Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~2S727~
-- 1 --
This invention relates to new indole derivatives
having valuable pharmacological properties.
It is an object of this invention to provide new
compounds having useful pharmacological proper-ties.
These objects have been achieved by providing
indole derivatives of the general formula I
Ind-A-N ~--L
~ Ar
~257273
in which Ind is a 3-indolyl radical which can ~e substituted
once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-
alkyl, OH, F, Cl, Br, CF3 and/or CN or by a methylenedioxy
group, A is ~(CH2)n~, n is 3, 4 or 5, Ar is a phenyl group
which is unsubstituted or is substituted once or twice by
alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br,
CF3 and/or CN or by a me-thylenedioxy group, and the two
radicals L are each H or together are a C-C bond, and in
which the alkyl groups each have l - 4 C atoms, and their
physiologically acceptable acid addition salts.
In the following text, for reasons of simplicity,
the group -N ~ L is denoted "Q", so that
the formula I can also be written in the form Ind-A-Q-Ar.
It was found that the compounds of the formula I
and their physiologic~lly acceptable acid addition salts have
valuable pharmacological properties. Thus, in particular,
they exhibit effects on the central nervous system,
especially dopamine-stimulating (anti-parkinsonism) effects.
Specifically, the compounds of the formula I induce
contralateral turning behavior in rats with
~;Z 57:273
hemiparkinsonism (which may be demonstrated by the method of
Ungerstedt et al., Brain Res. 24, (1970), 485-493) and they
inhibit the binding of tritiated dopamine agonists and
antagonists to striatal receptors (which may be demonstrated
by the method of Schwarcz et al., J. Neurochemistry, 34,
(1980), 772-773 and Creese et al., European J. Pharmacol.,
46, (1977), 377-381). In addition, the compounds inhibit the
linguomandibular reflex in the anaesthetized rat (which may
be demonstrated by methods derived from Barnett et al.,
European J. Pharmacol. 21, (1973), 178-182, and from Ilhan et
al., European J. Pharmacol. 33, (1975) 61-64). Moreover,
analgesic effects occur.
Thus, compounds of the formula I and their
physiologically acceptable acid addition salts can be used as
active compounds in medicaments and also as intermediate
products for the preparation of other active compounds in
medicaments.
The invention relates to the indole derivatives of
the formula I and their physiologically acceptable acid
addition salts.
In the radicals Ind and Ar, alkyl is preferably
methyl, but is also ethyl, n-propyl, isopropyl, n-butyl,
lZ~q~73
isobutyl, sec.-butyl or tert.-butyl. O-Alkyl is preferably
methoxy, but also ethoxy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, sec.-butoxy or tert.-butoxy. S-Alkyl is
preferably methylthio, but is also ethylthio, n-propylthio,
i~opropylthio, n-butylthio, isobutylthio, sec.-butylthio or
tert.-butylthio. SO-Alkyl is preferably methylsulfinyl, but
is also ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl,
n-butylsulfinyl, isobutylsulfinyl, sec.-butylsulfi~yl or
tert.-butylsulfinyl. SO2-Alkyl is preferably methylsulfonyl,
but is also ethylsulfonyl, n-propylsulfonyl,
isopropylsulfonyl, n~butylsulfonyl, isobutylsulfonyl, sec.-
butylsulfonyl or tert.-butylsulfonyl.
The radical Ind is, in particular, an unsubstituted
3-indolyl radical. However, if Ind is a substituted 3-
indolyl radical, then it is preferably substituted once, in
particular in the 2-, 5- or 6-position. Substitution in the
1-, 4- or 7-position is also possible. Preferred
disubstituted 3-indolyl radicals are substituted in the 5,6-
positions; disubstitution is also possible in the 1,2-, 1,4-,
1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-, 2,7-, 4,5-, 4,6-, 4,7-,
5,7- or 6,7-positions. In all these cases the substituents
can be identical or different.
~pecifically, the preferred substituents in the
benzene ring of the Ind radical are methyl, ethyl, methoxy,
ethoxy, methylthio, ethylthio, OH, F, Cl, Br, CF3 and CN.
Accordingly, some preferred meanings of the Ind radical are
3-indolyl, but also 1-, 2-, 4- r 5-, 6- or 7- methyl-3-
-- 5 --
~L257273
indolyl, 1-, 2-, 4-, 5-, 6- or 7-ethyl-3-indolyl, 4-, 5-, 6-
or 7-methoxy-3-indolyl, 4-, 5-, 6- or 7-ethoxy-3-indolyl, 4-,
5-, 6- or 7-methylthio-3-indolyl, 4-, 5-, 6- or 7-ethylthio
3-indolyl, 4-, 5-, 6- or 7-methylsulfinyl-3-indolyl, 4-, 5-,
6- or 7-methylsulfonyl-3-indolyl, 4-, 5-, 6- or 7-hydroxy-3-
indolyl, 4-, 5-, 6- or 7-fluoro-3-indolyl, 4-, 5-, 6- or 7-
chloro-3-indolyl, 4-, 5-, 6- or 7-bromo-3-indolyl, 4-, 5-, 6-
or 7-trifllloromethyl-3-indolyl, 4-, 5-, 6- or 7-cyano-3-
indolyl, 1,2-, 1,4-, 1,5-, 1,6-, 1,7-, 2,4-, 2,5-, 2,6-,
2,7-, 4,5-, 4,6-, 4,7-, 5,6-, 5,7- or 6,7-dimethyl-3-indolyl,
l-methyl-4-, -5-, -6- or -7-methoxy-3-indolyl, 1-methyl-4-,
-5-, -6- or -7-methylthio-3-indolyl, 1-methyl-4-, -5-, -6- or
-7-fluoro-3-indolyl, 1-methy1-4-, -5-, -6- or -7-chloro-3-
indolyl, l-methyl-4-, -5-, -6- or -7-bromo-3-indolyl, 1-
methyl-4-, -5-, -6- or -7-trifluoromethyl-3-indolyl, 1-
methyl-4-, -5-, -6- or -7-cyano-3-indolyl, 2-methyl-4-, -5-,
-6- or -7-methoxy-3-indolyl, 2-methyl-4-, -5-, -6- or -7-
methylthio-3-indolyl, 2-methyl-4-, -5-, -6-, or -7-fluoro-3-
indolyl, 2-methyl-4-, -5-, -6- or -7-chloro-3-indolyl, 2-
methyl-4-, -5-, -6- or -7-bromo-3-indolyl, 2-methyl-4-, -5-,
-6- or -7-trifluoromethyl-3-indolyl, 2-methyl-4-, -5-, -6- or
-7-cyano-3-indolyl, 4-methyl-5-fluoro-3-indolyl, 5-fluoro-6-
or -7-methyl-3-indolyl, 4-methyl-5-chloro-3-indolyl, 4-
chloro-5-methyl-3-indolyl, 5-methyl-6- or -7-chloro-3-
indolyl, 5-chloro-6- or -7-methyl-3-indolyl, 4,5-, 4,6-,
4,7-, 5,6-, 5,7- or 6,7-dimethoxy-3-indolyl, 4,5-, 4,6-,
4,7-, 5,6-, 5,7- or 6,7-dichloro-3-indolyl, 4-
trifluoromethyl-5-, -6- or -7-chloro-3-indolyl.
