Note: Descriptions are shown in the official language in which they were submitted.
L ~ 1 ~257597
Merck Patent Gesellschaft
mit beschrankter Haftung
D a r m s t a d t
Indole derivat;ves
The invention relates to new indole d~rivatives
of the general formula I
I nd-A-~<
\7~ Z
y \z
wher~in
Ind ;s an indol-3-yl radical which is substituted by a
hydroxymethyl or COW group and which can additiona!ly
be monosubstituted or disubstituted by alkyl, O-alkyl,
OH, F, Cl or ~r,
W is H, OH, Oalkyl, NH2, NHalkyl or Ntalkyl)2,
A is -~CH2)n-, -CH2-S-CH2CH2-, -CH2-SO-CH2CH2-
or -CH2-S02-CH2CH2-,
n is 2, 3~ 4 or 5,
the two radicals Y are each H or together are a C-C bond,
one radical Z is Ar,
the other radical Z ;s H and
Ar is a phenyl group wh;ch is unsubstituted or is mono-
substituted or disubstituted by O-alkyl and/or OH or
is substituted by a methylenedioxy group, or Ar is a
2-thienyl or 3-thienyl group,
in which formula each of the alkyl groups has 1 - 4 C
atoms, wherein, however, when n is 2 or 3, the hydroxy-
methyl or cnW group must be in the 4-, 5-, 6- or 7-position
of the indol-3-yl radical,
575~17
i ,~ . ,~
and also physiologically acceptable acid addition
sa1ts thereof.
Similar compounds are known from U.S. patent no.
3,639,414 and from Australian patent no. 36 833/68.
The invention was based on the object of
finding new compounds which can be used for the preparation of
medicaments.
It has been found that the compounds of the
formula I and their physiologically acceptable acid addi-
tion salts possess valuable pharmacological properties.
Thus they exhibit, in particular, an action on the
central nervous system, above all a dopamine-stimulating
presynaptic (neuro1eptic) or postsynaptic
:YY
~S7597
., ~
"r,..
(anti-Parkinsonian) action. In detail, the compounds of
the formula I induce contralateral turning behaviour in
hemiparkinson rats (detectable by the method of Unger-
stedt et al., Brain Res. 24 (1970), 485-493) and inhibit
the b1nding of tritiated dopamine-agonists and dopamine-
antagonists to striatal receptors (detectable by the
method of Schwarcz et al., J. Neurochem;stry 34 ~1980),
772~778 and Creese et al., European J. PharmacoL. 4S
(1977~, 377-381). In addition, the compounds inhibit the
linguomandibular reflex in anaesthetised rats (detectable
by a method based on the methods of Barnett et al.,
European J. Pharmacol. 21 (1973), 178-182 and of Ilhan et
al., European J. Pharmacol. 33 ~1975), 61-64). Anal-
2û gaesic and hypotensive effects also occur; thus in con-
scious, catheter-carrying, naturally hypertensive rats
~strain SHR/NIH-M0/CHB-EMD; for method see Weeks and
Jones, Proc. Soc. Exptl. Biol. Med. 104 ~1960), 646-648),
the directly measured blood pressure is lowered after
;ntragastr;c administrat;on of the compounds.
Compounds of the formula I and their physiologic-
ally acceptable acid addition salts can, therefore, be
used as act~ve compounds for medicaments and also as
intermediate products for the preparation of other active
compounds for medicaments.
The invention relates to the indole derivatives
of the formula I and to their physiologically acceptable
acid addition salts.
In the radicals Ind, W and Ar, alkyl is prefer-
ably methyl and also ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec.-butyl or tert.-butyl. 0-Alkyl is prefer-
ably methoxy, and also ethoxy, n-propoxy, isopropoxy, n-
butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.
~2575~
The radical Ind is, in particular, a monosubsti-
tuted indol-3-yl radical. It ;s preferably substituted
;n the 5-position or 6-position or in the 4-position or
7-position. Substitution in the 1-position or 2-position
;s also possible. Preferred d;substituted indol-3-yl
radicals are substituted in the 5,6-position; disubstitu-
tion is also possible in the 1,2~ 4-, 1,5-, 1,6-, 1,7-,
2,4-, 2,5-, 2,6-y 2,7-, 4,5-, 4,6-, 4,7-, 5,7- or 6,7-
position. In all these cases the substituents can be
identical or different.
Spec;f;cally, the preferred substituents in the
benzene ring of the radical Ind are hydroxymethyl,
formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, carb-
amoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethyl-
rarbamoyl and N,Nodiethylcarbamoyl; in the second placethey are propoxycarbonyl, isopropoxycarbonyl, butoxy-
carbonyl, isobutoxycarbonyl, sec.-butoxycarbonyl and
tert. butoxycarbonyl, N-propylcarbamoyl, N-isopropyl-
carbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, ~-sec.-
butylcarbamoyl, N-tert.-butylcarbamoyl, N-methyl-N-ethyl-
carbamoyl, N,N-dipropylcarbamoyl, N-methyl-N-propyl-
carbamoyl, N-ethyl-N-propylcarbamoyl and N,N-dibutylcar-
bamoyl and, additionally, methyl, ethyl, methoxy, ethoxy,
OH, F, Cl and/or ~r. Accordingly, some preferred mean-
ings of the radical Ind are 2-, 4-, 5-, 6- or 7-formyl-
;ndol-3-yl, 2-, 4-, 5-, 6- or 7-carboxyindol-3-yl, 2-,
4-, 5-, 6- or 7-methoxycarbonylindol-3-yl, 2-, 4-, 5-,
6- or 7-ethoxycarbonylindol-3-yl, 2-, 4-, 5-, 6- or 7-
carbamoylindol-3-yl, 2-, 4-, 5-, 6- or 7-N-methylcarbam-
3û oylindol-3-yl, 2-, 4-, 5-, 6- or 7-N-ethylcarbamoylindol-
3-yl, 2-, 4-, 5-, 6- or 7-N,N-dimethylcarbamoylindol-3-
yl, 2-, 4-, 5-, 6- or 7-N,N-diethylcarbamoylindol-3-yl,
1-methyl-4-, -5-, -6- or -7-hydroxymethylindol-3-yl, 1-
me~hyl-4-, -5-, -6- or -7-formylindol-3-yl, 1-methyl-4-,
-5-, -6- or -7-carboxyindol-3-yl, 1-methyl-4-, -5-, -6-
or -7-carbamoylindol-3-yl, 2-methyl-4-, -5-, -6- or -7-
hydroxymethyl;ndol-3-yl, 2-methyl-4-, -5-, -6- or -7-
formylindol-3-yl, 2-methyl-4-, -5-, -6- or -7-carboxy-
575~97
;ndol-3-yl, 2-methyL-4-, -5-, -6- or -7-carbamoylindol-
3-yl, 5-methoxy-4-, -6- or -7-methoxycarbonylindol-3-yl,
5-methoxy-4-, -6- or -7-ethoxycarbonyLindol-3-yl, 5-
methoxy~4-, -6- or -7-carboxyindol-3-yl, 5-methoxy-4-,
-6- or -7-carbamoylindol-3-yl, 5-fluoro-4-, -6- or -7-
carboxyindol-3-yl, 5-chloro-4-, -6- or -7-carboxyindol-3-
yl, 7-chloro-4-, -5- or -6-carboxyindol-3-yl, 5-bromo-4-,
-6- or -7-carboxyindol-3-yl, 5-hydroxy-4-, -6- or -7-
methoxycarbonylindol-3-yl, 5-hydroxy-4-, -6- or -7-
ethoxycarbonylindol-3 yl, 5-hydroxy~4-, -6- or -7~carboxy-
indol-3-yl, 5-hydroxy-4-, -6- or -7-carbamoylindol-3-yl.
