Note: Descriptions are shown in the official language in which they were submitted.
25~7
The present invention relates to derivatives of 1,2,3,3a,8,8a-hexa-
hydropyrrolo[2,3-b~indole and their salts with pharmaceutically acceptable
acids and to pharmaceutical compositions containing the same.
Useful analgesic activity is displayed by 1,2,3,3a,8,8a-hexahydro-
pyrrolo[2,3-b]indole compounds having the formula I
R H R
and their salts with pharmaceutically acceptable acids wherein: Rl is selected
from the group consisting of hydrogen, hydroxy, Cl-C12 alkoxy and C2-C12
~` alkenyloxy; R2 is selected from the group consisting of hydrogen and Cl-C12
`~ 10 alkyl; R3 and R4 are the same or different and are selected from the group con-
sisting of hydrogen, Cl-C12 alkyl and C2-C12 alkenyl-
Of these compounds, compounds in which Rl is hydrogen, hydroxy,
methoxy or ethoxy, R2 is methyl and R3 and R4 are hydrogen or methyl are known.
This application is directed to pharmaceutical compositions containing a suit-
:,:
able carrier and, as active substance, a compound of formula I in which Rl is
hydrogen, hydroxy, methoxy or ethoxy, R2 is methyl and R3 and R4 are the same
~- or different and are hydrogen or methyl, or a pharmaceutically acceptable salt
. .
thereof.
Novel compounds of formula I are the subject of a divisional applica-
tion.
- ~ Examples of pharmaceutically acceptable salts of the compounds of
formula I are those formed with both inorganic acids, for instance hydrochloric
-
~ ~ ~3 1-
. . .
.
. . ... .. ~ ~.
z~
acid, hydrobromic acid, sulphuric acid, and with organic acids such as for
instance benzoic acid, p-hydroxybenzoic acid, salicylic acid, tartaric acid
(both laevorotatory and dextrorotatory and racemic), mesotartaric acid, fumaric
acid, maleic acid, citric acid, gentisic acid, hydroxyphthalic acid, creatinin-
sulphuric acid and succinic acid.
Compounds having the above mentioned formula I include both the
optically active isomers and their mixtures. In the compounds of the above
formula I the substituent R2 in position 3a and the hydrogen atom in position
8a are in the cis configuration i.e. on the same side with respect to the
plane of the heterobicyclic ring.
Of particular importance are the salts of eseroline 1,3a,8-trimethyl-
1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol, especially the (-) eseroline
[(3aS,8aR)-1,3a-8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol],
with pharmaceutically acceptable acids, not including chloride, bromide,
sulphate, picrate, methopicrate, benzoate, methiodide, and ethiodide salts.
Of particular interest are the salts of eseroline with salicylic
acid, tartaric acid (both laevorotatory and dextrorotatory and racemic),
mesotartaric acid, p-hydroxybenzoic acid, fumaric acid, maleic acid, citric
acid, gentisic acid, hydroxyphthalic acid, creatininsulphuric acid and succinic
acid.
:~ `
5~7.
The alkyl, alkoxy, alkenyl and alkenyloxy groups of the described
compounds can have either a linear or a branched chain of carbon atoms.
Pre:Eerably the alkyl and alkoxy groups contain from 1 to 6 carbon atoms, in
particular from 1 to 4 carbon atoms while the alkenyl and alkenyloxy groups
contain preferably from 2 to 6 carbon atoms, in particular from 2 to 4 carbon
atoms.
Specific examples of new compounds or specific active substances of
the pharmaceutical compositions in accordance with the inven~ion will now be
given by way of example. They are: ~1) 1,8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indol-5-ol; ~2) 1,3a-dimethyl-8-ethyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indol-5-ol; ~3) 1,3a,8-triethyl-1,2,3,3a,8,8a-hexa-
hydropyrrolo[2,3-b]indol-5-ol; (4) 1-ethyl-8-dimethyl-1,2,3,3a,8,8a-hexa-
~ hydropyrrolo[2,3-b]indol-5-ol; ~5) 1,8-dimethyl-3a-ethyl-5-methoxy-1,2,3,3a,
; : 8,8a-hexahydropyrrolo[2,3-b]indol-5-ol; ~6) 1,8-dimethyl-3a-propyl-1,2,3,3a,
8,8a-hexahydropyrrolo[2,3-b]indol-5-ol;
;
., .
: ''
.