~572'73
The parameter n is prefera~ly 4. The group A is
thus preferably -~CH2)4-.
The radical Ar is preferably substituted phenyl,
preferably substituted once. However, the phenyl group can
also be unsubstituted or substituted twice, it being possible
for the subs~ituents to be identical or different. Preferred
substituents on the phenyl group are OH, also methyl,
methoxy, F, Cl, Br or trifluoromethyl. Specifically, Ar is
preferably m-hydroxyphenyl, also preferably o- or p-
hydroxyphenyl as well as phenyl, also o-, m- or p-
fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-
bromophenyl, o-, m- or p-tolyl, o-, m- or p-methoxyphenyl,
o-, m- or p-trifluoromethylphenyl, but also, for example, o-,
m- o~ p-ethylphenyl, o-, m- or p-n-propylphenyl, o-, m- or p-
isopropylphenyl, o-, m- or p-n-butylphenyl, o-, m- or p-
isobutylphenyl, o-, m- or p-ethoxyphenyl, also
dihalogenophenyl such as 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-
difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6~, 3,4- or 3,5-
dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di-
bromophenyl, 2-fluoro-4-chlorophenyl, 2-bromo-4-chloro-
phenyl; dimethylphenyl, such as 2,3-, 2,4-, 2,5-, 2,6-, 3,4-
or 3,5-dimethylphenyl; dimethoxyphenyl, such as 2,3-, 2,4-,
2,5-, 2, 6-, 3,4- o r 3,5-dimethoxyphenyl; or
methylchlorophenyl, such as 2-methyl-4-chlorophenyl.
Accordingly, the invention relates in particular to
those compounds of the formula I in which at least one of the
radicals mentioned has one of the meanings indicated above,
in particular one of the preferred meanings indicated above.
~257;Z73
Some preferred ~roups of compounds can be expressed by the
following part formulae Ia to In which correspond to the
formula I and wherein the radicals and parameters which are
not specified have the meaning indicated for formula I, but
wherein in Ia, Ind is 3-indolyl, methyl-3-indolyl, dimethyl-
3-indolyl, methoxy-3-indolyl, dimethoxy-3-indolyl, hydroxy-
3-indolyl, dihydroxy-3-indolyl, fluoro-3-indolyl, chloro-3-
indolyl, dichloro-3-indolyl, bromo-3-indolyl, cyano-3-indolyl
or methylenedioxy-3-indolyl, the substituents preferably
being in the 5- and/or 6-positions;
in Ib, Ind is 3-indolyl, 5- or 6-methyl-3-indolyl, 5,6-
dimethyl-3-indolyl, 5- or 6-methoxy-3-indolyl, 5,6-dimethoxy-
3-indolyl or 5-cyano-3-indolyl;
in Ic, Ind is 3-indolyl;
in Id, A is -(CH2)4-;
in Ie, Ar is hydroxyphenyl, phenyl, tolyl, methoxyphenyl,
fluorophenyl, chlorophenyl, trifluoromethylphenyl or
dimethoxyphenyl;
In If, Ar is hydroxyphenyl;
in Ig, Ar is phenyl;
in Ih, Ind is 3-indolyl or 5-methoxy-3-indolyl and Ar is
hydroxyphenyl, phenyl, tolyl, methoxyphenyl, fluorophenyl,
chlorophenyl, trifluoromethylphenyl or dimethoxyphenyl;
in Ij, Ind is 3-indolyl, A is -(CH2)4-, and Ar is 3- or 4-
hydroxyphenyl, phenyl, 3- or 4-methoxyphenyl or 3,4-
dimethoxypheryl;
in Ik, Ind is 3-indolyl, A is -(CH2)4-, and Ar is 3-
hydroxyphenyl or phenyl;
~257273;
in Il, Ind, A, n and Ar have the meaning indicated for
formula I, but Ind is an unsubstituted 3-indolyl radical or a
3-indolyl radical substituted once or twice by O-alkyl, OH,
F, Cl, Br and/or CF3 only when, simultaneously, Ar is a
phenyl group which is unsubstituted in the 3-position, or is
a phenyl group which is substituted in the 3-position by
alkyl, S-alkyl, SO-alkyl, SO2-alkyl, F, Cl, Br, CF3 or CN and
can be substituted additionally in one o~ the remaining
positions by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-alkyl,
OH, F, Cl, Br, CF3 or CN, or is a methylenedioxyphenyl group,
and/or the two radicals L together are a C-C bond;
in Im, Ar is phenyl, 4-hydroxyphenyl or ~-methoxyphenyl;
in In, the two radicals L together are a C-C bond;
in Io, Ar is phenyl or phenyl substituted by alkyl, S-alkyl,
SO-alkyl, SO2-alkyl, F, Cl, Br, CF3 and/or CN or by a
methylenedioxy group;
in Ip, Ind is 3-indolyl substituted by alkyl, S-alkyl, SO-
alkyl, SO2-alkyl, and/or CN or by a methylenedioxy group.
~25727:3
The compounds of the formula I can have one or more
asymmetric carbon a~oms. Thus they can exist as racemates
and, if several asymmetric carbon atoms are present, they can
also exist as mixtures of several racemates and in various
optically active forms.
The invention also relates to a process for the
preparation of the compounds of the formula I and their
physiologically acceptable acid addition salts, which is
characterized in that a compound of the general formula II
Ind-A-X1 II
in which xl is X or NH~ and X is Cl, Br, I, OH or a reactive
derivative of an OH group, and Ind and A have the indicated
meanings, is reacted with a compound of the general formula
III
X2C~2_CH2 \
CHL III
X3-CH2-CArL
in which x2 and X3 can be identical or different andt if xl
is NH2, are each X, but otherwise are together NH, and Ar and
L have the indicated meanings, or in that a compound which
other~ise corresponds to the formula I, but contains one or
more reducible group(s) and/or one or more additional C-C
and/or C-N bond(s) in place of one or more hydro~en atoms, is
treated with a reducing agent, or in that a compound which
otherwise corresponds to the formula I, but contains one or
more group(s) which can be eliminated by solvolysis in place
of one or more hydrogen atoms, is treated with a solvolyzing
agent, or in ~hat, to prepare a compound of the formula I
- 10 -
:~2572~73
in which the two radicals L are together a C-C bond, a
compound of the formula IV
Ind-A- ~ E IV
~ Ar
in which one radical E is X, CN or NH2, the other radical E
is H, and Ind, A, Ar and X have the indicated meanings, is
treated with an agent which eliminates HE, and/or in that,
where appropriate, in a compound of the formula I, a
thioether group is oxidized to an SO group or SO2 group, or
an SO group is oxidized to an SO2 group, and/or an alkoxy
group is cleaved with the formation of an OH group, and/or in
that a base of the formula I obtained is converted into one
of its physiologically acceptable acid addition salts by
treatment with an acid.