5-hydroxy-2-, -4-, -6- or -7-hydroxymethylindol-3-yl,
6-hydroxy-4-, -5- or -7-carboxyindol-3-yl,
6-hyd~oxy-2-, -4-, -5- or -7-hydroxymethylindol-3-yl.
The parameter n is preferably 4 and the rad;cal
preferably tCH2)4 or -CH2-S-CH2CH2- and
also preferablY -tCH2)2-, -tCH2)3 or tCH2 5
The radical Ar ;s preferably unsubstituted
phenyl. If Ar is a substituted phenyl group, the latter
is preferably monosubstituted. It can, however, also be
disubstituted, and the substituents can be identical or
different. Preferred substituents on the phenyl group
are methoxy and OH. Specifically, Ar is preferably
phenyl, o-, m- or p-methoxyphenyl, o-, m- or p-hydroxy-
phenyl and also o-, m- or p-ethoxyphenyl, 2,3-, 2,4-,
2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3-hydroxy-4-
methoxyphenyl, 3-methoxy-4-hydroxyphenyl, 2,3-, 2,4-,
2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3- or 3,4-
methylenedioxyphenyl, 2-thienyl or 3-thienyl.
Accordingly, the invent;on relates espec;ally to
the compounds of the formula I ;n wh;ch at least one of
the sa;d radicals has one of the mean;ngs ;nd;cated
above, part;cularly the preferred meanings indicated
above. Some preferred groups of compounds can be
expressed by means of the following partial formulae Ia
to Ik, which correspond to the formula I and in wh;ch the
rad;cals and parameters not designated in detail have the
meaning ind;cated ;n formula I, but ;n which:
in Ia Ind is hydroxymethylindol-3-yl, formylindol-3-
yl, carboxy;ndol-3-yl, methoxycarbonylindol-3-yl,
ethoxycarbonylindol-3-yl, carbamoylindol-3-yl,
~ S7~97
ethoxycarbonylmethoxyindol-3-yl or carboxymethoxy-
indol-3-yl, the substituents being preferably in
the 5-posit;on and/or 6-position;
In Ib Ind is 4-, 5-, 6- or 7-hydroxymethylindol-3-yl,
5-, 6- or 7~formylindol-3-yl, 5-, 6- or 7-carboxy-
indol-3-yl, 5-, 6- or 7-methoxycarbonyLindol-3-
yl, 5-, 6- or 7-ethoxycarbonyLindol-3-yl, 5-, 6-
or 7-carbamoylindol-3-yl, 5-methoxy-6-ethoxy-
carbonylindol-3-yl or 5-methoxy-6-carboxyindol-
3-yl;
in Ic A is -(CH2)n- or -CH2-S-CH2CH2-;
in Id A is -(CH2)4 ;
in Ie the two radicals Y are together a C-C bond;
in I~ Ar is phenyl, hydroxyphenyl or methoxyphenyl;
in Ig Ar is in the 4-position and is phenyl;
in Ih Ind is 4-, 5-, 6- or 7-hydroxymethylindol-3-yl,
5-, 6- or 7-formylindol-3-yl, 5-, 6- or 7-carboxy-
indol-3-yl, 5-, 6- or 7-methoxycarbonylindol-3-
yl, 5~, 6- or 7-ethoxycarbonylindol-3-yl, 5-, 6-
or 7-carbamoylindol-3-yl, 5-methoxy-6-ethoxy-
carbonylindol-3-yl or 5-methoxy-6-carboxyindol-
3-yl,
A is -(CH2)n- or -CHz-S-CH2CH2- and
. Ar is phenyl, hydroxyphenyl or methoxyphenyl;
25 in Ii Ind is 4-, 5-, 6- or 7-hydroxymethylindol-3-yl,
5-, 6- or 7-formylindol-3-yl, 5-, o- or 7~carboxy-
indol-3-yl, 5-, 6- or 7-methoxycarbonylindol-3-
yl, 5-, 6- or 7-ethoxycarbonylindol-3-yl, 5-, 6-
or 7-carbamoylindol-3-yl, 5-methoxy-6-ethoxy-
carbonylindol-3-yl or S-methoxy-6-carboxyindol-
3-yl,
A is -(CH2)4- or -CH2-s CH2CH2 and
Ar is phenyl, m-hydroxyphenyl or p-hydroxyphenyl;
in Ij Ind is carboxyindol~3-yl or carbamoylindol-3-yl,
A is -(CH2)4- or -CH2-S-CH2CH2- and
Ar is phenyl, m-hydroxyphenyl or p-hydroxyphenyl;
in Ik Ind is 5-carboxyindol-3-yl or 5-carbamoylindol-
3-yl,
., 1 1~:575~7
;
~,
A is -(CH2)4- or~cH2-s-cH2cH2 and
the two radicals Y together are a C-C bond and
Ar ;s in the 4-position and is phenyl.
The compounds of the formula I can contain one
or more asymmetric carbon atoms. They can, therefore,
exist as racemates and, if several asymmetric carbon
atoms are present, also as mixtures of several racemates,
as well as in different optically active forms.
The invention also relates to the process des-
1û cribed in Patent Claim 3 for the preparation of the com-
pounds of the formula I and of their physiologically
acceptable acid addition sal~s.
The preparation of the compounds of the formula
I is effected in other respects by methods which are in
themselves known~ such as are described in the literature
(for example in the standard works, such as Houben-Weyl,
Methoden der Organischen Chemie (Methods of Organic
Chemistry), Georg-Thieme-Verlag, Stuttgart; or Organic
Reactions, John Wiley ~ Sons, Inc., New York), specific-
ally under reaction conditions such as are known andsu;table for the reactions mentioned. In these reac~ions
it is also possible to make use of variants which are in
themselves known but not mentioned here in detail.
The starting mater;als for the claimed process
can, if desired, also be formed in situ, in such a way
that they are not isolated 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, X
is preferably X; accordingly, in the compounds of the
formula III, x2 and X3 together are preferably NHo
The radical X is preferably Cl or Br; it canp however,
also be I, OH or a reactive, functionally modified OH
group, especially alkylsulfonyloxy having 1-6 C atoms
(for example methanesulfonyloxy) or arylsulfonyloxy
having 6-10 C atoms tfor example benzenesulfonyloxy, p-
toluenesulfonyloxy, 1-naphthalenesulfonyloxy or 2-naphtha-
lenesulfonyloxy).
.~
57597
AccordingLy, the indole derivatives of the
formula I are obtainable, in particular, by reacting com-
pounds of the formula Ind-A-Cl or Ind-A-Br with piperi-
dine or tetrahydropyridine derivatives of the formula III
wherein x2 and X3 together are an NH group (desig-
nated below as IIIa).
The compounds of the formulae II and especially
III are in part known; the compounds of the formulae II
and III which are not known can readily be prepared
1û analQgously to the known compounds. Compounds of the
formula II (A = -CH2-S-CH2CH2-) can be prepared, for
example, from Mannich bases of the formula IV and thioLs
of the formula HS-CH2CH2-X1, for example HS-CH2CH20H.
The sulfoxides and sulfones of the formula II (A =
-CH -SO-CH2CH2- or -CH2-s02 CH2CH2
accessible by oxid;sing the thioethers ~II, A =
-CH2-S-CH2CH2-). Primary alcohols of the formula
Ind-A-OH can be obtained, for example, by reducing the
corresponding carboxylic acids or their esters~ Ireat-
ment with thionyl chloride, hydrogen bromide, phosphorustribromide or similar halogen compounds gives the corres-
ponding halides of the formula Ind-A-Hal. The corres-
ponding sulfonyloxy compounds can be obtained from the
alcohols Ind-A-OH by reaction with the corresponding
sulfonyl chlorides.