' :
:~
.-
-' ~ ' , ' . '. ~ '
-
7) 1,3a,8-trimethyl-5-propyloxy-1,2,3,3a,8,8a-hexahydro-
pyrrolo [2,3-b~ indol-5-ol;
8) 3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]
indol-5-ol (1,8-dinor-eseroline);
9) 1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol (H8-nor-eseroline);
10) 1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo
~2,3-b~ indol-5-ol;
11) 1-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo
~2,3-b~ indole;
12) 1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo
~2,3-b] indol-5-ol (eseroline);
13) 1,3a,8-trimethyl-5-methoxy-1,2,3,3a,8,8a-hexahydropyrrolo
[2,3-b~ indol-5-ol (eseromethole);
1~) 1,3a-8-trimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo
~2,3-b~ indol-5-ol (eserethole);
15) 1,3a-8-trimethyl-1,2,3,3a,8,8a.-hexahydropyrrolo
~2,3-b~ indole (desoxyeseroline);
- 16) 3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrol ¦2,3-b~
indole (desoxy-Nl-noreseroline);
17) 1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
: indole (desoxy-N8-noreseroline);
18) 3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indole (Nl,N~-dinor-desoxyeseroline);
19) 3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol (Nl-nor-eseroline);
as well as the salts o~ the compounds iormed with pharmaceutic-
cally acceptable acids, in particular those re~erred to above.
' ' . - .
-
-- 5 --
Amon~ the compounds previously mentioned, the first eleven arenew compounds whereas the others are;known per se, but their use
for therapeutic purposes or as active substances in pharmac-
euticals is unknown. In particular eseroline is described
in J.Chem.Soc.lOlJ 978 (1912); eseromethole and eserethole
in J.A.C.S., 57, 755 (1935); desoxyeseroline in J.A.C.S.,
57, 755 (1935), in C.A., 63, 18059a (1965), in Chem.Ber.108(1),
208 (1975) and in C.~., 82, 11978n; desoxy-Nl-noreseroline
in C.A., 63, 18059a (1965) and in Tetrahedron Letters, 52,
4539 (1970) and in J.A.C.S., 56, 1797 (1934); desoxy-N8-
noreseroline in Ann.520, 11 (1935); Nl,N8-dinor-desoxyeseroline
in Ann.539, 213 (1939); Nl-nor-eseroline in Chem.and Ind.87
(1965).
In addition, hydrochloride and picrate of (-) eseroline
for instance, are described in J.Chem.Soc.)101, 978 (1912),
hydrobromide and sulphate of (-) eseroline in Bull.Soc.Chim.~,
; 17, 2~0 (1915) and benzoate of (-) eseroline is described in
Ann.,~01, 350 (1913).
As active substances in pharmaceutical compositions, the
salts of the compounds o~ ~ormula (I) with pharmaceutically
acceptable acids are preferred over the ~ree bases, since the
free bases can be easily oxidised, for instance in aqueous
solution, giving degradation products having a quinone type
structure and thereby losing its pharmacological proper-ties.
~he easy oxidation and degradation of the ~ree bases of ~,
the invention and/or of the corresponding salts can be
eliminated by using special pharmaceutical techniques, for
. .
.: .
~ ~: ~ i - . . :
' . ' ., , ~ - '~
:: . :
~5~57
instance keeping the pll value of the solutions 1OWJ or protecting the bases and
their salts against attack from atmospheric oxygen, or by the addition of
compounds which can be oxidized more easily and so act as antioxidant agents.
Particularly preferred active substances for pharmaceutical composi-
tions are both isomers of eseroline, preferably the ~-) eseroline and in
particular the salts of (-) eseroline, such as for instance salicylate,
fumarate, tartrate.
The derivatives of the 1,2,3,3a,8,8a-hexahydropyrrolo~2~3-b]indole
in accordance with the invention can be prepared by the following processes,
1 10 (a) by reductive cyclization a compound of formula II
Rl lR2
C - C~l2 II
N ~ ~0 / 12
R
'~ R3
: wherein Rl, R2, R3 and R4 are as referred to above or
(b) by o~idative cyclization of a compound of formula III
R 1 3
~ CH2 CH2 III
k N~ H
~ R4 R3
; or a salt thereof wherein:
.
'~
..