The preparation of the compounds of the formula I
is otherwise carried out by methods known per se as are
described in the literature (for example in the standard
works, such as Houben-Weyl, Methoden der Organischen Chemie
(Nethods of Organic Chemistry), Georg-Thieme Verlag,
Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New
York), namely under reaction conditions as are known and
suitable for the reactions mentioned. Use can also be made
in these prepar~tions of variants known per se which are not
mentioned in more detail here.
The starting materials can, if desired, also be
formed in situ in such a manner that they are not isolated
~257273
from the reaction mixture but are immediately reacted further
to give the compounds of the formula I.
In the indole derivatives of the formula II, xl is
preferably ~; accordingly, in the compounds of the formula
III, x2 and X3 together are preferably NH. The radical X is
preferably Cl or Br; however, it can also be I, OH or a
reactive derivative of an OH group, in particular
alk~lsulf~nyloxy having 1 - 6 ( for example
methanesulfonyloxy) or arylsulfonyloxy having 6 - 10 C atoms
( for example benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or
2-naphthalenesulfonyloxy) .
Accordingly, the indole derivatives of the formula
I can be obtained, in particular, by reaction of the
compounds of the formulae Ind-A-Cl or Ind-A-Br with compounds
of the formula III, wherein X2 and X3 together are an NH
group (denoted IIIa in the following text).
Some of the compounds of the formula II and III are
known; the unknown compounds of these formulae II and III can
be easily prepared in analogy to the known compounds. Thus,
some of the compounds of the formula II are known from German
Of fenlegungsschrift 2, 827, 874 .
Alcohols of the formula Ind-A-OH can be obtained,
for example, by reduction o~ the corresponding carboxylic
acids or their esters. Treatment with thionyl chloride,
hydrogen bromide, phosphorus tribromide or similar halogen
compounds proYides the corresponding halides of the formula
Ind-A-Hal (wherein ~al is Cl, Br or I ) . The corresponding
sulfonyloxy compounds can be obtained form the alcohols Ind-
A-OH by reaction with the corresponding sulfonyl chlorides.
12 - ~25727~
The iodine compounds of the formula Ind-A-I, for example 3-
(4-iodobutyl)indole are obtained, for example, by the action
of potassium iodide on the pertinent p-toluenesulfonic
esters. The amines of the formula Ind-A-NH2 can be obtained,
for example, from the halides with potassium phthalimide or
by reduction of the corresponding nitriles.
The piperidine derivatives IIIa can be obtained,
for example, by reaction of 3-piperidone with organo-metallic
compounds of the formula M-Ar (in which M is an Li atom or
Mg~al), subsequent hydrolysis to give the corresponding 3-Ar-
3-hydroxypiperidines and, if desired, subsequent hydration to
give 3-Ar-3,4-dehydropiperidines. Compounds of the formula
III (X2 and X3 each being X) can be prepared, for example, by
reduction of 2-Ar-glutaric esters to give 2-Ar-1,5-
pentanediols and, if appropriate, subse~uent reaction with
SOCl2 or PBr3.
The reaction of the compounds II and III takes
place by methods as are known from the literature for the
alkylation of amines. It is possible to fuse -the components
together in the absence of a solvent, if appropriate in a
closed tube or in an autoclave. However, it is also possible
to react the compounds in the presence of an inert solvent.
Examples of suitable solvents are hydrocarbons, such as
~enzene, toluene or xylene; ketones, such as acetone or
butanone; alcohols, such as methanol, ethanol, isopropanol or
n-butanol; ethers, such as tetrahydrofuran (THF) or dioxane;
amides, such as dimethylformamide (DMF) or N-
methylpyrrolidone; nitriles, such as acetonitrile, and,
~Z5~2~73
if appropriate, mixtures of these solvents with one anoth4er
or mixtures with water. The addition of an acid-binding
agent, for example an aikali metal or alkaline earth metal
hydroxide, carbonate or bicarbonate or another weak acid salt
of the alkali metals or alkaline earth metals, preferably o~
potassium, sodium or calcium, or the addition of an organic
base, such as triethylamine, dimethylaniline, pyridine or
quinoline or an excess of the amine component Ind-A-NH2 or
the piperidine derivative of the formula IIIa can be
advantageous. The reaction time depends on the conditions
used and is between a few minutes and 14 days, and the
reaction temperature is between about 0 and 150, normally
between 20 and 130.
Furthermore, it is possible to obtain a compound of
the formula I by treating a precursor which, in place of
hydrogen atoms, contains one or more reducible group(s)
and/or one or more additional C-C and/or C-N bond(s) with
reducing agents, preferably at temperatures between -80 and
+250 in the presence of at least one inert solvent.
Reducible groups (replaceable by hydrogen) are, in
particular, oxygen in a carbonyl group, hydroxyl,
arylsulfonyloxy (for example p-toluenesulfonyloxy), N-
benzenesulfonyl, N-benzyl or O-benzyl).
It is possible in principle to convert compounds
which contain only one of the abovementioned groups or
additional bonds or those compounds which contain together
two or more of the abovementioned groups or additional bonds
into a compound of the formula I by reduction. Nascent
~25q2~3
hydrogen or complex metal hydrides, but also reduction by the
- method of Wolff-Kishner, is preferably used for this purpose.
Preferred starting materials for the reduction
correspond to the formula V
Ind'-G-Q'-Ar' Y
in which Ind' is a 3-indolyl radical which can be substituted
once or twice by alkyl, O-alkyl, S-alkyl, SO-alkyl, SO2-
alkyl, OH, F, Cl, Br, CF3, CN and/or O-benzyl or by a
methylenedioxy group and/or by an arylsulfonyl group or a
benzyl group in the l-position, G is a -(CH2)n- chain in
which, however, one or more -CH2- group~s) can be replaced by
-CO-, and/or one or more hydrogen atoms can be replaced by OH
groups, Q' is Q or
-N ~ ~n~
An~ is an anion of a strong acid, and Ar' is a phenyl which
is unsubstituted or substituted once or twice by alkyl, O-
alkyl, S-alkyl, SO-alkyl, SO2-alkyl, OH, F, Cl, Br, CF3, CN
and/or O-benzyl or by a methylenedioxy group, but in which it
is not possible at the same time for Ind' to be Ind, G to be
A, Q' to be Q and Ar' to be Ar.
G in the compounds of the formula V is preferably
-CH2CH2CO-, -(CH2)3-CO- or -(CH2)4-cO-~
Compounds of the formula V can be prepared, for
example, by reaction of 3-Ar'-1,2,3,6-tetrahydropyridines, 3-
Ar'-piperidines or 3-Ar'-pyridines with compounds of the
formula VI
- 15 - ~25727~3
Ind'-G-Xl VI
in which Ar', Ind', G and xl have the meanings indicated
above, under the conditions indicated above for the reaction
of II with III. Amides of the formula V [G = -(CH2)n_1-CO-,
Q' = Q] can be obtained, for example, from the free
carboxylic acids of the formula Ind'-(CH2)n_1-COOH and amines
of the ~ormula IIIa, preferably in the presence of a
dehydrating agent, for example carbonyldiimidazole or
dicyclohexylcarbodiimide, in an inert solvent, preferably
THF.
