterile `
solutions, suspensions or emulsions. As solvent or vehicle one
may use propyleneglycol, polyethyleneglycol, vegetable oils,
particularly olive oil, injectable organic esters, for example
ethyl oleate. These compositions may also contain adjuvants,
particularly wetting agents, emulsifiers or dispersants. The
sterilisation may be carried out in a number of ways, for example ~
by means of a bacteriological filter, incorporating sterilising -~ ;
agents in the composition, by irradiation or by heating. They
; may also be prepared in the form of sterile solid compositions
which can be dissolved at the moment of use in sterile water
or any other injectable sterile medium.
The compositions for rectal administration are
suppositories which may contain, in addition to the active
product, excipients such as cocoa butter or suppository wax.
In human therapy, the compositions according to the
invention are particularly useful in the treatment of cerebro-
vascular accidents and functional disorders of cerebralcirculatory insufficiency, in the treatment of arteriopathies
of the limbs and circulatory troubles of the extremities.
The doses to be used depend on the effect aimed at
and the duration of the treatment. They are generally
between 25 and 500 mg per day by oral route for an adult, by
intramuscular route they may be between 20 and 50 mg per day and
by intravenous route, in slow perfusion, they may be between
10 and 30 mg per day.
Generally speaking, the physician will determine the
3~ dosage which he deems most appropriate, according to the age,
- 39 -
`` 1078376
':
weight and all the other factors connected with the patient to
: be treated.
EXAMPLE 16
One prepares according to the usual technique tablets
containing 25 mg of active product having the following
composition:
- 1,12b-trans-1,2,3,4,6,7,12,12b-octahydro-1,12-methanooxymethano-
2,3-a-indolo-quinolizine 0.025 g
- starch 0.090 g
10 - precipitated silica 0.030 g
- magnesium stearate 0.005 g
- 40 -