-- 7 --
Rl is hydrogen or hydroxy, R3 and R4 are the same, and as
referred to above but not hydrogen. Thus compounds of formula
(I) are obtained wherein Rl is hydrogen or hydroxy and R3=R4
which are Cl-C12 alkyl or C2 C12 a Y ;
c) by reduction of a compound of formula (IV)
R~
(IV)
R4 R3
wherein:
Rl, R2, R3 and R4 are as defined above;
or
d) by hydrolysis of a compound of formula (V)
R
~ J (v)
: R4 R3
wherein:
R2, R3 and R4 are as previously mentioned and R"l is an acyloxy,
carbamoyloxy or alkylcarbamoyloxy group. Thus compounds of
formula (I) are obtained wherein Rl is a hydroxy group which
can, if desired, undergo etherification to give compounds of
formula (I) wherein Rl is Cl-C12 alkoxy or C2-C12 alkenyloxy; or
e) by reaction of a compound of formula (VI)
1 ~ T CN2-cN2NNR3 (Vl)
- 8 -
wherein
Rl, R3 and R4 are as described previously, first with a halide
of alkylmagnesium ~MgX wherein R is a general Cl-C6 alkyl, and
with an alkyl halide R2X, wherein R2 is Cl-C12. Thus compounds
of formula (I) are obtained wherein R2 is Cl-C12 alkyl.
In addition compounds of formula (I) can be produced by
the transformation of other compounds of formula (I) having
different Rl, R2, R3 and/or R4 substituents and/or by salifying
a compound of formula (I) with a pharmaceutically acceptable
acid, and/or by separating a mixture of optical enantiomers
of formula (I) into the single enantiomers.
l'he reductive cyclization of the compound of formula (II)
is preferably carried out using sodium in an aliphatic low
molecular weight alcohol, for instance methanol or ethanol.
Metal sodium is added in small portions to an alcoholic
solution ofthe compound of formula (II), preferably at
temperatures of about room temperature, at intervals of about
two hours. The resulting solution is then acidified with a
mineral acid, for ins-tance hydrochloric acid, and the alochol `
evaporated under reduced pressure. The solution is then made
alkaline, preferably by the addition of an inorganic base, for
instance an alkaline hydroxide. The product is then extracted
into a suitable organic solvent, for instance ethyl ether,
which is evaporated to dryness.
The oxidative cyclization of the compound of formula (III),
preferably salified with acids, for instance inorganic acids,
such as hydrobromic acid, is preferably carried out in aqueous
.
, .
_ 9 _
solution, using as oxidating agent an alkaline ferricyanide
for instance, potassium ferricyanide, in the presence of an
alkaline bicarbonate, for instance sodium bicarbonate. The
cyclisation is carried out under stream of inert gas, for
instance nitrogen, at a temperature of about the room
temperature.
The reduction of the compound of formula (IV) is preferably
carried out using a mixed hydride, for instance lithium alumin-
ium hydride The compourld of formula (IV) is refluxed in
a suitable organic solvent such as ethyl ether or tetrahydro-
furan.
The hydrolysis of the compound of formula (V) is prefer-
ably carried out by reacting with an alkaline hydroxide, ~or
instance sodium or potassium hydroxide, in a hydroalcoholic
solution, for instance hydroethanolic solution, in a stream of
hydrogen, or preferably nitrogen, at a temperature of about the
room temperature. The compounds of formula (I) produced by
the hydrolysis, have Rl as a hydroxy group. These can be
converted to compounds of formula (I) wherein Rl is Cl-C12
alkoxy or C2-C12 alkenyloxy by etheri~ication, preferably by
treatment with a corresponding Cl-C12 alkyl or C2-C12 alkenyl
tosylate or mesylate.
In the compound of formula (V) R"l is preferably methyl-
carbamoyloxy (C~3NHCOO-). When R"l is acyloxy, the acyl
group is preferably a Cl-C12 aliphatic acyl group, or a
benzoyl group or a p-hydroxybenzoyl group.
All the compounds of formula (II), (III), (IV) and (V) can
- ~ ' , ' '
: , '
'
10 -
be either optically active or racemic, and thus the compounds
of formula (I) obtained by the previously described reactions
are also either optically active or racemic. As mentioned
above, a compound of formula (I) can be transformed into
another compound of formula (I) having different Rl, R2, R3
and/or R4 substituents and such transformation can be carried
out according to any of the methods used in organic chemistry.
For instance a compound of formula (I) wherein Rl is
hydrogen or hydroxy and R3 and R4 are both hydrogen, can be
transformed into a compound of formula (I) wherein Rl is
hydrogen orhydroxyJ R3 is hydrogen and R4 is Cl-C12 alkyl
or C2-C12 alkenyl by reaction of one of its salts, for instance
hydrochloride or hydrobromide, with an alkyl halide having
formula R4X, wherein R4 is Cl-C12 alkyl or C2-C12 alkenyl
and X is halogen, preferably iodine. The reaction is carried
out in an alcoholic solvent, for instance ethyl alcohol, in
a sealed tube, by boiling the reactLon mixture on water bath
for about 7 hours. By the same method but with a reaction
time of about 15 hours, a compound of formula (I) wherein Rl
is hydrogen or hydroxy, R4 is hydrogen and R3 is Cl-C12 alkyl,
can be transformed into the corresponding compound of formula
(I) wherein R3 and R~ are both Cl-C12 alkyl.