If nascent hydrogen is used as the reducing agent,
this can be produced by, for example, treatment of metals
with weak acids or with bases. Thus, for example, a mixture
of zinc with alkali metal hydroxide solution or of iron with
acetic acid can be used. It is also suitable to use sodium
or another alkali metal in an alcohol, such as ethanol,
isopropanol, butanol, amyl or isoamyl alcohol or phenol. It
is also possible to use an aluminum/nickel alloy in an
aqueous alkaline solution, optionally with the addition of
ethanol. Sodium amalgam or aluminum amalgam in aqueous
alcoholic or aqueous solution are also suitable to produce
nascent hydrogen. The reaction can also be carried out in
heterogeneous phases, it being preferable to use an aqueous
and a benzene or toluene phase.
Moreover, it is possible to use with particular
advantage complex metal hydrides, such as LiAlH4, NaBH4,
diisobutylaluminum hydride or NaAl(OCH2CH2OCH3)2H2 and
diborane, as the reducing agent, if desired with the addition
of catalysts, such as BF3, AlC13 or LiBr.
~2S72~73
Solvents which are particularly suit~ble for this
purpose are ethers, such as diethyl ether, di-n-butyl ether,
THF, dioxane, diglyme or 1,2-dimethoxyethane, and
h~drocarbons, such as benzene. For reduction with NaBH4,
alcohols, such as methanol or ethanol, but also water and
aqueous alcohols, are primarily suitable as the solvent.
Reduction by these methods is preferably carried out at
emperatures between -80 and +150, in particular between
about 0 and about 100.
It is also possible particularly advantageously to
reduce -CO- groups in amides (for example those of the
formula V in which G is -(CH2)n_l-CO- and Q' is Q) with
LiAlH4 in THF at temperatures between 0 and 66 to give CH2
groups. During this, arylsulfonyl protective groups located
in the 1-position of the indole ring can simultaneously be
reductively split off.
It is possible to reduce the pyridinium salts of
the formula V (wherein Q' is
-N ~
Ane and An is preferably Cl or Br) to give compounds of the
formula I, for example, using NaBH4 in water, methanol or
ethanol or in mixtures of these solvents, with the addition,
if desired, of a base, such as NaOH, at temperatures between
about 0 and 80.
N-Benzyl groups can be reductively split off using
sodium in liquid ammonia.
Moreover, it is possible to reduce one or more
carbonyl groups to CH2 groups by the method of Wolff-
~25~2'7~
Kishner, for example, by treatment with anhydrous hydrazine
in absolute ethanol under pressure at temperatures between
about l50 and 250.
Sodium alcoholate is advantageously used as a
catalyst. The reduction can also be modified by the method
of Huang-Minlon by carrying out the reaction with hydrazine
hydrate in a high-boiling solvent which is miscible with
water, such as diethylene glycol or triethylene glycol, in
the presence of alkali, such as sodium hydroxide. As a rule,
the reaction mixture is boiled for about 3-4 hours. The
water is then distilled off and the hydrazone formed is
decomposed at temperatures up to about ~00. The Wolff-
Kishner reduction can also be carried out with hydrazine in
dimethyl sulfoxide at room temperature.
Compounds which o-therwise correspond to formula I
but, in place of one or more H atoms, contain one or more
group(s) which can be split off by solvolysis can be
solvolyzed, in particular hydrolyzed/ to give compounds of
the formula I. The starting materials for the solvolysis can
be obtained, for example, by reaction of IIIa with compounds
which correspond to the formula II (Xl = X) but, in place of
one or more H atoms, contain one or more group(s) which can
be split off by solvolysis. Thus, l-acylindole derivatives
(corresponding to the formula I but containing an acyl group,
preferably an alkanoyl, alkylsulfonyl or arylsulfonyl group
each having up to lO C atoms, such as methane-, banzene- or
p-toluene-sulfonyl in the l-position of the Ind radical) can
be hydrolyzed to give the corresponding
- 18 -
IL2~;7273
indole derivatives which are unsubs-tituted in the 1-position
of the indole ring, for example, in acid, but better in
neutral or alkaline medium at temperatures between 0 and
200. Sodium, potassium or calcium hydroxide, sodium or
potassium carbonate or ammonia are preferably used as the
basic catalysts. The solvents which are preferably chosen
are water, lower alcohols, such as methanol or ethanol,
ethers, such as THF or dioxane, sulfones, such as
tetramethylenesulfone or their mixtures. Hydrolysis can even
take place just on treatment with water alone, in particular
at the boiling point.
Moreover, compounds of the formula I can be
obtained by splitting off HE from compounds of the formu~a IV
to form a double bond. According to the definition of E,
this can comprise, for example, splitting off hydrogen
halide, water (dehydration), a carboxylic acid or another
acid, ammonia or HCN. The starting materials of the formula
IV can be obtained, for example, by reaction of II (X1 = X)
with a compound of the formula VII
HN ~ E VII
E Ar
in which E and Ar have the indicated meanings.
If one of the radicals E is Hal, this substituent
can easily be eliminated under basic reaction conditions.
The following can be used as bases: alkali metal hydroxides,
~2s~2q3
alkali metal carbonates, alcoholates, such as, for example,
potassium tert.-butylate, amines, such as, for example,
dimethylaniline, pyridine, collidine or quinoline; the
solvent used îs, for example, benzene, toluene, cyclohexane,
methanol, dioxane, THF or tert.-butanol. The amines used as
bases can also be employed in excess as the solvent. If one
of the radicals E is an OH group, then acids, such as acetic
acid, hydrochloric acid or mixtures of the two, are
preferably used as the agent to split off water. The
addition of a solvent (for example water or ethanol) can be
ad~antageous. The elimination of acyl, alkylsulfonyl and
alkoxysulfonyloxy or amino radicals can be carried out under
similar conditions. An elimination of sulfonic acid
radicals, for example mesylates or tosylates, takes place
under mild conditions by boiling in DMF or dimethyl sulfoxide
with alkali metal carbonates, for example Li2CO3 or with
potassium acetate. Ammonia can be split off by just heating
the salts of the corresponding amino compounds (especially
the 3-amino derivatives). In a similar manner, HCN can be
split off from compounds of the formula IV (one group E = CN)
by heating. The elimination of HE from IV generally takes
place at temperatures between about 0 and about 250,
pre~erably between 50 and 200.
