Note: Descriptions are shown in the official language in which they were submitted.
tJ~
E-homo-eburnane derivatl_es, process for th.ir
preparatiorl, and_pharmaceutical compositions
containin~ these comr,ounds
This invention relates to new E-homo eburnane
derlvatives, process for their preparation, and
pharmaceutical compositions containing them as active
ingredient. More particularly, the invention concerns ne~"
racemic or optically active E-homo-eburnane derivatives
of the forn~ula /I/,
~ /I/
0
~\/
2 ) R2
wherein
Rl and R2 independently represent an alkyl group having
1 to 6 carbon atoms,
and acid addition salts thereof.
According to another aspect of the invention there
is provided a process for the preparation of racemic or
optically active E-homo-eburnane derivatives of the
formula /I/, which process comprises subjecting a racemic
A 2915 - 67 PT/Gi
or opticall.y active octahydroindolo/~,3-a7quinoline
derivative of the formula /II/,
P 3 2 C/~ C H 2
wherein
A is hydrogen or a -CH2-CH/C02R1/2 or
-CH2-c/co2R /2-CH2~cH/co2R /2
in which
Rl and R2 are as defined above,
R3 is identical with Rl or, il A represents 'nydrosen,
R3 may also stand for hydrogen,
or an acid addition salt thereof to ring closure, resol.v-
ing, if desired, the compounds of the formula /I/ obtained
and/or convertin~ the racemic or optically active compounds
of the formula /I/ into acid~addition salts thereof.
The compounds of the formula /I/ are pharmaceutical-
ly active, for example their certain representatives, in
particular those from the cis-series, show antidepressive
activity, while others, especially the compounds of the
trans-series, are potent antihypoxial agents.
According to a further aspect of the invention
there are provided pharmaceutical compositions, which
comprise as an active ingredient at l.east one racemic or
optically active E-homo-eburnane derivative of the
formula /I/ or a pharmaceutically acceptable acid addition
salt thereof, in admixture with inert solid or liquid
pharmaceutical carriers and/or additives.
The term "alkyl group having 1 to ~ carbon atoms"
as used herei.n means ~traight or branched chained aliphatic
hydrocarbon groups having l to 6 carbon atoms, e.g. methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, ter~.-
-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl groups,
etc.
If desired, the compounds of the formula /I/ may be
converted into their acid addition sal s. ~uitable acids
for this purpose include inorganic acids, such as hydrogen
halides, e~G~. hydrochloric acid, hydrogen bromide, sulfuric
acid, phosphoric acid, nitric acid, perhaloic acids e.g.
perchloric acid, etc.; organic carboxylic acids such as
formic acid 9 acetic acid, propionic acid, glycolic acid,
maleic acid, hydroxymaleic acid, fumaric acid, succinic
acid, tartaric acid, ascorbic acid, citric acid, malic acid,
salicyli.c acid, lactic acid, cinnalmic acid, benzoic acid,
phenylacetic acid, ~-amino-benzoic acid, ~-hydroxy-benzoic
acid, p-amino-salicylic acid, etc.; alkylsulfonic acids,
such as methanesulfonic acid, ethanesulfonic acid, etc ;
cycloaliphatic acids, e.g cyclohexylsulfonic acid; aryl-
sulfonic acids, e~g. p-toluene-sulfonic acid, naphthyl-
sulfonic acid, sulfanylic acid, etc.; amino acids, such asasparaginic acid, glutaminic acid, ~ acetyl-asparaOinic
acid, N-acetyl-glutaric acid, etc.
The starting compounds oE` the for;nula /II/ can be
prepared as described in the Belgian patent specification
~lo. 883,576 by electrophilic alkylation of tr.e correspond-
ing hexahydroindolo/2,3-a7quinolizinium salts with a
methylenemalonic acid dialkylester and subsequent hydrogena-
tion and, if desired, a further partial hydrolysis.