A compound of formula (I) wherein Rl is Cl-C12 alkoxy can
be transferred into the corresponding compound of formula (I)
wherein Rl is hydroxy by heating with anhydrous aluminium
chloride in an inert solvent such as for instance petroleum
ether, according to the procedure described in J.Am.Chem.Soc.
57, 1935, p.757. Alternatively, it can be treated with
.
: . i
halogenhydric acids such as hydrobromic acid, according to the
method referred to for instance in Chemistry and Ind., 1965,
page 87.
The reaction of a compound of formula (I) with a pharmac-
eutically acceptable acid to form a salt is carried out using
conventional methods, for instance a solution of the base of
formula (I) is added to a solution of the pharmaceutically
acceptable acid in the same solvent, that can be for instance
ethyl ether, and the salt is precipitated, or a solution of
the pharmaceutically acceptable acid in a given solvent, e.g.
ethanol is added to a solution of the base of formula (I)
in a different solvent, for instance ethyl ether, and again
the salt is precipitated. In both these cases the salification
reaction can be carried out in a stream of nitrogen and is
preferably carried out at room temperature.
Also the separation of a mi~ture of optical enantiomers
into the individual enantiomers can be carried out according
to methods known in organic chemistry, for instance by reacting
the racemic compound of formula (I) with an optically active
acid, thus obtaining the two diastereoisomeric salts which can
then be separated from each other using their different
solubilities in various solven-ts.
Thus for instance the separation of racemic eseroline
into the two opticallaevorotatory and dextrorotatory enantiomers
can be carried out by adding, at room temperature, to a
solution of racemic eseroline in a low molecular weight
aliphatic alcohol, for instance ethanol or methanol, a solution
.
- ::
. ~ ''" '
~z~
- 12 --
of tartaric dextrorotatory acid in the same solvent, thus
obtaining crystallizing and precipitating the acid tar-trate
of (+) eseroline((3aR, 8aS) 1,3a,8-trimethyl-1,2,3,3a,8,8a-
hexahydropyrrolo [2,3-b~ indol-5-ol).
The acid tartrate oflaevorotatory isomer (-j of eseroline,
(i.e. the 3aS,8aR-derivative) remains in solution in the
alcoholic mother liquor, from which free (-) eseroline can be
obtained by evaporating the solvent at a reduced pressure,
alkalinizing the residue, extracting the (-) eseroline into
an organic solvent, for instance, ethyl ether and evaporating
this solvent at a reduced pressure. Free (~) eseroline
can be obtained from the a.bove-mentioned salt using a similar
method.
The compound of ~ormula (II) can be prepared by reaction
of a compound of ~ormula tVII)
(Vll)
R
wherein: .
Y is an akaline metal, preferably sodium, and Rl,R2 and Rg
are as defined previously with a compound o~ formula (VIII)
X-C~2
CH2 (VIII)
.
; R
'
2~S7
- 13 -
wherein:
X is halogen, preferably bromine or chlorine, and R3 is as
defined previously.
The reaction between the compound of formula (VII) and
-the compound of formula (VIII) is preferably effected by
adding the compound of formula (VIII), for instance a chlor-
hydrate or bromhydrate, to a solution, cooled to 0-10C, of
the compound of formula (VII) in an organic solvent such as for
instance benzene, xylene or ethyl ether, in the presence of
a base, preferably triethylamine. The reaction mixture is
maintained at room temperature for some hours and then heated
under reflux for 1-2 hours. The solvent is evaporated and
the residue is treated with water and acidified e.g. with
hydrochloric acid or hydrobromic acid. An organic extraction
is carried out using solvent, Eor instance ethyl ether, and
after alkalinization e.g. with an alkaline hydroxide, i-t is
extracted again into an organic solvent, for instance e-thyl
ether, and the solvent is evapora-ted at a reduced pressure.
Alternatively the compound of :Eormula (II) can be obtained
by reaction of a compound of formula (VII) with a compound of
formula (IX)
X-CH2
(IX)
wherein:
X is halogen, preferably chlorine or bromine, thus obtaining
a compound of formula (X)
,
:
5~
'C~,~ CH2-cH2-x ( X )
N~C~o
R~
wherein:
Rl, R2, R4 and X have the previously mentioned meanings, and
by subsequent reaction of a compound of formula (X) with an
amine of formula R3NH2, wherein R3 is as defined above.