Furthermore, the thioether group in a thioether of
the formula I can be oxidized to a SO group or to an SO2
group, or the SO group in a sulfoxide of the formula I can be
oxidized to an SO2 group. The thioether or sulfoxide groups
to be oxidized can be present as substituents in the radical
- 20 -
~257273
Ind and/or in the radical Ar. If the intention is to obtain
the sulfoxides, then the oxidation is carried out, for
example, with hydrogen peroxide, peracids, such as m-
chloroperbenzoic acid, Cr(VI) compounds, such as chromic
acid, KMnO4, l-chlorobenzotriazole, Ce(IV) compounds, such as
(NH4)2Ce(NO3)6, negatively substituted aromatic diazonium
salts, such as o- or p-nitrophenyldiazonium chloride, or
electrolytically under relatively mild conditions and at
relatively low temperatures (about -80 to -~100). If, on the
other hand, the intention is to obtain the sulfones (from the
thioethers or the sulfoxides), then the same oxidizing agents
are used under more forcing conditions and/or in excess and,
as a rule, at higher temperatures. It is possible in these
reactions for the customary inert solvents to be present or
absent. Examples of suitable inert solvents are water,
aqueous mineral acids, aqueous al~ali metal hydroxide
solutions, lower alcohols, such as methanol or ethanol,
esters, such as ethyl acetate, ketones, such as acetone,
lower carboxylic acids, such as acetic acid, nitriles, such
as acetonitrile, hydrocarbons, such as benzene, and
chlorinated hydrocarbons, such as chloroform or CCl~. A
preferred oxidizing agent is 30% aqueous hydrogen peroxide.
On using the calculated amount in solvents such as acetic
acid, acetone, methanol, ethanol or aqueous sodium hydroxide
~olution at temperatures between -20 and 100, this leads to
the sulfoxides, while in excess at higher temperatures,
preferably in acetic acid or in a mixture of acetic acid and
acetic anhydridel this leads to the sulfones.
~:~S72~73
Ethers of the formula I in which the radicals Ind
and/or Ar are substituted once or twice by O-alkyl can be
cleaved by methods which are known from the literature, the
corresponding hydroxyl derivatives being produced. For
example, the ethers can be cleaved by treatment with HBr or
~I in aqueous or acetic acid solution, by heating with Lewis
acids, such as AlC13 or boron trihalides, or by fusing with
pyridine or aniline hydrohalides, preferably pyridine
hydrochloride, at about 150 - 250. Reductive cleavage with
diisobutylaluminium hydride (for method, compare Synthesis
1975, 617) is particularly mild.
A base of the formula I which has been obtained can
be converted into -the relevant acid addition salt using an
acid. Acids which provide physiologically acceptable salts
are suitable for this reaction. Thus, inorganic acids can be
used, for example, sulfuric acid, hydrohalic acids, such as
hydrochloric acid or hydrobromic acid, phosphoric acids, such
as orthophosphoric acid, nitric acid, sulfamic acid, but also
organic acids, specifically aliphatic, alicyclic,
araliphatic, aromatic or heterocyclic monobasic or polybasic
carboxylic~ sulfonic or sulfuric acids, such as formic acid,
acetic acid, propionic acid, pivalic acid, diethylacetic
acid, malonic acid, succinic acid, pimelic acid, fumaric
acid, maleic acid, lactic acid, tartaric acid, malic acid,
benzoic acid, salicylic acid, 2-phenylpropionic acid, citric
acid, gluconic acid, ascorbic acid, nicotinic acid, iso-
- ~257273
nicotinic acid, methane- or ethanesulfonic acid, ethane-
disulfonic acid, 2-hydroxyethanesulfonic acid, benzene-
sulfonic acid, p-toluenesulfonic acid, naphthalenemono-
sulfonic acids and naphthalenedisulfonic acids and lauryl
sul~uric acid.
It is possible, if desired, to liberate the free
bases of the formula I from their salts by treatment with
strong bases, such as sodium or potassium hydroxide or sodium
or potassium carbonate.
The invention also relates to the use of the
compounds of the formula I and their physiologically
acceptable salts for the preparation of pharmaceutical
formulations, in particular by non-chemical means. For this
purpose, it is possible to convert them into a suitable
dosage form together with at least one vehicle or auxiliary
and, where appropriate, combined with one or more other
active compound(s).
The invention also relates to agents, especially
pharmaceutical formulations, containing at least one compound
of the formula I and/or one of its physiologically acceptable
salts. These formulations can be employed as medicaments in
human or veterinary medicine. Suitable vehicles are organic
or inorganic substances which are suitable for enteral (for
example oral), parenteral or topical administration and which
do not react with the new compounds, for example water,
vegetable oils, benzyl alcohols, polyethylene glycols,
gelatine, carbohydrates, such as lactose or starch, magnesium
stearate, talc and vaseline. In particular, tablets, coated
tablets, capsules, syrups, liquids, drops or suppositories
- 23 -
~257273
are used for enteral administration, solutions, preferably
oily or aqueous solutions, but also suspensions, emulsions or
implants are used for parenteral administration, and
ointments, creams or powders are used ~or topical
application. It is also possible to freeze-dry the new
compounds and use the lyophilizates obtained, for example,
for the preparation of products ~or injection.
The indicated formulations can be sterilized and/or
contain auxiliaries, such as lubricants, preservatives,
stabilizers and/or wetting agents, emulsifiers, salts to
modify the osmotic pressure, buffer substances, dyes,
flavorings and/or aromatic substances. If desired, t~ley can
also contain one or more other active compounds, for example
one or more vitamins.
The invention also relates to the use of the
compounds of the formula I and their physiologically
acceptable salts for the therapeutic treatment of the human
or animal body and for the control of illnesses, especially
of parkinsonism, of extrapyramidal disturbances associated
with neuroleptic therapy, of depression and/or psychosis and
of side effects of treatment for hypertension (for example
with ~-methyldopa). The compounds can also be used in
endocrinology and gynecology, for example for the therapy of
acromegaly, hypogonadism, secondary amenorrhoea, premenstrual
syndrome, undesired puerperal lactation and generally as
prolactin inhibitors, also for the therapy of cerebral
disturbances (for example migraine) and especially
geriatrics, similar to certain ergot alkaloids.
24 -
~257:27
For these purposes, as a rule the substances
according to the invention are administer~d in analogy to
known and commercially available products (for example
bromocriptine and dihydroergocornine), preferably in doses
between about 0.2 and 500 mg, in particular between 0.2 and
50 mg per dosage unit. The daily dose is preferably between
about 0.001 and 10 mg/kg of body weight. In this con-text,
the low doses (about 0.2 to l mg per dosage unit; about 0.001
to 0.005 mg/kg of body weight) are particularly suitable for
use as agents for migraine; doses between 10 and 50 mg per
dosage unit are preferred for the other indications.
Preferred dose ranges for specific indications are as
follows: parkinsonism 1 to 200, preferably 40 to 100;
dyskinesia 40 to 100; psychosis, for example schizophrenia, 2
to 20; acromegaly 2 to 50 mg per dosage unit. However, the
specific dose for each particular patient depends on a wide
variety of factors, for example on the efficacy of the
specific compound employed, on the age, body weight, general
state of health, sex, on the diet, on the timing and mode of
administration, on the rate of excretion, and on medicaments
used in combination and the severity of the particular
disorder to which the therapy is applied. Oral
administration is preferred.
- 25 -
~257273
The chemical reactions described above are
generally disclosed in terms of their broadest application to
the preparation of the compounds of this invention.