The iodine compounds of the formula Ind-A-I can
be obtained, for example, by the action of potassium
iodide on the appropriate p toluenesulfonic acid esters.
The amines of the formula Ind-A-NH2 can be prepared, for
example, from the halides by means of potassium phthal-
imide or by reducing the corresponding nitriles~
The piperidine derivatives IIIa are, for the most
part, known ~cf. German Offenlegungsschrift 2,060,816)
and can be obtained, for example, by reacting 3-piperi-
done or 4-piperidone with organometallic compounds of the
formula M-Ar (wherein M is an Li atom or MgHal), subse-
quently hydrolysing the product to give the corresponding
3-Ar-3 hydroxypiperidines or 4-Ar-4-hydroxypiperidines
q ~2575~7
and, if desired, subsequently dehydrating the latter to
g;ve 3-Ar-3,4-dehydropiperidines or 4-Ar-3,4-dehydro-
piperidines. Compounds of the formula III ~x2 and X3
being X in each case) can be prepared, for example, by
reducing diesters of the formula alkylOOC-CHz-CYZ-CYZ-
COOalkyl to give diols of the formula HO-cH2CH2-cY
CH20H (III, X = X = OH) and, if appropriate, subsequently
reacting the latter with SOCl2 or PBr3.
The reaction of the compounds II and III takes
place in accordance with methods such as are known from
the literature for the alkylation of amines. The compon-
ents can be meLted with one another in the absence of a
solvent, if appropriate in a sealed tube or in an auto-
clave. It is also possible, however, to react the com-
pounds in the presence of an inert solvent. Examples ofsuitable solvents are hydrocarbons, such as benzene,
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-methyl-
pyrrolidone; nitriles, such as acetonitrile, and also, if
appropr;ate, ~ixtures of these solvents w;th one another
or mixtures with water. It can be advantageous to add
an acid-binding agent~ for example an alkali metal or
alkaline earth metal hydrox;de, carbonate or bicarbonate
or another salt of a weak acid of the alkali or alkaline
earth metals, preferably the potassium, sodium or calcium
salt, or to add an organic base, such as triethylamine,
dimethylaniline, pyridine or quinoline, or an excess of
- 30 the amine component Ind-A-NH2 or of the piperidine
; derivative of the formula IIIa. Depending on the condi-
tions employed, the reaction time is between a few
minutes and 14 days, while the reaction temperature is
between about O and 150, normally between 20 and 130.
It is also possible to obtain a compound of the
formula I by treating a precursor containing one or more
reducible group(s~ and/or one or more additional C-C and/
or C-N bond(s) instead of hydrogen atoms with a reducing
57S~7
agent, preferably at temperatures between -80 and +250
and 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.
In principle, it is poss;ble to convert compounds
containing only one of the groups or additional bonds
l;sted above, or compounds contain;ng two or more of the
groups or additional bonds listed above, adjacent to one
another, to a compound of the formula I by reduction; COW
groups present in the starting compound can be reduced at
the same time~ For this purpose it is preferable to use
nascent hydrogen or complex metai hydrides, and also the
Wolff-Kishner method of reduction.
The most preferred starting materials for the
reduction correspond to the formula VII
Ind'-L-Q VII
wherein
Ind' is an indol-3-yl rad;cal which is substituted by a
hydroxymethyl or C0W group and which can, in addi-
tion, be monosubst;tuted or disubst;tuted by alkyl,
0-alkyl, OH, F, Cl, Br and/or 0-benzyl and/or can be
subst;tuted ;n the 1-pos;t;on by an arylsulfonyl
group or a benzyl group,
L ;s A or a cha;n which corresponds to the radical A
but in which one or more -CH2- group(s) have been
replaced by CO- and/or one or more hydrogen atoms
have been replaced by OH groups~
3û Q is
~ ~ or ~ Z An ~ ;
one radical Z' is Ar',
S7597
-- ,,,~4 --
the other rad;cal Z' is H,
An is an anion of a strong acid and
Ar' is a phenyl group which is unsubstituted or is mono-
substituted or disubstituted by O-alkyl, OH and/or 0-
benzyl or is substituted by a methylenedioxy group,
but wherein it is not possible at the same time for Ind'
r~/ Y
to be Ind, L to be A, Q to be - ~ Z and Ar' to
be Ar.
In the compounds of the formuLa VII, L is prefer-
ably -CO-(CH2~n_2-CO- ~specifically -COCO-, -COCH2CO-,
-CO-(CH2)z-CO- or -CO-(CH2)3-CO-], -(CH2)n_1-CO-
[specifically -CH2CO-, -CH2CH2-CO-, (CH2)3-CO- or
-(CH2)4-CO-~, -CH2-S-CH2-CO-, -CH2-SO-CH2-CO- or
-CH2-S02-CH2-CO- and also, for example, -CO-CH2CH2-,
CH2-CO-CH2-~ -co-(cH2)3-~ CH2 CO CH2CH
CH CH2-CO-CH2-, -CO-(CH2)4-, CH2 CO (C 2 3
-cH2cH2-co-cH2cH2 or tCH2)3 CO CH2
Colnpounds of the formula VII can be prepared, for
example, by react;ng 4-Ar'-1,2,3,6-tetrahydropyridine or
4-Ar'-pyridine with a compound of the formula VIII
Ind'-L-X1 VIII
wherein
Ar', Ind', L and Xl have the meanings indicated above,
under the conditions indicated above for the reaction of
II with III.
If the reducing agent used is nasrent hydrogen,
the latter can be produced, for example, by treating
metals with weak acids or with bases. Thus it is pos-
sible, for example, to use a mixture of zinc and an
alkali metal hydroxide solution or of iron and acetic acid.
It is also possible to use sodium or another alkali metal
in an alcohol, such as ethanol, isopropanol, butanol,
amyl alcohol or isoamyl alcohol or phenol. It is also
possible to use an aluminium/nickel alloy in an aqueous
/ ~ ~2575~7
,~
alkaline solution, if appropriate with the addition of
ethanol. Sodium amalgam or aluminium amalgam in an
aqueous alcoholic or aqueous solution are also suitable
for the production of the nascent hydrogen. The react;on
can also be carried out in a heterogeneous phase, prefer-
ably using an aqueous phase and a benzene or toluene
phase.
Complex metal hydrides, such as LiAlH4, NaBH4,
diisobutylaluminium hydride or NaAl~OCH2CH20CH3)2H2
and diborane can also be employed with particular advan-
tage as the reducing agent, if desired with the addition
of catalysts, such as aF3, AlCl3 or Li9r. Solvents
suitable for this reaction are, in particular, ethers,
such as diethyl ether, di-n-butyl ether, THF, dioxane,
diglyme or 1,2-dimethoxyethane, and also hydrocarbons,
such as benzene. Alcohols, such as methanol or ethanol,
and also water and aqueous alcohols are primarily suit-
able as solvent for reduction with Na~H4. Reduction by
these methods is preferably carried out at temperatures
between -80 and +150, in particular between about O and
about 100.
CO groups in acLd amicles or vinyLogous acid amides (for
example those of the formula Vll wherein L is a -(CH2)n l-CO-,
-C~l2-S-C~l2-CO- or -CO-(C~I2)n_2-CO- group) can be reduced to give
CH2 groups particularly advantageously by means of LiAlH4 in
THF at temperatures between about O and 66. In the
course of this it is possible to split off by simultane-
ous reduction arylsulfonyl protective groups present in
the 1-position of the indole ring and/or to reduce COW
groups present on the indole ring, for example to reduce
COOalkyl, COOH or CHO groups to give CH20~ groups~
A reduction of the pyridinium salts of the
formula VII (wherein Q is - ~ Z' A ~ and An
is preferably Cl, Br or CH3S03) to give compounds of
the formula I can be effected, for example, by means of
NaBH4 in water, methanol or ethanol or in mixtures of
, 3 ~5759~
these solvents, if desired with the addition of a base,
such as NaOH, at temperatures between about O and 80.