The reaction of a compound of formula (VII) and a compound
of formula (X) can be carried out using approximately the same
reaction conclitions as described above for the reaction between
a compound of Eormula (VII) and a compound of formula (VIII).
The reaction between a compound of formula (X) and an
amine of formula R3NH2 can be effected by heating the reactants
in a closed tube without solvents, preferably using 2 moles
of amine per one mole of the compound of formula (X). The
compound of :Eormula (VII) can be pre~pared according to P.L.
Julian and J.Pike, J.A.C.S., 57, 563 (1935) and J.A.C.S.,` 57,
755 (1935) preferably, replacing metal sodium, used by these
authors, by sodium hydride. The compound of formula (III),
wherein Ri is hydrogen or hydroxy and R3 and R4, are the same,
and are Cl-C12 alkyl or C2-C12 alkenyl, can be obtained by
reaction of a compound of formula (XI)
Rl ~ H2_cH2_N_cH_c~H5 (XI)
OR I 2
6 5
- wherein:
;
, ~
;
.
,
~5~
- 15 -
R is a Cl C6 alkyl radical and Rl has any of the above
mentioned definitions with a Cl-Cl2 alkyl or C2-Cl2 alkenyl
halide, preferably iodide. The reactive is preferably effected
by maintaining the reactants in a closed tube at a temperature
of about 100C for a reaction time of about 2 hrs and
subsequently heating them with a halogenhydric acid, for
instance hydrobromic acid, thus obtaining the salt e.g. the
dibromhydrate of the compound of formula (III). The compound
of formula (XI) can be obtained according to J.Harley-Mason
and A.H.Mackson, J.Chem.Soc.3651 (195~).
The compound of formula (IV) can be prepared by reaction
of a compound of formula (XII)
~7~o (XII)
R~
wherein:
Rl, R2 and R~ are as defined above, with ammonium hydrate or
with an amine of formula NH2R3.
; The reaction is pre~erably carried out at a temperature
of about 50C and in a low molecular weight aliphatic alcohol,
e.g.methanol.
The compound of formula (XII) can be prepared according
to the method of P.Rosenmund and A.Sotiriou, Angew.Chemie 76,
187 (1964),
The compound of formula (~), in particular when R"l is
methylcarbamoyloxy, is known per se and can be prepared using
~ S ~
- 16 -
known methods (J.Prakt, Chem.116, 59 (1927)). The compounds
of formula (VI) are also described in literature, for instance
in Ann.Chem.500, 42 (1933), Ann.Chem.516, 76 (1935), Ann.Chem.
516, 81 (19~5), Ann.Chem.520, 11 (1935).
The described compounds have an analgesic activity,as
shown for instance by the fact that they are active in the
mouse tail pinch test, carried out according to the technique
described by P.Haffner Deutsche Med.Wecherschr.,55, 731 (1929)
and in the mouse hot plate test, carried out according to the
technique described by Eddy N.B.et al., J.Pharmacol.Exp.Ther.,
07, 385 (1953).
They are useful therefore for treating a variety of pains
such as those resulting from fractures.
The toxicity of these compounds is very low; for instance
`~ for salicylate of (-) eseroline the toxicity (LD 50) in a
mouse, as determined by the administration of a single oral
dose and ascertained on the seventh day from treatment, was
found to be 600 mg/Kg.
The compounds of the invention are active both parenterally
and enterally, ~or instance by mouth. The parenteral adminis~
tration is generally preferred.
" The doses (e.g. for salicylate of (-) eseroline are
preferably 2-20 mg (calculated on the free base) per dose given
from~l to 4 times a day if administered parenterally and 5-80 mg,
preferably 10-30 mg (calculated on free base), per dose given
1 to 4 times a day if administered orally.
Pharmaceutical compositions containing the compounds
~ , ' '.
.~
;
~.~.....
:~ ' .
. ~ -- - , '
s , ~ :
.:
. .
5~
- 17 -
object of the presen-t invention can be in the form of for
instance vials, vials for extemporary solution, lyophilized
vials, troches, pills, tablets, drops, syrups, supposi-tories,
or gelatinous capsules containing the active substance
possibly together with stabilizing or antioxidant substances
such as e.g. sodium pyrosulphite, ascorbic acid and suitable
carriers, for instance diluents, lubricants, bonding agents,
disintegrating agents, effervescents, dyes, edulcorating
agents, wetting agents etc.
Diluents for the vials can be for instance water and
physiological solutions. Diluents for the oral administration
of the product can be for instance lactose, dextrose,
saccha.rose, mannitol, sorbitol or cellulose. Lubricants can
be for instance silica, talc, stearic acid, magnesium stearate
or calcium stearate and/or polyethylene glycols.