Occasionally, the reactions may not be applicable as
described to each compound included within the disclosed
scope. The compounds for which this occurs will be readily
recognized by those skilled in the art. In all such cases,
either the reactions can be successfully performed b~
conventional modifications known to those skilled in the art,
e.g., by appropriate protection of inter~ering groups, by
changing to alternative conventional reagents, by routine
modification of reaction conditions, etc., or other reactions
disclosed herein or otherwise conventional, will be
applicable to the preparation of the corresponding compounds
of this invention. In all preparative methods, all starting
materials are known or readily preparable from known starting
materials.
Without further elaboration, it is believed that
one skilled in the art can, using the preceding description,
utilize the present invention to its fullest e~tent. The
following preferred specific embodiments are, therefore, to
be construed as merely illustrative. In the following
26 -
;72'73
examples, all temperatures are set forth uncorrected in
degrees Celsius; unless otherwise indicated, all parts and
percentages are by weight.
In the examples below, "usual work-up " denotes:
Water is added if necessary, the mixture is
extracted with an organic solvent, such as toluene,
chloroform or dichloromethane, the phases are separated, the
organic phase is dried over sodium sulfate, filtered,
evaporated and the product is purif ied by chromatography
and/or crystallisation. Temperatures are reported in degrees
centigrade, and Rf values are on silica gel
( toluene/triethylamine 8: 2 unless otherwise indicated ) .
~2s72q3
Example 1
A solution of 2 . 08 g of 3- ( 4-chlorobutyl ) indole [ or
2 . 52 g of 3- ( 4-bromobutyl ) indole I and 1 . 6 g of 3-phenyl -
1, 2, 3, 6-tetrahydropyridine in lO ml o~ acetonitrile is
stirred at 20 for 12 hours, worked up as usual and 3-[4-(3-
phenyl-1, 2, 3, 6-tetrahydropyridyl ) butyl ] indole is obtained .
Hydrochloride, m.p. 209-212.
~n analogy, the following are obtained from the
appropriate chloro- or bromoalkylindoles with the appropriate
3-aryl-1, 2, 3, 6-tetrahydropyridines or -piperidines: 3- [ 3- ( 3-
phenyl-1, 2, 3, 6-te trahydropyridyl ) propyl ] indole,
hydrochloride, m.p. 175-177
3 - [ 3 - ( 3 -m-methoxyphenyl- 1, 2, 3, 6 -tetrahydropyridyl ) propyl ] -
indole
3- [ 3 - ( 3 -p-methoxyphenyl- 1, 2, 3, 6-tetrahydropyridyl ) -propyl ] -
indole
3 - [ 3 - ( 3-m-hydroxyphenyl -1, 2, 3, 6 -tetrahydropyridyl ) propyl ] -
indole
3- [ 3- ( 3-p-hydroxyphenyl-1, 2, 3, 6-tetrahydropyridyl)propyl] -
indole
3- [ 4- ( 3-phenyl-1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -2-methyl-
indole
3- [ 4 - ( 3 -phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -5-methoxy-
indole
3 - [ 4 - ( 3-phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -6-methoxy-
indole
3- [ 4 - ( 3 -phenyl -1, 2, 3, 6 -tetrahydropyridyl ) butyl ] -4-hydroxy-
indole
- 28 - ~2572'73
3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-hydroxy-
indole
3-r4~(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-6-hydroxy-
indole
3-[4-(3-phenyl-ll2~3/6-tetrahydropyridyl)butyl]-5-~luor
indole
3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-chloro-
indole
3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-7-bromo-
indole
3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-cyano-
indole
3-~4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-methyl-
lenedioxyindole
3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-di-
methylindole
3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-di-
methoxyindole
3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl~butyl]-5,6-di-
chloroindole
3-[4-(3-o-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole
3-~4-(3-m-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole
3-[4-(3-p-tolyl-1,2,3,6-tetrahydropyridyl)butyl]indole
3-[4-(3 o-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-~4-(3-m-methoxyphenyl-1,2~3,6-tetrahydropyridyl)butyl]-
indole, R~ 0.42
3-[4-(3-p-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole
- 29 -
~257:~'73
3-[4~(3-o-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole, Rf 0.32 (CH2Cl2/methanol 9:1)
3-[4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-o-~luorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-m-fluorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-p-~luorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-o-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-m-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-p-chlorophenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-p-bromophenyl-1,2,3,6-tetrahydropyridyl)butyl]-
indole
3-[4-(3-m-trifluoromethylphenyl-l~2~3~6-tetrahydropyridyl)
butyl]indole
3-[4-~3-p-cyanophenyl-1,2,3,6-tetrahydropridyl)butyl]-
indole
3-[4-(3-(3,4-dimethoxyphenyl)-1,2,3,6-tetrahydropyridyl)-
butyl]indole, Rf 0.48 (CH2Cl2/CH3OH 9:1)
3-[4-(3-(3,4-methylenedioxyphenyl)-1,2,3,6-tetrahydro~
pyridyl)butyl]indole
3-[4-(3-(4-chloro-3-tri~luoromethylphenyl)-1,2,3,6-tetra-
hydropyridyl)butyl]indole
~l257273
3-~4-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-
methoxyindole
3 - [ 4 - ( 3-m-methoxypheny~ 2 ~ 3 ~ 6-tetrahydropyridyl )butyl ] -6
methoxyindole
3-[4-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5,6-
dimethoxyindole
3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)butyl]-5-
hydroxyindole
3-[4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropridyl)butyl]-6-
hydroxyindole
3-[5-(3-phenyl-1,2,3,6-tetrahydropyridyl)pentyl]indole,
hydrochloride, m.p. 114-116
3-[5-(3-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-
indole
3-~5-(3-p-methoxyphenyl-l~2~3~6-tetrahydropyridyl)pentyl]
i~dole
3-~5-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-
indole
3-[5-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)pentyl]-
indole
3-[3-(3-phenyl-1-piperidyl)propyl]indole
3-[3-(3-m-methoxyphenyl-1-piperidyl)propyl]indole
3-[3-(3-p-methoxyphenyl-1-piperidyl)propyl]indole
3-[3-(3-m-hydroxyphenyl-1-piperidyl)propyl]indole
3- L 3-(3-p-hydroxyphenyl-1-piperidyl)propyl]indole
3-[4-(3-phenyl-1-piperidyl)butyl]indole, hydrochloride, m.p.