N-Benzyl groups can be split off by reduction by
means of sodium in liquid ammonia.
It is also possible to reduce one or more car-
bonyl groups to CH2 groups by the Wolff-Kishner method,
for example by treatment with anhydrous hydraz;ne in
absolute ethanol under pressure at temperatures between
about 150 and Z50. Sod;um alcoholate is advantageously
used as a catalyst. The reduction can also be varied in
accordance with the Huang-Minlon method, by carrying out
- the reaction ~ith hydrazine hydrate in a high-boiling, water-
miscible solvent, such as diethylene gLycol or triethylene
glycol, in the presence of an alkali, such as sodium
hydroxide. As a rule, the reaction mixture is boiled for
about 3-4 hours. The water is then removed by distilla-
tion, and the resulting hydrazone is decomposed at tem-
peratures up to about 200. The Wolff-K;shner reduc-
t;on can also be carried out at room temperature in
dimethyl sulfox;de us;ng hydrazine.
Compounds wh;ch in other respects correspond to
the formula I, but conta;n one or more solvolysable
group(s) instead of one or more H atoms, can be solvolysed,
in particular hydrolysed, to give the compounds of the
formula I.
The starting materials for the solvolysis can be
obtained, for example, by reacting IIIa with compounds
which correspond to the formula II (X1 - X), but contain
- one or more solvolysable group(s) instead of one or more
H atoms. Thus it is possible, in particular, to hydro-
lyse, for example in an acid medium, or, bet~er~ in a
neutral or alkaline medium and at temperatures between O
and 200, 4-, S-, 6- or 7-cyanoindole derivatives to
give the corresponding 4-, 5-, 6- or 7-carbamoylindole
derivatives or to hydrolyse 4-, 5-, 6- or 7-carboxyindole
derivatives of the formula I or 1-acylindole derivatives
(corresponding to the Formula I, but containing, in the
1-position of the Ind radical, an acyl group, preferably
~2575~37
/s~
,~
an alkanoyl, alkylsulfonyl or arylsulfonyl group hav;ng
in each case up to 10 C atoms, such as methanesulfonyl,
benzenesulfonyl or p-toluenesulfonyl) to give the corres-
ponding indole derivatives which are unsubstituted in the
1-position of the indole ring.
The basic catalysts used are preferably sodium
hydroxide or carbonate, potassium hydroxide or carbonate
or calcium hydroxide or ammon;a. The selected solvent ;s
preferably water; lower alcohols, such as methanol or
ethanol; ethers, such as THF or dioxane; sulfones, such
as tetramethylene sulfone; or mixtures thereof, prefer-
ably mixtures conta;ning water. Hydrolysis can also be
carr;ed out merely by treatment w;th water alone, part;-
cularly at the bo;l.
Indole derivatives of the formula I (A =
-CH2-S-CH2CH2-) can also be obtained by react;ng
Mannich bases of the formula IV with th;ols of the
formula V tor salts thereof).
Some o,f the starting materials of the formulae
IV and V are known; those of the start;ng mater;als
wh;ch are not known can readily be prepared analogously
to the known compounds. Thus the Mannich bases of the
formula IV can be obtained, for example, from ;ndoles of
the formula Ind-H, formaldehyde and amines of the formula
HN(R)2, and the thiols of the formula V can be obtained
from the bases of the formula IIIa and th;ol derivatives
of the formula HS-CH2CH2-X1 (;t being also possible
to protect the HS group intermediately).
Spec;fically, the reaction of IV with V is
carried out in the presence or absence of an inert sol-
vent at temperatures between about -20 and 250, prefer-
ably between 60 and 150. Examples of suitable solvents
are hydrocarbons, such as benzene, toluene, xylenes or
mesitylene; tertiary bases, such as triethylamine; pyri-
dine or picolines; alcohols, such as methanol, ethanolor butanol; glycols and glycol ethers, such as ethylene
glycol, diethylene glycol or 2-methoxyethanol; ketones,
such as acetone; ethers, such as THF or dioxane; amides,
)s~ ~575~37
- .J 8' -
such as DMF; or sulfoxides, such as dimethyl sulfoxide.
Mixtures of these solvents are also suitable. The thiols
of the formula V are preferably first converted into the
corresponding mercaptides, preferably into the corres-
ponding sodium or potassium mercaptides by reaction withsodium hydroxide or ethylate or potassium hydroxide or
ethylate.
Compounds of the formula I are also obtained by
eliminating HE from compounds of the formula VI, with the
formation of a double bond. Depending on the definition
of E, this can be, for example, an elimination of hydro-
gen halide, water (dehydration), a carboxylic acid or
another acid, ammonia or HCN. The starting miterials of
the formula VI can be obtained, for example, by reacting
II (X1 = X) with a compound of the formula IX
H ~ Z
IX
E Z
wherein E and Z have the meanings ;ndicated.
If one of the rad;cals E ;s Hal, th;s subst;tuent
can be eliminated read;ly under bas;c react;on conditions.
The following bases can be used: alkal; metal hydrox;des,
alkal; metal carbonates, alcoholates, such as, for
example, potass;um tert.-butylate, or am;nes, such as,
for example, d;methylan;l;ne, pyridine, collidine or
quinoline; examples of solvents used are benzene, tolu-
ene, cyclohexane, THF or tert.-butanol. The amines used
- as bases can also be employed in an excess as solventsO
If one of the radicals E ;s an OH group, ;t ;s preferable
to use acids, such as acetic acid or hydrochloric acid
or m;xtures of both, as dehydrating agents. It can be
advantageous to add a solvent (for example water or
ethanol). Elimination of acyl, alkylsulfonyl and alkoxy-
sulfonyloxy or am;no radicals can be carried out under
s;m;lar condit;ons. A gentle el;m;nat;on of sulfon;c
ac;d radicals, for example those of mesylates or tosyl-
57~ 37
,~. .~ ~
ates~ is effected by boiling in DMF or dimethyl sulfoxidewith alkali metal carbonates, for example Li2C03, or
with potassium acetate~ Ammonia can be elim;nated merely
by heating the salts of the corresponding amino compounds
(in particular the 4-amino derivat;ves). HCN can be elimina-
ted similarly from compounds of the formula VI (one group
E is CN) by heating. The elimination of HE from VI is
generally effected at temperatures between û and about
250, preferably between 50 and 200~
It is also possible, if desired, to convert a
compound of the formula I into another compound of the
formula I by methods which are in themselves known.
Thus, in a thioether of the formula I (A =
-CH2-S-CH2CH2-), the thioether group can be oxidised
to give an S0 group or an S02 group, or, in a sulfoxide
of the formula I ~A = -CH2-S0-CH2CH2-), the S0 group
can be oxidised to give an S02 group. If it is desired
to obtain the sulfoxide, oxidation is carried out with,
for example, hydrogen peroxide, per-acids, such as m-
chloroperbenzoic acid, Cr~VI) compounds, such as chromicacid, KMnO4, 1-chlorobenztriazole, Ce(IV) compounds,
such as tNH4)2Ce~N03)6, aromatic diazonium salts
containing negative substituents, such as o-nitrophenyl-
diazonium or p-nitrophenyldiazonium chloride, or electro-
lytically, under relatively mild conditions and at rela-
tively low temperatures ~about -80 to +100)~ If, on
the other hand, it is desired to obtain the sulfones
~from the thioethers or the sulfoxides), the same oxidis-
ing agents are used under more vigorous conditions and/or
in excess and, as a rule, at higher temperatures. The
customary inert solvents can be present or absent in
these reactions. Examples of suitable inert solvents are
water~ aqueous mineral acids, aqueous alkali me~al
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, or chlorinated hydrocarbons, such as chloroform
12~57~97
or CCl4. A preferred oxidising agent is 30% aqueous
hydrogen peroxide. If it is used in the calculated
amount in solvents such as acetic acid, acetone, methanol,
ethanol or aqueous sodium hydroxide solution at tempera-
tures between -20 and 100, this oxidising agent gives
the sulfoxides~ wh;le in excess, at h;gher temperatures,
preferably in acetic acid or in a mixture of acetic acid
and acetic anhydride, it gives the sulfones.