Further, as mentioned above, the pharmaceutical composition
can contain bonding agents such as starches, gelatin, gum
arabic, gum tragacanth a.nd polyvinylpyrrolidone, disintegrating
agents such as alginic acid and alginates; effervescent agents,
dyes, edulcorating agents, wetting agents such as lecithins
and polysorbates, as well as any other pharmacologically
non-toxic carrier employed in conventional pharmaceutical
formulations.
The pharmaceutical preparations containing the compounds
are produced according to the usual methods.
The following examples are given by way of illustration
only.
- 18 -
Example 1
In this preparation, 2 g of (-) physostigmine dissolved
in 12 ml of ethyl alcohol were placed in a flask and a stream
of nitrogen passed through the solution to expel air. Then
10 ml of a solution of 10% sodium hydroxide (p/p) previously
de-aired was added, and the mixture maintained at room
temperature for about 4 hours, under a nitrogen stream.
27.5 ml of hydrochloric acid lN were then added and the
reaction mixture was poured into a separating iunnel. Then
100 ml o~ ethyl ether and sodium chloride were added until
the aqueous phase was saturated. The ether layer was washed
with a saturated aqueous solution of sodium chloride previously
de-aired. A~ter evaporation of the ethyl ether white crystals
of (-) eseroline were obtained which melted at 129C (yield
95%).
The ~ollowing compounds were obtained by a si~ilar method:
1,8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol;
1,3a-dimethyl-8-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b]
indol-5-ol;
1,3a,8-triethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol;
l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo
_ _
2 J 3-b indol-5-ol;
1,8-dimethyl-3a-propyl J 1 J 2 J 3 J 3a J 8,8a-hexahydropyrrolo [2,3-b]
indol~5-ol;
3a-methyl-1,2 J 3 J 3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol;
1 J 3a-dimethyl-1,2 J 3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
.
-
-
: ~ '
:.
-. . . , ~:
5~
- 19 -
1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~
indol-5-ol;
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b]
indol-5-ol;
3a,8-dimethyl-1,2,3,3a,8,8a-jexahydropyrrolo ~2,3-b] indol-5-ol;
Example 2
. _
A solution of (-) eseroline (1.5 g) in ethyl ether (100 ml)
de-aired wi-th a nitrogen stream, was added to a solution o~
salicylic acid (1.3 g) in ether (20 ml) with stirring. A
white crystalline solid was precipitated which was collected
by filtration, washed with a small quantity of ether and dried
under vacuum. Needle-like crystals of (-) eseroline salicylate
which melt at 178--180C (with slight decomposition) were
obtained.
The salts o~ the following compounds with salicylic acid
were prepared in a similar manner;
1,8-dimethyl-3a-ethyl-1,2,3,3a,8,8a-hexahydropyrrolo. [2,3-b~
indol-5-ol;
1,3a-dimethyl-8-ethyl 1,2,3,3a,8>8a-hexahydropyrrolo.~2,3-b~
indol-5-ol;
1,3a,8-triethyl-1,~,3,3a,8,8a-hexahydropyrrolo [2,3-.b~ indol 5-ol;
l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo
[2,3-b] indol-5-ol;
1,8-dimethyl-3a-ethyl-5-methoxy-1,2,3,3a,8,8a-hexahydropyrrolo
[2,3-b~ indol-5-ol;
1,8-dimethyl-3a-propyl-1,2,3,3a,8,8a-hexahydropyrrolo. [2,3-b]
indol-5-ol;
5~7
- 20-
1,3a,8-trimethyl-5-propy].oxy-1,2,3,3a,8,8a-hexahydropyrrolo
[2,3-b] indol-5-ol;
3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol
(1,8-dinor-eseroline);
1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indol-5-ol
(N8-nor-eseroline);
1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol;
l-ethyl-3a,8-~imethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indole;
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~
indol-5-ol (eseroline);
1,3a-8-trimethyl-5-,ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo
~2,3-b~ indol-5-ol (eseromethole);
1,3a,8-trimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo
[2,3-b] indol-5-ol (eserethole);
1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b] indole
(desoxyeseroline);
3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indole
( desoxy-Nl -noreseroline);
1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo l2,3-b] indole
(desoxy-N8-noreseroline);
3a-methyl-1,2,3,3a,8,8a-hexahydropyrrolo ~2,3-b~ indole
(Nl,N8-dinor-desoxyeseroline);
3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo [2,3-b~ indol-5-ol
(Nl-nor-eseroline).
,
', .:
57
Ex~mple 3
A solution of (-) eseroline (0.005 moles) in ethyl ether
(50 ml) was added to a solution of fumaric acid (0.006 moles)
in ethanol (30 ml) under a nitrogen stream.