180-182
3-[4-(3-phenyl-1-piperidyl)butyl]-2-methylindole
~257;~73
3-[4-(3-phenyl-1-piperidyllbutyl]-5-methoxyindole
3-[4-(3-phenyl-1-piperidyl)butyl]-6-methoxyindole
3-[4-(3-phenyl-1-piperidyl)butyl]-4-hydroxyindole
3-[4-(3-phe.nyl-1-piperidyl)butyl]-5-hydroxyindole
3-[4-(3-phenyl-1-piperidyl)butyl]-6-hydroxyindole
3-[4-(3-phenyl-1-piperidyl)butyl~-5-fluoroindole
3-[4-(3-phenyl-l-piperidyl)butyl]-5-chloroindole
3-[4-(3-phenyl~l-piperidyl)butyl]-7-bromoindole
3-[4-(3-phenyl-1-piperidyl)butyl]-5-cyanoindole
3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-methylenedioxyindole
3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dimethylindole
3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dimethoxyindole
3-[4-(3-phenyl-1-piperidyl)butyl]-5,6-dichloroindole
3~ r 4-(3-o-tolyl-1-piperidyl)butyl]indole
3-[4-(3-m-tolyl-1-piperidyl)butyl]indole
3-[4-(3-p-tolyl-1-piperidyl)butyl]indole
3-[4-(3-o-methoxyphenyl-1-piperidyl)butyl]indole
3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]indole, Rf ~.41
3-[4-(3-p-methoxyphenyl-l~piperidyl)butyl]indole, hydro-
chloride, m.p. 184-185
3-[4-(3-o-hydroxyphenyl-1-piperidyl)butyl]indole
3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]indole, m.p. 135-
143 (decomposition)
3-[4-(3-p-hydroxyphenyl-1-piperidyl)butyl]indola
3-[4-(3-o-fluorophenyl-1 piperidyl)butyl]indole
3-[4-(3-m-fluorophenyl-1-piperidyl)butyl]indole
3-[4-(3-p-~luorophenyl-1-piperidyl)butyl~indole
3-[4~(3-o-chlorophenyl-1-piperidyl)butyl]indole
3-[4-(3-m-chlorophenyl-l-piperidyl)butyl]indole
57273
3-[4-(3-p-chlorophenyl-1-piperidyl)butyl]indole
3-[4-(3-p-bromophenyl-l-piperidyl)butyl]indol0
3-[4-(3-m-trifluoromethylphenyl-l-piperidyl)butyl]indole
3-[4-(3-p-cyanophenyl-1-piperidyl)butyl]indole
3-[4-(3-(3,4-dimethoxyphenyl)-1-piperidyl)butyl]indole,
hydrochloride, m.p. 177.5-178.5
3-[4-(3-(3,4-methylenedioxyphenyl)-l-piperidyl)butyl]-
indole
3-[4-(3-(4 chloro-3-trifluoromethylphenyl)-1-piperidyl)-
butyl]indole
3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]-5-methoxyindole,
hydrochloride, m.p. 102-104
3-[4-(3-p-methoxyphenyl-1-piperidyl)butyl]-5-methoxyindole,
m.p. 109
3-[4-(3-methoxyphenyl-l~piperidyl)butyl]-6-methoxyindole, Rf
0.29 (CH2C12/CH3OH 9:1)
3-[4-(3-m-methoxyphenyl-1-piperidyl)bu-tyl]-5,6-dimethoxy-
indole
3-[4-(3-m-hydroxyphenyl-1-piperidyl)butyl]-5-hydroxyindole,
m.p. 102-104
3-[4-(3-m~hydroxyphenyl-1-piperidyl)butyl]-6-hydroxyindole,
Rf 0.76 (CH~Cl2/CH3OH/triethylamine 7:2:1)
3-[4-(3-p-hydroxyphenyl-1-piperidyl)butyl]-5-hydroxyindole,
m.p. 182-185
~572q3
3-[5-~3-phenyl-1-piperidyl)pentyl]indole
3-[5-(3-m-methoxyphenyl-1-piperidyl)pentyl~indole,
hydrochloride, m.p. 164.5 - 165.5
3-[5-(3-p-methoxyphenyl-1-piperidyl)pentyl]indole
3-[5-(3-m-hydroxyphenyl-1-piperidyl)pentyl3indole and
3-[5-(3-p-hydroxyphenyl-1-piperidyl)pentyl]indole
3-[4-(3-m-hydroxyphenyl-1-piperidyl)-butyl]-4-hydroxy-7-
chloroindole
3-[4-(3-p-hydroxyphenyl-1-piperidyl)-butyl]-4-hydroxy-7-
chloroindole
Example 2
A mixture of 4.43 g of 3-t4-p-toluenesulfonyloxy-
butyl)indole and 3.2 g of 3-phenylpiperidine is heated -~o
130. After the exothermic reaction has subsided and the
mixture has cooled down, it is worked up as usual and 3-[4-
(3-phenyl-1-piperidyl)butyl]indole hydrochloride, m.p. 180-
182 is obtained.
~2S72~:~
In analogy, the following are obtained from the
appropriate tosylates:
3-[4-(3-phenyl-1-piperidyl)butyl]-5-butylindole
3-[4-(3-phenyl-1-piperidyl)butyl]-5-ethoxyindole
3-[4-(3-phenyl-1-piperidyl)butyl]-5-butoxyindole
3-[4-(3-phenyl-1-piperidyl)butyl]-5-methylthioindole
3-[4-(3-phenyl-l-piperidyl)butyl]-5-butylthioindole
3-[4-(3-phenyl-l-piperidyl)butyl]-5-methylsulfinylindole
and
3-[4-(3-phenyl-1-piperidyl)butyl]-5-methylsulfonylindole.
Example 3
2.99 g of 3-(4-iodobutyl)indole, 1.91 g of 3-m-
methoxyphenylpiperidine and 1.5 g of anhydrous potassium
carbonate in 25 ml of n-butanol are boiled, with stirring,
for 2 hours, the mixture is allowed to cool, worked up as
usual and 3-[4-(3-m-methoxyphenyl-1-piperidyl)butyl]-indole,
Rf 0.41, is obtained.
In analogy, the following are obtained from the
appropriate 3-Ar-piperidines:
3-[4-(3-p-butoxyphenyl-1-piperidyl)butyl]indole
3-[4-(3 p-methylthiophenyl-l-piperidyl)butyl]indole
3-[4-t3-p-butylthiophenyl-1-piperidyl)butyl]indole
3-[4-(3-p-methylsulfinylphenyl-l-piperidyl)butyl]indole and
3-[4-(3-p-methylsulfonylphenyl-l-piperidyl)butyl]indole.
Example 4
A mixture of 1.8~ g of 3-(4-aminobutyl)indole and
2.15 g of 1,5 dichloxo 2-phenylpentane (obtainable by
reduction of diethyl 2-phenylpentane-1,5-dioate with
- 35 -
~257zq3
LiAlH4 and subsequent reaction with 5OC12) in 40 ml of
acetone and 40 ml of water is boiled for 24 hours and worked
up as usual. 3-[4-(3-Phenyl-1-piperidyl)butyl]-indole
hydrochloride m.p. 180-182, is obtained.
In analogy, from the appropriate amines and the
appropriate 1,5-dichloro-2-Ar-pentanes or ~-pentenes, the
other compounds of the formula I indicated in Examples 1, 2
and 3 are obtained.
Example 5
1 g of NaBH4 in 20 ml of water is added, with
stirring, to a solution of 4.23 g of 1-~4-(3-indolyl)-butyl]-
3-m-hydroxyphenylpyridinium bromide [obtainable from 3-(4-
bromobutyl)indole and 3-m-hydroxyphenylpyridineJ in 50 ml of
lN NaOH, and the mixture is then stirred at 60C for 3 hours.