Ethers of the formula I in wh;ch the rad;cals Ind
and/or Ar are monosubst;tuted or d;substituted by O-alkyl
can be split, whereupon the corresponding hydroxy deriva~
t;ves are formed. For example, the ethers can be split
by treatment with the dimethyl sulf;de/boron tr;bromide
complex, for example in toluene, ethers, such as THF, or
d;methyl sulfoxide, or by fus;ng w;th hydrohalides of
pyridine or aniline, preferably pyridine hydrochloride,
at about 15û-250~ or by treatment with diisobuty1aluminium
hydride in to1uene at about 0-110~.
COW groups can also be converted into other COW
groups by methods which are in themselves known. Thus
;t ;s poss;ble to ox;d;se aldehyde groups to give car-
boxyl groups, for example by means of MnO2 ;n an lnert
solvent, such as methylene dichlor;de. On the other
hand, carboxyl groups can be reduced, for example by
means of d;isobutylalumin;um hydride in toluene. Carboxyl
groups can be esterified, for example by treatment with
alcohols in the presence of an acid catalyst, or by reac-
tion with diazoalkanes. Converting the carboxylic acids
into their chlorides, for example by means of SOCl2, and
subsequently reacting the product with NH3 or amines
results in the corresponding carboxamides, which can also
be obtained by treating the carboxyl;c ac;d esters w;th
ammonia or am;nes. Solvolys;s of the esters or amides,
preferably hydrolysis under the conditions ;ndicated
above, results in the carboxylic ac;ds; ;n particular,
carboxylic acids can be obtained from the carbamoyl com-
pounds by treating the latter w;th NaOH or KOH ;n aqueous
glycols or glycol ethers, for example diethylene glycol
monomethyl or monoethyl ether, preferably at temperatures
57S97
~ .
between about 50 and about 200.
Reduction of COW groups, in particular formyl,
alkoxycarbonyl or carboxyl groups, can also result in
hydroxymethyl groups. It is preferable to use a complex
hydride, such as LiAlH4; aldehydes and esters can also
be reduced by means of other reducing agents out of those
listed above. It is preferable to carry out the reaction
under the conditions indicated above. Conversely,
hydroxymethyl groups can be oxid;sed to give formyl or
carboxyl groups, for example by means of MnO2 or CrO3
or derivatives thereof r
The resulting base of the formula I can be con
verted ;nto the appropriate acid addition salt by means
of an acid. Acids which afford physiologically accept-
able salts are suitable for this reaction. Thus it ispossible to use ;norganic ac;ds, for example sulfuric
acid, hydrogen halide acids, such as hydrochloric acid or
hydrobrom;c ac;d, phosphor;c acids, such as orthophos-
phor;c acid, nitric ac;d or sulfam;c ac;d, and also
organ;c acids, specifically aliphatic, alicyclic, arali-
phat;c, aromatic or heterocyclic monobasic or polybasic
carboxylic, sulfon;c or sulfuric acids, such as formic
ac;d, acetic ac;d, propion;c ac;d, p;val;c ac;d, d;ethyl-
acet;c acid, malon;c acid, succinic ac;d, p;melic acid,
fumaric acid, maleic acid, lactic acid, tartaric acid,
mal;c ac;d, benzoic acid, salicylic acid, 2-phenylpro-
pionic acid, citric acid, gluconic acid, ascorbic acid,
nicotinic acid, isonicotinic acid, methanesulfonic or
ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxy-
3û ethanesulfonic acid, benzenesulfonic acid, p-toluene-
sulfonic acid, naphthalenemonosulfonic and naphthalenedi-
sulfonic acids and laurylsulfuric acid.
The free bases of the formula I can, if desired,
be liberated from their salts by treatment with strong
bases, such as sodium hydroxide or carbonate or potassium
hydroxide or carbonate.
The invention also relates to the use of the com-
pounds of the formula I and the;r physiologically accept-
able salts for the preparation of pharmaceutical formula-
, CJ ~Z575~7
tions, especially by a non-chemical route. In this
connection, they can be brought into a suitable dosage
form together with at Least one excipient or auxiliary
and, if appropriate, in combination with one or more
further active compoundts).
The invention also relates to agents, especially
pharmaceutical formulations, containing at least one com-
pound 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
excipients are organic or inorganic substances which are
suitable for enteral (for example oral) or parenteral
administration or for topica~ application 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, mag-
nesium stearate, talc or petroleum jelly. Tablets,
coated tablets, capsules, syrups, elixirs, drops or
suppositories, in particular, are used for enteral
2û administration, solutions, preferably oily or aqueous
solutions, and also suspensions, emulsions or implants
are used for parenteral administration, while ointments,
creams or powders are used for topical appl;cation. The
new compounds can also be lyophilised, and the resulting
lyophilisates can be used, for example, for the prepara-
tion of inject;on formulations.
The formulations indicated can be sterilised and/
or can contain auxiliaries, such as lubricants, preserva-
tives, stabilisers and/or wetting agents, emulsifiers,
salts for influencing the osmotic pressure, buffer sub-
stances, colorants, flavouring substances and/or aroma
substances. If desired, they can also contain one or
more further active compounds, for example one or more
vitamins.
The invention also relates to the use of the com-
pounds of the formula I and their physiologically accept-
able salts in the therapeutic treatment of the human or
animal body and in combating diseases, in particular
7S97
r~d
Parkinson's disease, extrapyramid~l disorders in neuro-
leptic therapy, depressions and/or psychoses and side
effects in the treatment of hypertension (for example by
means of c~-methyldopa). The compounds can also be used
in endocrinology and gynaecology, for example for the
therapy of acromegalia~ hypogonadism, secondary amenorr-
hoea, premenstrual syndrome, undesirable puerpera~ lac-
tation and generally as a prolactin inhibitor, and also
for the therapy of cerebral disorders (for example
migraine), particularly in geriatrics, in a manner simi-
lar to that of certain ergot alkaloids,and also for lowering
the blood pressure.
In this respect, the substances according to the
invention are, as a rule, administered analogously to
known, commercially available formulations ~for example
bromocr;ptin or d;hydroergocornin), preferably in dosages
between about 0.2 and 500 mg, in particular between 0.2
and 50 mg, per dosage unit. The daily dosage is prefer-
ably between about 0.001 and 10 mg/kg of body weight.
The low dosages ~about 0.2 to 1 mg per dosage unit; about
0.001 to O.OOS mg/kg of body weight) are particularly
suitable in this respect for use as migraine agents; for
the other indications dosages between 10 and 50 mg per
dosage unit are preferred. The particular dose for each
specific patient depends, however, on a very wide variety
of factors, for example on the effectiveness of the par-
ticular compound employed, on age, body weight, general
state of health, sex, diet, periods and means of adminis-
tration, the rate of excretion, the combination of
medicaments and the severity of the particular disease
to ~hich the therapy relates. Oral administration is
preferred.