The cyclization of the compounds of the form~lla /II/,
in which A stands for a hydrogen atom or a CH2-CH/C02~1/2
or -CH2-C/C02Rl/2-CE~2-CEI/C02Rl/2 group, ~3 `~s the same
meaning as Rl and Rl and R2 are as defined above, can be
carried out with sufficiently strong bases, e.g. alkali
metal hydri~es, such as sodium nydride, potassium hydride,
etc,, alkali metal alcoholates, suc~ as ootassium or
sodium ethylate, preferably potassium ter .-butylate in
aprotic or-,anic solvents, such as xy]ene, toluene,
preferably benzene. The cyclization is preferably perform-
ed at the boiling temperature of the reaction mixture.The reaction is completed in a very short timie, generally
in 10 to 40 minutes, preferably 15 to 30 minutes.
The ring closure of the compounds of the
formula /II/, in which A and R3 stand for a hydrogen atom,
Rl and R2 have the same meaning as defined above, is
carried out with a dehydrating agent, preferably phosphorus
oxychloride or phosphorus pentoxide, preferably in an
organic solvent inert under the reaction conditions, such
Df~
-- 5
as aromatic hydrocarbons, preferably ben~ene, or
chlorina~ed hydrocarbons r e.~. chloroform or carbon
tetrachloride.
If the compounds of the formula /II/ are used in
the form of their acid addition salts, e.g. hydrogen
halides, perchlorates, etc., it is preferred to set free
the basic compounds from their salts before cyclization.
The liberation of the bases can for example be carried out
with a dilute aqueous solution of an inor~anic base, such
as an alkali metal carbonate, e.g. sodium carbonate,
potassium carbonate, an alkali metal hydroxide, e.~.
sodium hydroxide, potassium hydroxide, etc., in a ~.iater-
-i;nmiscible inert organic solvent, such as halogenated
hydrocarbons, e.g. dichloromethane, chloroform etc.
By the process according to the invention both
cis- and trans-compounds of the for.nula /I/ can be
prepared from the corresponding cis- and trans-compounds
of the formula /II/, respectively.
3y th- process according to the invention racemic
and optically active cornpounds of the formula /I/ can
equally be prepared. Starting from racemic compouncs,
racemic end products of the formula /I/ are obtained
which, if desired, can be resolved by conventional
techniques. From optically active starting compounds
directly optically active end products can be obtained.
The racemic or optically active compounds of the
formula /I/ can be converted into their acid addition
-- 5
scllts ;~ith an organic or inorganic acid.
T'ne salls are generally prepared in an inert
organic solvent, for examp1e in an aliphatic alcohol
havinT 1 to 6 carbon atoms, by dissolvinO the raCeMiC
or optically active compounds of the formula /1/ in said
solvent addin~ he correspondin T acid into the solution
while the p~ becomes slightly acidic /about pH 6/ ar.d
subsequently separatinT the acid addition salt obtained
from the re~ction mixture preferably by precipitatinO with
a water-immiscible organic solvent, such as diethyl ether.
If desired, the racemic or optically active
COmDO-In~S of the formula /I/ or acid addition salts there-
of nay be s~lbJected to further purification e.g. re-
crystall zation. The solvents used for recrystallization
a~e selec'el in accordanc- with the solubility and
crystallizability of the comDounds ~o be recrystalli7ed.
Th.e -ntihypoxial activi y of certain compounds
~itnin th-- scope of t'ne invention, par icllarly of
3~,17cL-Irans-derivatives was ~ested on T;he survival
time of mice, in normobaric hypoxia.
The test was carried out as follows:
Five male mice are placed into a 3-litre glass
cylinder through which a mixture of 96 3,/ nitrogen and
4 % oxygen is passed. The interval between placing the
mice into the cylinder and the deat'n of the animals is
measured. Animals livinO at least t~lice as long as the
average survival time of the untreated animals are
cor.sidered protected. The animals are treated in groups
of 10, administering an intraperitoneal dose of 50 m3./k,g.
of bodyweight 30 minutes before placing them into the ~lass
cylinder.