The white precipitate obtained was collected by filtration
and dried, and whi-te cyrstals of fumarate of (-) eseroline
were obtained which after recrystallization from ethyl alcohol
melted at 197-199C with decomposition.
The salts of all the compounds listed in Example 2 with
fumaric acid were prepared in a similar manner.
Example ~
A de-aired solution of (-) eseroline (0.005 moles) in
ethyl ether (50 ml) was added to a solution of (~)-tartaric
acid (0.006 moles) in ethanol (30 ml).
The resulting precipitate was collected by filtration and
re-crystallized from ethyl alcohol. The salt of the (~)
tartaric acic with (-) eseroline was obtained, m.p. ]97-200C
(decomposition).
The salts of all the compounds listed in Example 2 with
tartaric acid were prepared in a similar manner.
Example 5
~- To a solution of 5-ethoxy-1,3-dimethyl-3-(~ -ethylamino-
ethyl)-indolinone (5 g) in absolute ethanol (500 ml), metal
sodium (20 g) was added over a period of two hours. After the
sodium dissolution, de-aired water (200 ml) was added cautiously
to the cooled solution and ethyl alcohol removed by distillation
under vacuum. The residue was then repeatedly extracted into
:
: . ., ' ' :
.
' ~
~ ' . ' ,
- 22 -
ethyl e-ther and -the ether extracts evaporated to dryness give
(+)-l-ethyl-3a,8-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydro-
pyrrolo ~2,3-b~ indole which was puri~ied by distillation
under vacuum (4 g). This latter compound (4 g) was added to
a solution obtained by dissolving (+) tartaric acid (2.~ g) in
ethyl alcohol (30 ml). The mixture was added to some ethyl
ether and left overnight. Crystalline masses separated out
which were ~iltered and ~ound to melt at about 150-160C.
A~ter several crystallizations ~rom ethyl alcohol containing
tartaric acid needle-like colourless crystals o~
(+)-l-ethyl-3,3a,8-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydro-
pyrrolo ~2,3-b] indole-bitartrate were obtained (1.6 g).
The alcoholic filtrates were evaporated and a residue
obtained which was treated with aqueous sodium hydroxide and
extracted twice with ether. The ether extracts were concen-
trated to dryness and the residue d:istilled under vacuum.
A colourless oil was obtained consisting o~ (-)-1-ethyl-3a,
8-dimethyl-5-ethoxy-1,2,3,3a,~,8a-hexahydropyrrolo ~2,3-b]
indole (2.6 g). To a solution of this latter compound (2.6 g)
in petroleum ether (20 ml) aluminium trichloride (4 g) was
added. The mixture was heated under reflux on a water bath
~or about 12 hours and the petroleum ether was removed by
decanting, leaving a crystalline mass which was decomposed by
treatment with ice. The aqueous solution obtained was trea-ted
with sodium bicarbonate and repeatedly extracted into ethyl
ether. The residue obtained a~ter removing the solvent was
distilled under high vacuum and the oil obtained was dissolved
in ethyl ether-petroleum ether ~rom which needle-like crystals
o~ (-)-l-ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo
. .
'' ' ' ` ' :
'
. ~ . . .
5~5~
- 23 -
[2,3-b~ indol-5-ol were obtained.
Example 6
A mixture o~ ethyl iodide (2 moles) and o~ dibenzyliden-
derivative of 2-methyl-2-(3,6-dimethoxyphenyl)-butyl-1,4-
diamine (1 mole) was heated to 100C for about 2 hours in a
closed tube. The solid o~tained was extracted into aqueous
ethanol, the solvent was evaporated and the residue dissolved
in diluted hydrochloric acid. An extraction into ethyl ether
was carried out and the benzaldehyde ~ormed by extraction with
ethyl ether was removed. The aqueous phase was then saturated
with potassium carbonate and extracted again wi-th ethyl ether.
N,N-diethyl-2-(3,6-dimethoxy-phenyl)-2-methyl-butyl-1,
~-diamine (4 g) was obtained by evaporating the solvent and
distilling under vacuum. This was dissolved in hydrobromic
acid having a density o~ 1.49 (25 ml) and the solution was
heated under re~lux for about 1 hou:r, cooled and treated with
a mixture o~ propyl alcohol and ethyl ether. The dibromhydrate
obtained by ~iltration (1.3 g) was dissolved in water (75 ml)
and mixed with an aqueous solution obtained by dissolving
potassium ~erricyanide (1.95 g) and sodium bicarbonate (1 g)
in water (75 ml). The reaction mixture was extracted several
times into ethyl ether and the ether extracts were evaporated
to dryness. Raw (~) 1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-
hexahydropyrrolo ~2,3-b] indol~5-ol was obtained, which was
puri~ied by crystallization or by sublimation under high vacuum.