In the examples below, "customary working up"
means as follows: if necessary, water is added~ the
mixture is extracted with methylene dichloride, the
phases are separated, the organic phase is dried over
sodium sulfate and filtered and evaporated and the resi-
due is purified by chromatography over silica gel and/or
by crystallisation. Temperatures are quoted in ~
,~ ~2575517
Example 1
A solution of 28~4 ~ of methyl 3-t4-chloro-2-
th;abutyl)-indole-5-carboxylate Cor 32.8 9 of methyl 3-
~4-bromo-2-thiabutyl)-indole-5-carboxylate; obtainable
by reacting methyl gramine-5-carboxylate with 2-mercapto-
ethanol to give methyl 3-t4-hydroxy-2-thiabutyl)-indole-
5-carboxylate and subsequently reacting the latter with
SOCl2 or P~r3] and 16 9 of 4-phenyl-1,2,3,6-tetra-
hydropyridine in 100 ml of acetonitrile is stirred for
12 hours at 2~ and is worked up in the customary
manner to give methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydro-
pyr;dyl)-2-thiabutyl]-indole-5-carboxylate ("P"); hydro-
chloride, m.p. 202-203.
The following are obtained analogously from the
corresponding starting materials of the formulae II and
III;
3-~4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl~-5-
hydroxymethylindole, m.p~ 178,
3-~4-(4-phenyl-1,2,3,o-tetrahydropyr!idyl)-2-thiabutyl]-
4-hydroxymethylindole,
3-~4-~4-phenyl~1,2,3,6-tetrahydropyridyL)-2-thiabutyl]-
5-hydroxymethylindole~ m.p. 118-120,
3-~4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
6-hydroxymethylindole, m.p. 142-143,
3-~4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
7-hydroxymethylindole,
3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
4-methoxycarbonylindole,
3-[4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl~-
6-methoxycarbonylindole,
3-C4-t4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
7-methoxycarbonylindole,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
4-ethoxycarbonylindole,
3-~4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
5-ethoxycarbonylindole,
3-[4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
6-ethoxycarbonylindole, m.p. 127~129 and
~"" 1;~57597
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
7-ethoxycarbonylindole.
Example 2
A mixture of 2.64 9 of methyl 3-(4-amino-2-thia-
butyl)-indole-5-carboxylate Cobtainable by reacting
methyl 3-(4-bromo-2-thiabutyl)-indole-5-carboxylate with
potass;um phthalimide and subsequent hydrolysis] and
2.15 9 of 1,5 dichloro-3-phenyl-2-pentene (obtainable by
reduc;ng diethyl 3-phenyl-2-pentene-1,5-dioate wi~h
LiAlH4 and subsequently reacting the product with SOCl2)
in 40 ml of acetone and 40 ml of water is boiled for 24
hours and worked up in the customary manner. This gives
"P", hydrochloride, m.p. 202-203.
Example 3
A suspension of 41.6 9 of methyl 3-C4-(4-phenyl-
1,2,3,6-tetrahydropyridyl)-1,4-dioxobutyl]-indole-5-
carboxylate Cm.p. 218; obtainable from 4-~5-methoxy-
carbonyl-3-indole)-4-oxobutyric acid and 4-phenyl-1,2,3~6-
tetrahydropyridine~ in 3 litres of hot absolute THF is
added dropwise, w;th st;rring, to a suspension of 23.4 9
of LiAlH4 in 1,100 ml of absolute THF, the mixture is
boiled for 1 hour and cooled and the product is decom-
posed with water and sod;um hydroxide solution and worked
up ;n the customary manner. This gives 3-C4-(4-phenyl-
1,2,3,6-tetrahydropyridyl)-butyl~-5-hydroxymethylindole,
m.p. 178.
From the corresponding dioxo esters, for example:
methyl 3-C4-t4-phenyl-1,2,3,6-tetrahydropyridyl)-1,4-
dioxobutyl]-indole-4-carboxylate, m.p. 228,
methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyL) 1,4-
dioxobutyl]-indole-6-carboxylate, m.p. 237 and
methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-1,4-
dioxobutyl]-indole-7-carboxylate, m.p. 208,
the following can be obtained analogously:
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-4-
hydroxymethylindole, m.p. 183-184,
3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-6-
hydroxymethyl;ndole, m.p. 179 and
~: 3 1257597
,~
3-C4-t4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-7-
hydroxymethylindole, m.p. 178.
The following is obtained analogously from 3-C4-
oxo-4 (4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-
2-carboxylic acid by means of LiAlH4 in THF:
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-
2-carboxylic acid, m.p. 206-208.
Example 4
1 9 of NaBH4 in 20 ml of water is added, with
stirring, to a solution of 4.51 9 of 1-C4-t5-carboxy-3-
indolyl)-butyl]-4-phenylpyridinium bromide Cobtainable
from 3 (4-bromobutyl)-indole-5-carboxylic acid and 4-
phenylpyridine] in 50 ml of 1N NaOH, and stirring is con-
tinued for a further 3 hours at 60. Working up in the
customary manner gives 3-C4-(4-phenyl-1,2,3,6-tetrahydro-
pyridyl)-butyl]-indole-5-carboxylic acid, m.pO 284-Z85.
Example 5
A mixture of 35.5 9 of 3-C4-t4-phenyl-1,2,3,6-
tetrahydropyridyl)-butyl]-5-cyanoindole Cm.p. 167;
obtainable from the corresponding 5-formyl compound via
the ox;me], 27.1 9 of NaOH, 520 ml of water and 42~ ml of
diethylene glycol monoethyl ether is stirred for 3 hours
at a bath temperature of 140. The mixture is cooled
and worked up in the customary manner to gi~e 3-C4-(4~
phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carbox-
amide, m.p. 200-205.