The results are set forth in the following ~able.
Table
-
~urvival time Protection
Compound
Average
min.
_
J+/-Trans-14-oxo-
15-ethoxycarbonyl-
E homo-eburnane
15/3 p,l7c~/ 8.3+1.1 +32 20
Control 6.3+1.45 - 0
Vincamine 7.1+1.30 +13 0
Of the compounds of the formula /I/ especially
the 3 ~,17c~-cis compounds are potent antidepressive agents.
The active ingredients of the formula /I/ or
pharmaceutically acceptable acid addition salts thereof
can be converted into pharmaceutical compositions for
parenteral or enteral administration by admixing them with
solid and/or liquid carriers and/or further adclitives
conventionally used in the preparation of pharmaceutical
compositions. As a carrier for example ~ater, gelatine,
JL~
lac~ose, starch, pectine, magnesium stearate, stearic acid,
talc, vegetable oils, e,g, peanut oil, olive oil, etc,
can be employed,
The compositions may be finished in the forrn of
solid, e.g. tablets, lozen~es, dragées, capsules, such as
hard gelatine capsules, suppositories, etc, or liquid,
e.g, oily or aqueous solutions, suspensions, emulsions,
syrups, soft gelatine capsules, injectable oily or aqueous
solutions or suspensions, etc. formulations, The quantity
of the solid carrier can be varied within a wide range
but preferably is between about 25 mg. and 1 g, The
pharrilaceutical compositions optionally contain also
conventional pharmaceutical additives, such as preservatives,
s'abilizing, wetting, emulsifying agents, salts ca?able
of adjusting the osmotic oressure, buffers, flai;ouring
agents, aroma aOents, etc. Optionally further phar~aceutical-
ly active compoun~s can also be present in the formulations.
lhe pharmaceutical cormpositions are ?ref-rably
manufactured in dosage units, suitable for ~he ~esired
route of administration, The pharmaceutical com?ositions
may be prepared by conventional techni~ues, which comprise
i`or example screening, admixing, granulating, pressing or
dissolving of the components, The compositions obtained
can be subjected to further operations conventionally used
in the pharmaceutical industry, for example sterilization;
Further details of the present invention are to be
found in the following Examples which are, however, by no
means intended to limit the scope of the protection sought,
Example 1
/+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane
/3 ~L,17 ~/
From &00 mg. /1.90 mmoles/ of /+/~lo~-ethy~
/2',2'-diethoxycarbonylethyl/-1,2,3,4,6,7~12bC~-octahydro-
indolo/~,3-a7quinolizine hydrochloride prepared according
to the Belgian patent specification No. 883,576 the base
is liberated in 25 ml. of dichloromethane with 10 ml. of a
10 % aqueous sodium carbonate solution. After separation
the extraction is repeated by 5 ml. of dichloromethane.
The organic phases are collected, dried over solid,
anhydrous magnesium sulfate, filtered and from the filtrate
the solvent is eliminated by distillation in vacuo.
The oily residue is dissolved in 15 ml. of absolute
benzene, to the solution ~58 mg. /2.3 mmoles/ of potassium
tert.-butylate are added and the reaction mixture is
refluxed under nitrogen atmosphere for 20 minutes.
After cooling, under cooling with ice the reaction
mixture is neutralized to pH 6 with acetic acid and the
solvent is then eliminated by distillation in vacuo. The
evaporation residue is dissolved in 20 ml. of dichloro-
methane, the solution is shaken with 10 ml. of a 5 %
aqueous sodium carbonate solution to adjust the pH to 9~
After separation the extraction is repeated with a further
5-ml. portion of dichloromethane and the organic phase is
separated~ The combined organic phases are dried over
solid, anhydrous magnesium sulfate, filtered and from the
filtrate the solvent is eliminated by distillation in
- 10 - .
acuo.