After working up as usual, 3-t4-(3-m-hydroxyphenyl-1,2,3,6-
tetrahydropyridyl)butyl]indole, ~f 0.32 (CH2C12/methanol
9:1), is obtained.
In analogy, the other tetrahydropyridines of the
formula I indicated in Examples 1, 2 and 3 are obtained by
reduction of the appropriate pyridinium bromides.
Example 6
A solution of 3.76 of indole-3-butyric 3-m-
methoxyphenylpiperidide (Rf 0.86 in CH2C12/CH3OH 9:1;
obtainable from indole-3-butyric acid and 3-m-methoxyphenyl-
piperidine in the presence of l,l'-carbonyldiimidazole) in 20
ml of THF is added dropwise, with stirring, to a suspension
of 0.38 g of LiAlH4 in 10 ml of THF. After the reaction has
subsided, 5 ml of ethyl acetate are added, the mixture is
worked up as usual and 3-~4-(3-m-methoxy-phenyl-1-
piperidyl)butyl]indole, Rf 0.41, is obtained.
~25'7~7:~
In analogy, from the appropriate amides, for
example:
indole-3-propionic 3-phenyl-1,2,3,6-tetrahydropyridide (m.p.
152-154)
indole-3-butyric 3-phenyl-1,2,3,6-tetrahydropyridide (Rf 0.44
in toluene/CH30H/triethylamine 7:2:1)
indole-3-butyric 3-~-methoxyphenyl-1,2,3,6-tetrahydropyridide
(Rf 0.88 in CH2Cl2/CH30H 9:1)
indole-3-butyric 3-(3,4-dimethoxyphenyl)-1,2,3,6-tetra-
hydropyridide (Rf 0.78 in OEI2Cl2/CH3H 9 1)
indole-3-butyric 3-phenylpiperidide (Rf 0.8 in
CH2Cl2/CH30H/ethyl acetate 7:2:1)
indole-3-butyric 3-m-methoxyphenylpiperidide (Rf 0.86 in
CH2Cl2/cH30H 9:1)
indole-3-butyric 3-p-methoxyphenylpiperidide (P~f 0.6~ in
CHCl3/CH30H/ethyl ac0tate 7:2:1)
indole-3-butyric 3-(3,4-dimethoxyphenyl)piperidide (Rf 0.75
in CH2C12/CH30H 9:1) and
indole-3-valeric 3-phenyl-1,2,3,6-tetrahydropyridide (m.p.
155-156), the other compounds of the formula I indicated in
Examples 1, 2 and 3 are obtained.
Example 7
4.88 g of 1-benzenesulfonyl-3-[4-(3-m-hydroxy-
phenyl-1-piperidyl)butyl]indole (obtainable from l-ben-
zenesulfonyl-3-(4-chlorobutyl)indol~ and 3-m-hydroxyphenyl-
piperidine) are boiled with 1 g of ~OH in 7 ml of water and
14 ml of ethanol for 16 hours, the mixture is concentrated,
worked up as usual and 3-[4-(3-m-hydroxyphenyl-1-
piperidyl)butyl]indole, m.p. 135-143 (decomposition), is
obtained.
- 37 -
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Example 8
3.80 g of 1-methyl-3-[4-(3-hydroxy-3-phenyl-1-
piperidyl)butyl]indole (obtainable by reaction of 1-methyl-3-
(4-bromobutyl)indole wi~h 3-piperidone, subsequent reaction
with C6HsLi and hydrolysis) are heated with 40 ml of lN
hydrochloric acid at 50 for 2 hours, worked up as usual and
1-methyl-3-[4-(3-phenyl-1,2,3,6-tetrahydropyridyl)butyl]
indole is obtained.
Example 9
6 ml of 30% H22 are added to a boiling solution of
3.78 g of 3-[4-(3-phenyl-1-piperidyl)butyl]-5-methyl-
thioindole in 50 ml of ethanol, and the mixture is then
boiled for 3 hours. After addition of a further 4 ml of the
oxidising agent, the mixture is boiled a further 9 hours,
cooled, worked up as usual and 3-[4-(3-phenyl-1-piperidyl)
butyl]-5-methylsulfinylindole is obtained.
Example 10
9 ml of 30% H2O2 are added to a solution of 3.78 g
of 3-[4-(3-phenyl-1-piperidyl)butyl3-5-methylthioindole in 20
ml of acetic acid, and the mixture is boiled for 90 minutes.
After working up as usual, 3-[4-(3-phenyl-1-piperidyl)butyl]-
5-methylsulfonylindole is obtained.
Example 11
A mixture of 3.99 g of 3-[4-(3-p-methoxyphenyl-1-
piperidyl)butyl3indole hydrochloride and 3.5 g of pyridine
hydrochloride is stirred at 160 for 3 hours. Aft~r
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- 38 -
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working up as usual, 3-[4-(3-p-hydroxyphenyl-1-piperidyl)-
butyl]indole hydrochloride, m.p. 234-236, is obtained.
Example 12
A solution of 12.3 g of boron tribromide/dimethyl
sulfide complex in 50 ml o~ dichloroethane is added
dropwise, with stirring, to a solution of 3.62 g of 3-[4-(3-
m-methoxyphenyl-l-piperidyl)butyl]indole in 50 ml of 1,2-
dichloroethane at 60-80. After cooling down and working up
as usual, 3-[4-~3-m-hydroxyphenyl-1-piperidyl)butyl]indole,
m.p. 135-143 (decomposition) is obtained.
The examples below relate to pharmaceutical
formulations containing amines of the formula I or their acid
addition salts:
Example A: Tablets
A mixture of 1 kg of 3-[4-(3-m-hydroxyphenyl-1-
piperidyl)butyl]indole, 4 kg of lactose, 1.2 kg of potato
starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is
compressed to form tablets in a customary manner such that
each tablet contains 10 mg of active compound.
Example B: Coated Tablets
Tablets are formed by compression in analogy to
Example A and these are then coated in a customary manner
with a coating of sucrose, potato starch, talc, tragacanth
and dyestuff.
Example C: Capsules
2 kg of 3-[4~(3-m-hydroxyphenyl-1-piperidyl)-
butyl]indole are filled into hard gelatine capsules in a
customary manner such that each capsule contains 20 mg of the
active compound.
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Example D: Ampoules
A solution of 1 kg of 3-[4-(3-m-hydroxyphenyl-1-
piperidyl)butyl]indole hydrochloride in 30 li-tres of double
distilled water is sterilized by filtration, filled into
ampoules, freeze-dried under sterile conditions and closed
sterile. Each ampoule contains 10 mg of active compound.
In analogy, tablets, coated tablets, capsules and
ampoules can be obtained which contain one or more of the
other active compounds of the formula I and/or their
physiologically acceptable acid addition salts.
The preceding examples can be repeated with similar
success by substituting the generically or specifically
described reactants and/or operating conditions of this
invention for those used in the preceding examples.