The following are obtained analogously by hydro-
lysing the corresponding nitriles:
3-C2-(4-phenyl-1,2,3,6-tetrahydropyridyl)-ethyl~-indole-
5-carboxamide,
3-C3-(4-phenyl-1,2,3,6-tetrahydropyridyl)-propyl]-indole-
5-carboxamide,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-
4-carboxamide,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl] indole-
6-carboxamide, m.p. 226,
3-C4-(4-phenyl-1,2,3~6-tetrahydropyridyl)-butyl~-;ndole-
7-carboxamide, m.p. 203,
t~ 575~37
,~
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl~-5-
methoxyindole-6-carboxamide,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-S-
hydroxyindole-6-carboxamide,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-7-
chloroindole-4-carboxamide,
3-C4-(4-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-
butyl]-indole-5-carboxam;de~
3-C4-(4-p-hydroxyphenyl-1,2,3,S-tetrahydropyridyl)-
butyl]-indole-S-carboxamide,
3-CS-(4-phenyl-1,2,3,6-tetrahydropyridyl)-pentyl]-indole-
S-carboxamide,
3-t4-(3-phenyl-1,2,3,6-tetrahydropyr;dyl)-butyl]-indole-
5-carboxamide,
3-C4-t3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-S-carboxamide,
3-C4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-6-carboxamide,
3-~4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
2û indole-S-carboxamide,
3-~4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl~-
indole-6-carboxamide,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
indole-4-carboxamide,
3-~4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
indole-5-carboxamide,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
indole-6-carboxamide,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
indole-7-carboxamide,
3-~4-(4-phenyl-1,2~3,6-tetrahydropyridyl)-2-thiabutyl]-
S-methoxyindole-6-carboxamide,
3-~4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
S-hydroxyindole-6-carboxamide,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
7-chloroindole-4-carboxamide,
3-C4-(4-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-thia-
butyl]-;ndole-5-carboxamide,
1.25~597
3-C4-~4-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-5-carboxamide,
3-C4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-5-carboxamide,
5 3-C4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-6-carboxamide,
3-C4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-5-carboxamide,
3-[4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
10 thiabutyl]-indole-6-carboxamide,
3-C4-(4-phenylpiperidino)-butyl] indole-5-carboxamide,
3-[4-(4-phenylp;perid;no~-butyl]-indole-6-carboxamide,
3-C4-(4-m-hydroxyphenylpiperidino)-butyl]-indole-5-
carboxamide,
15 3-C4-(4-m-hydroxyphenylpiper;dino)-butyl~-indole-6-
carboxamide,
3-C4-(4-p-hydroxyphenylpiperidino)-butyl]-indole-5-
carboxamide,
3-C4-(4-p-hydroxyphenylpiperidino)-butyl]-indole-6-
20 carboxamide,3-C4-~3-m-hydroxyphenylpiperidino)-butyl]-indole-5-
carboxamide,
3-C4-t3-m-hydroxyphenylpiperidino)-butyl]-indole-6-
carboxamide,
25 3-C4-~3-p-hydroxyphenylpiperidino)-butyl]-indole-5-
carboxamide,
3-[4-(3-p-hydroxyphenylpiperidino)-butyl]-indole-6-
carboxamide,
3-C4-(4-phenylpiperidino)-2-thiabutyl]-indole-5-carbox-
30 amide,3-C4-(4-phenylpiperidino)-2-thiabutyl]-indole-6-carbox-
amide,
3-C4-(4-m-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
5-carboxamide,
35 3-[4-(4-m-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
6-carboxamide,
3-[4-(4-p-hydroxyphenylpiperidino)-2-thiabu~yl]-indole-
5-carboxamide,
~575~37
,~6
,;~
3-C4-(4-p-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
6-carboxamide,
3-[4-(3-m-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
5-carboxamide,
5 3-C4-(3-m-hydroxyphenylpiperidino) 2-thiabutyl~-indole-
6-carboxamide,
3-C4-(3-p-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
5-carboxamide and
3-C4-(3-p-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
10 6-carboxamide.
Example 6
The reaction is carried out as descr;bed in
Example 5, but the mixture is boiled for 16 hours and,
after working up in the customary manner, gives 3-C4-(4-
15 phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-car-
boxylic acid, m.p. 284-285.
The following are obtained analogously by hydro-
lysing the corresponding nitriles:
3-C2-(4-phenyl-1,2,3,6-tetrahydropyridyl)-ethyl]-;ndole-
20 5-carboxylic acid,
3-C3-~4-phenyl-1,2,3,6-tetrahydropyridyl)-propyl]-indole-
5-carboxylic acid,
3-C4-t4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-
4-carboxylic acid,
25 3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-butyL]-indole-
6-carboxylic acid, m.p. 268,
3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-
7-carboxylic acid, m.p. 262-265,
3-C4-~4-phenyl-1 ,2,3,6-tetrahydropyridyl)-butyl]-5-
30 methoxyindole-6-carboxylic acid,
3-C4 (4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-
hydroxyindole-6-carboxylic acid,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-7-
chloroindole-4-carboxylic acid, m.p. 263-266U
35 3-C4-(4-o-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl~-
indole-5-carboxylic acid,
3-C4-(4-m-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-5-carboxylic acid,
575~7
3-C4-(4-p-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-5-carboxyl;c acid,
3-C4-(4-o-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
;ndole-5-carboxylic acid,
3-C4-(4-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl~-
indole-5-carboxylic acid,
3-C4-t4-p hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-5-carboxylic acid,
3-C4-(4-(3-methoxy-4-hydroxyphenyl~-1,2,3,6-tetrahydro-
pyridyl)-butyl]-indole-5-carboxylic acid,
3-C4-t4-~3,4-dimethoxyphenyl)-1~2,3,6-tetrahydropyridyl)-
butyl~-indole-5-carboxylic acid,
3-C4-(4-(3,4-methylenedioxyphenyl)-1,2,3,6-tetrahydro-
pyridyl)-butyl]-indole-5-carboxylic acid,
3-C4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)-butyl~-
indole-5-carboxylic arid,
3-C4-(4-(3-thienyl)-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-5~carboxylic acid,
3~CS-(4-phenyl-1,2,3,6-tetrahydropyridyl)-pentyl~-;ndole-
5-carboxylic acid,
3-C4-(3-phenyl-1,2,3,6-tetrahydropyridyl)-buty!~-indole-
5-carboxyl;c ac;d,
3-C4-~3~p-methoxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl~-
indole-5-carboxyl;c ac;d,
3-C4-t3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl~
;ncdole-5-carboxylic acid,
3-C4-(3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl~-
indole-6-carboxylic acid,
3-C4-(3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl~-
indole-5-carboxyl;c acid,
3-C4-(3-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-butyl~-
indole-6-carboxylic acid,
3-C4-(4-phenylpiperidino)-butyl]-indole-5-carboxylic ac;d,
3-C4-(4-phenylp;perid;no)-butyl~-;ndole-6-carboxylic acid,
3-C4-(4-m-hydroxyphenylp;per;dino)-butyl~-;ndole-5-
carboxylic acid,
3-C4-(4-m-hydroxyphenylpiperidino)-butyl~-indole-6-
carboxylic acid,
57597
9 ~
_ ~ _
3-~4-(4-p-hydroxyphenylpiperidino)-butyl]-indole-5-
carboxyllc ac;d,
3-~4-(4-p-hydroxyphenylpiperidino)-butyl]-indole-6-
carboxylic acid,
3-~4-t3-m-hydroxyphenylpiperidino)-butyl]-indole-S-
carboxylic acid,
3-~4-(3-m-hydroxyphenylpiperidino)-butyl]-indole-6-
carboxylic acid,
3-~4-(3-p-hydroxyphenylpiperidino)-butyl~-indole-5-
carboxylic acid,3-~4-(3-p-hydroxyphenylpiperidino)-butyl]-indole-6-
carboxyl;c acid,
3-C4-(4-phenyLpiperidino)-butyl]-7-chloroindole-4-car-
boxylic acid and
3-~4-(3-m-hydroxyphenylp;per;d;no)-butyl]-7-chloro;ndole-
4-carboxyl;c ac;d.
Example 7
4.68 ~ of methyl 1-benzenesulfonyl-3-C4-t4-
phenyl-1,2,3,~-tetrahydropyr;dyl)-butyl]-;ndole-5-carboxy-
late Cobtainable from methyl 1-benzenesulfonyl-3-~4-
chlorobutyl)-indole-5-carboxylate and 4-phenyl-1,2,3,6-
tetrahydropyrid;ne~ are boiled with 1 9 of KOH ;n 7 ml of
water and 14 ml of ethanol for 16 hours, and the mixture
is concentrated and worked up in the customary manner to
give 3-~4-(4-phenyl-1,2,3,6-tetrahydropyr;dyl)-butyl]-
indole-5-carboxylic acid, m.p. 284-285.
Example 8
2.76 9 of Na are d;ssolved in 180 ml of ethanol,
21.9 9 of 1-(2-mercaptoethyl)-4-phenyl-1,203,6-tetra-
hydropyr;dine ~obta;nable by reacting 4~phenyl-1,2,3,6-
tetrahydropyridine w;th th;oglycol;c ac;d to give 1-(2-
mercaptoacetyl)-4-phenyl-1,2r3,6-tetrahydropyridine and
reducing the latter with LiAlH4] and 23.2 9 of methyl
gramine-5-carboxylate are added, the mixture is boiled
for 16 hours and evaporated, and the res;due ;s ~orked
up ;n the customary manner to g;ve "P", hydrochloride,
m.p. 202-203.