960 mg. of an oily product are obtained, which is
then crystallized from 1.5 ml. of methanol.
480 mg. of the aimed compound are obtained.
Yield: 66.5 %.
Melting point: 143 to 144 C /ethanol/.
I~ spectrum /KBr/: 1738 /ester/, 1690 cm 1 /lactame/.
Mass spectrum /m/e, %/: 380 /M+, 100/, 379/35/,
363/20/, 352/17/, 351/26/, 335/12/, 323/9.1/, 307/55/,
252/35/, 237/17/.
lH-NMR sepctrum /CDC13, ~ /: 8.52-7.35 /4H, m,aromatic/,
4.31 /2H, q, J=7, 2Hz, OCH2/, 4.08 /lH, m, 3-H/,
3.75 /lH, d, J=ll Hz, 15-H/, 1.34 /3H, t, J+7.6 Hz, OCH2CH
0.91 /3H, t, J+8.1 Hz, CH2CH3/.
Example 2
/~/-Trans-14-oxo-15-ethoxycarbonyl-E-homo-eburnane
/3 d~,17o_/
400 mg. /0.94 mmoles/ of /+/-1~ -ethyl-l~ -/2',2'-
-diethoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b p -octahydro-
indolo/2,3-a7quinolizine obtained as a by-product in
Example 1 of the Belgian patent specification ~o. 883,576
are dissolved in 10 ml. of absolute benzene, then 125 mg.
/1.11 mmoles/ of potassium tert.-butylate are added to the
solution. The reaction mixture is refluxed under nitrogen
atmosphere for 20 minutes.
The pH of the reaction mixture is adjusted to 6
with acetic acid under cooling with ice. Tne solvent is
evaporated in vacuo, the residue is dissolved in 10 ml.
39
11 --
of dichloromethane and the solution is shaken with a 5 %
aqueous sodium carbonate solution to adjust the pH to 9.
The extraction is repeated with a further 5-ml portion
of dichloromethane, and the combined organic phases are
dried over solid anhydrous ma~nesium sulfate, filtered
and from the filtrate the solvent is eliminated by
distillation in vacuo. 300 mg. of an oily product are
obtained which is then crystallized from 2 ml. of ethanol.
260 mg. of the aimed compound are obtained.
Yield: 73.0 %.
Meltin~ point: 173 to 175 C /ethanol/.
IR spectrum /KBr/: 2750-2700 /Bohlmann/, 1735 /ester/,
1680 cm 1 /lactame/.
Mass spectrum /m/e, %/: 380 /M~, 100/, 379/38/, 363/14/,
352/11/, 351/16/, 335/11/, 323/5.5/, 307/34/...
lH-NMR spectrum /CDC13, ~ /: 8.56-7.24 /4H, m, aromatic
protones/, 4.32 /2H, q, J=7.6 Hz, OCH2/, 4.08 /lH, dd,
Jl= 13-6 Hz J2=2.7 Hz, 15-H/, 3.41 /lH, s~ 3-H/,
1.35 /3H, t, J=7, 6Hz, OCH2CH3/, 0.74 /3H, t, J=6Hz,
CH2CH3/
Example 3
/+/-Cis-14-oxo-15-ethQxycarbonyl-E-homo-eburnane
/3dL,17c~/
From 634~5 mg. and 698.0 mg. /1 mmole/ of /+/-1~-
-ethyl-l ~-/2',2',4',4'-tetraethoxycarbonylbutyl/-
-1,2,3,4,6,7 t 12,12bO~-octahydroindolo/2,3-a7quinolizine
hydrochloride and hydrogen perchlorate, respectively,
the corresponding base is liberated with 10 ml. of a 10 %
- 12 -
aqueous sodium carbo~late solutlon in 25 ml. of dichloro-
methane. The organic phases are combined, dried over
solid, anhydrous magnesium sulfate, flltered and from the
filtrate the solvent is distilled off in vacuo.