To a solution of the racemic compound thus obtained (0.5 g)
in anhydrous ethanol (40 ml) ethyl p-toluenesulphonate was
.
.. . :
.,
~ .
.
5~,
- 2~ _
added together with a solution of metal sodium (0.1 g) in
absolute ethanol (10 ml). The residue obtained after removing
the solvent was treated with aqueous diluted sodium hydroxide
and extracted several times into ethyl ether. By evaporation
of the ether extracts the racemic mixture of (+) and (-)
1,8-diethyl-3a-methyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo
~2,3-b~ indole was obtained, which was separated into the
individual (~) and (-) isomers by the procedure described in
the previous example. By treatment of the (-)-1,8-diethyl-3a-
methyl-5-ethoxy-1,2,3,3a,8,9a-hexahydropyrrolo [2,3-b~ indole
thus separated with aluminium chloride in petroleum ether,
following the procedure described in the previous example,
one obtains (-)-1,8-diethyl-3a-methyl-1,2,3,3a,8,8a-hexahydro-
_ _
pyrrolo 2,3-b indol-5-ol.
Exam~le 7
A solut iOII of (~)-3a,8-dimethyl-2,3,3a,8a-tetrahydrofuro
~2,3-b~ indolin-2-one (5 g) in ethyl alcohol (100 ml) was
mixed with ethylamine (excess 20%) and heated to 50C for some
hours. By evaporation of the solvent, (~)-l-ethyl-3a,
8-dimethyl-2-oxa-pyrrolo ~2,3-b~ indole (3 g) was separated,
which was suspended in anhydrous tetrahydrofuran (100 ml) and
treated with a slight excess of lithium, aluminium hydride. The ~,
reaction mixture was first heated under reflux with stirring
for about 2 hours, and then cooled and decomposed by treatm,ent ``
:, , .
with water. The ether phase was separated, dried and evaporated
to dryness. Thus (~ ethyl-3a,8-dimethyl-1,2,3,3a,8,8a-
hexahydropyrrolo [2,3-b~ indole (2.5 g) was obtained. ~`~
~ ;.
~ - - - , . . . . .
:
;: '' ' ` . ' ' " ~ ~ , '
.,
.
, ' .: , `- ~ : "~ ,
~ 25 -
Example 8
. .
To an ether solution of ethyl magnesium iodide obtained
~rom magnesium (2 g), ethyl iodide (12.8 g) and ethyl ether
(20 ml) 5-ethoxy-3-methy1-triptamine (5.8 g) was added in
small portions. The reaction mixture was heated to 100C
with stirring to fully evporate the ethyl ether. Then methyl
iodide (15 g) was added over a period of about 3 hours.
After adding some benzole and ethyl ether to dissolve the
excess of methyl iodide, the reaction mixture was treated
with diluted acetic acid under cooling conditions. The
aqueous phase was cautiously alkalinized with sodium hydroxide
and repeatedly extracted with ethyl ether. The ether extracts
were evaporated a~d the residue oil was distilled under vacuum
Thus (~) -1,3a-dimethyl-5-ethoxy-1,2,3,3a,8,8a-hexahydropyrrolo
[2,3-b~ indole was obtained which was converted into -the
corresponding (-~)-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo
[2,3-b~ indol-5-ol, by treatment wit;h aluminium trichloride
in petroleum ether using the same procedure described in
Example 5.
~xample 9
Tablets with a weight of 200 mg and containing 25 mg of
active substance, calculated as free base, have been prepared
as follows:
(composition for 10,000 tablets)
(~) eseroline hydrogentartrate g 587
lactose g 893
mais starch g 450
talc powder g 50
magnesium stearate g 20
~ 5~
- 26-
Example 10
A pharmaceutical composition, that can be injected, has
been prepared by dissolving 10 mg of (-) eseroline salicylate
in 2 ml of sterile water or sterile physiological solution
containing sodium pyrosulphite (2%).
It is noted that eseroline in some cases and with certain
dosages cou]d give rise to an activity of cholinomimetic type.
This possible undesired effect is not due to eseroline itself,
but to an oxidation product, rubrosine, whichforms more easily
in an alkaline environment. To avoid this undesired effect
in those few cases where it might appear, a very small quantity
of atropine or some other muscarinic blocking agents can be
included in the pharmaceutical preparations which would annul
the cholinomimetic action without af~ecting the analgesic
action of the product.
~.
'