The residual oil is dissolved in 15 ml. of
absolute benzene, then 145 mg. /1.3 mmoles/ of potassium
tert.-butylate are added to the solution and the reaction
mixture is refluxed under nltrogen atmosphere for half an
hour. The reaction mixture is cooled down and its pH is
adjusted to 6 with acetic acid. The solvent is distilled
off in vacuo, the residue is dissolved in 10 ml. of
dichloromethane, the solution is alkalized with 10 ml. of
a 5 % aqueous sodium carbonate solution to oH 9 and is
then extracted with a further 5-ml. portion of aqueous
dichloromethane. The organic phases are collected, dried
over solid, anhydrous magnesium sulfate, filtered and
from the filtrate the organic solvent is eliminated by
distillation in vacuo. Tne residual oily oroduct is
crystal]ized from 1 ml. of ethanol.
307 mg. of the aimed compound are obtalned.
Yield: 80.& /0.
~lelting point: 143 to 144 C /ethanol/
Example 4
/ /-Cis-14-oxo-15-ethoxycarbonyl-~-homo-eburnane
/30_,17d~J
The procedure described in Example 3 is followed
starting from 870 mg. /1 mmole/ of /~/-ld_-ethyl~
/2',2',4',4',6',6'-hexaethoxycarbonylhexyl-1,2,3,4,6,7,12,-
12b ~octahydroindolo~,3-a7quinolizine hydrogenper-
chlorate prepared according to the Belgian patent
specification No. 883,576,
264 mg. of the aimed compound are obtained,
Yield: 69.5 %.
Melting point: 142 to 143 C /ethanol/.
Example 5
/+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane
/3 ~,17 ~ hydrochloride
200 mg. of /+/-cis-14-oxo-15-ethoxycarbonyl-E-homo-
-eburnane/3 ~,170~/ are dissol~ed in a mixture of 3 ml.
of dichloroethane and 2 ml, of ethyl alcohol and the pH of
the solution is adjusted to 2 with hydrochloric acid in
ethanol. The reaction mixture is evaporated to dryness and
the evaporation residue is crystallized from 1.5 ml. o
ethanol.
165 mg. of the aimed compound are obtained.
Yield: 75.2 ',~,.
~lelting point: 204 to 207 C /toluene/.
Example 6
/+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane
/3 dL,17 ~J
300 mg. of /+/-lo~rethyl-l ~-/2'-carboxy-2'-ethoxy-
carbonylethyl/-1?2,3,4,6,7,12,12ba~-octahydroindolo-
/ 2,3-a7quinolizine prepared according to Example 5 o;r
Example 6 of the F3elgian patent specification No. 883,576
are suspended in 2 ml, of absolute benzene and 2 ml. of
phosp'norus oxychloride are added to the suspension under
_ 14 -
cooling with ice, Th- reaction mixture is then refluxed
for 8 to 9 hours, with stirring.
The reaction mixture is cooled and is evaporated
to dryness in vacuo The residue is triturated with 2 ml.
of ice water, its pH is adjusted to 9 wi~h a lO % aqueous
sodium carbonate solution and the organic substance is
extracted with three 2-ml. portions of dichloromethane.
The combined organic phases are dried over solid, anhydrous
magnesium sulfate, filtered and from the filtrate the
solvent is eliminated by distillation in vacuo. 226 mg.
of an oily product are obtained, which is then crys-
tallized from 0.5 ml. of ethanol.
156 mg. of /~/-cis-14-oxo-15-ethoxycarbonyl E-
-homo-eburnane/3 d~,17d~/ are obtained.
Yield: 54,3 %,
~lelting point: 142 to 144 C /ethanol/.
IR spectrum /K3r/: 1725 /ester C0/, 1680 /lactame C0/.