The following are obtained analogously from the
57597
-,3~2 -
corresponding starting materials of the formulae IV and
V :
methyl 3~C4-~4-phenyl-1,2~3,6-tetrahydropyridyl)~2-thia-
butyl]-5-methoxyindole-6-carboxylate,
ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thia-
butyl]-5-methoxyindole-6-carboxylate, hydrochloride,
m.p. 169-173,
methyl 3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thia-
butyl]-5-hydroxyindole~6-carboxylate,
ethyl 3-[4-(4-phenyl~1,2,3,6-tetrahydropyridyl)-2-thia-
butyl~-5-hydroxyindole-6-carboxylate and
methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thia-
butyl]-7-chloroindole-4-carboxylate.
Example 9
4.05 9 of 1-methyl-3-C4-(4-hydroxy-4-phenyl-1-
piperidyl)-butyl]-indole-5-carboxamide Cobtainable by
reacting 1-methyl-3-(4-bromobutyl)-indole-5-carboxamide
with 4-piperidone, followed by reaction with C6HsLi and
hydrolys;s~ are heated at 5û with 40 ml of hydrochloric
Z0 acid for 2 hours, and the mixture is worked up in the
customary manner to give 1-methyl-3-C4-(4-phenyl-1,2,3,6-
tetrahydropyridyl)-butyl]-indole-5-carboxamide.
Example 10
6 ml of 30% H202 are added to a boiling solution
of 4.06 9 of "P" in 50 ml of ethanol, and the mixture is
then boiled for 3 hours. After a further 4 ml of the
oxidising agent have been added, the mixture is boiled
for a further 9 hours and is cooled and worked up in the
customary manner to give methyl 3-C4-(4-phenyl-1,2,3,6-
tetrahydropyridyL)-2-thiabutyl~-indole-5-carboxylate-S-
oxide.
Example 11
9 ml of 30% H202 are added to a solution of
4.06 9 of "P" in 20 ml of acetic acid, and the mixture is
boiled for 90 minutes. Working up in the customary
manner gives methyl 3-C4-(4-phenyl 1,2,3,6-tetrahydro-
pyridyl)-2-thiabutyl]-indole-5-carboxylate-S,S-dioxide.
~ ~2575~7
Example 12
A mixture of 4.04 9 of 3-C4-(4-p-methoxyphenyl-
1,2,3,6-tetrahydropyridyl)-butyL]-indole-5-carboxylic
acid and 3.5 9 of pyridine hydrochloride is stirred for
3 hours at 160. Working up in the customary manner
gives 3-[4-(4-p-hydroxyphenyL-1,2,3,6-tetrahydropyridyl)-
butyl]-indole-5-carboxylic acid~
Example 13
36 9 of 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-
butyl]-5-hydroxymethylindole are dissolved in 1.6 litres
of THF, and 300 ml of ether are added. 55 9 of MnO2 are
added with stirring. The mixture is stirred for 16 hours
at 20, a further 100 9 of MnO2 are added in port;ons~
and st;rring is continued for a further 100 hours at 20.
Filtration and working up in the customary manner gives
3-C4-(4-phenyl~1,2,3,6-tetrahydropyridyl)-butyl]-5-formyl-
indole, m.p. 131.
The following are obtained analogously by oxidis-
;ng the correspond;ng hydroxymethylindoles:
3-~4-t4-phenyl-1,2,3,6-tetrahydropyridyl)-butylJ-2-formyl-
indole, m.p. 129-130,
3-~4-t4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-4-formyl-
;ndole,
3-C4-~4-phenyl~1,2,3,6-tetrahydropyridyl)-butylJ-6-formyl-
;ndole,3-C4-t4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-7-formyl-
indole,
3-~4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
4-formylindole,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
5-formylindole,
3-~4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
5 formylindole and
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
7-formylindole.
Example 14
3.9 9 of 3-C4-(4-phenyl-1,2,3,6-tetrahydropyrid-
yl)-butyl~-6-hydroxymethylindole are dissolved in 50 ml
~ ;25~59~ 26474-48
- 31 -
of methylene dichloride, 9 9 of MnO2 are added to the
solution, the mixture is stirred for 60 hours at 40 and
the insoluble components are filtered off. Working up
the filtrate in the customary manner gives 3-[4-(4-phenyl-
1~2~3~6-tetrahydropyridyl)-butyl]-indole-6-carboxylic
acid, m.p. 268.
Example 15
3~88 9 of 3-~4-(4-phenyl-1,2,3,6-tetrahydropyrid-
yl)-butyl~5-formylindole are dissolved in 80 ml of
methylene dichloride, 9 9 of MnO2 are added, and the
suspension is stirred for 48 hours at 40. Filtration
and working up in the customary manner give 3-~4-(4-
phenyl-1,2,3,6-tetrahydropyridyl)-butyl~-indoLe-5-
carboxylic acid, m.p. 284-285.
Example 16
4.04 9 of 3-~4-(4-phenyl-1,2,3,6-tetrahydropyrid-
yl)-butyl~-indole-5-carboxylic acid are suspended in
25 ml of toluene, and a 3-fold molar amount of a 20%
strength solution of diisobutylaluminium hydride in
toluene is added dropwise, under N2 and with stirring,
the mixture is boiled for 2 hours and cooled and is de-
composed with water, and the product is worked up in the
customary manner to give 3-~4-~4-phenyl-1,2,3,6-tetra-
hydropyridyl)-butyl~-5-formylindole, m.p. 131.
Example 17
A solution of 4~04 9 of 3-~4-(4-phenyl-1,2,3,6-
tetrahydropyridyl)-butyl~-indole-5-carboxylic acid in
40 ml of THF is added dropwise, with stirring and under
N2, to a suspension of 0.76 9 of lithium aluminium
hydride in 30 ml of THF. The mixture~is stirred for a
further 2 hours at 20, is decomposed with dilute
sodium hydroxide solut;on and then with water and is
filtered. The filtrate is worked up in the customary
manner. This gives 3-~4-(4-phenyl-1,2,3,6-tetrahydro-
pyridyl)-butyl]-5-hydroxymethylindole, m.p. 178.
Example 18
A solution of 4.18 9 of methyl 3-[4-(4-phenyl-
1~2~3~6-tetrahydropyridyl)-butyl]-indole-5-carboxylate in
~` JJ
~575~7 26474-48
32 ..
40 ml of THF is added dropwise, ~ith stirring and under
N2, to a suspension of 0.57 9 of lithium aluminium
hydride in 20 ml of THF. The mixture is stirred for 1
hour at 20 and s decomposed with dilute sod;um hydrox-
5 ide solution and then with water and is f;ltered, and thefiltrate is worked up in the customary manner to give 3-
C4-(4-phenyl-1,2,3,6-tetrahydropyr;dyL)-butyl]~5~hydroxy-
methyl;ndole, m.p. 178.
The hydroxymethyl compounds ment;oned ;n Example
10 3 and also 2-hydroxymethyl-3-c4-(4-phenyl-1~2~3~6-tetra-
hydropyridyl)-butyl~-indole, m.p. 162-16305 are obtained
analogously from the correspond;ng esters.
Example 19
A solution of 3.88 9 of 3-C4-(4-phenyl-1,2,3,6-
15 tetrahydropyridyl)-butyl~-5-formylindole in 40 ml of THF
is added dropwise, under N2 and with stirring, to a
suspension of 0.57 9 of lithium aluminium hydride in
20 ml of THF. The mixture ;s stirred for a further hour
at 20 and is decomposed with dilute sodium hydroxide
Z0 solution and then with water and is filtered and ~orked
up in the customary manner to g;ve 3-C4-(4-phenyl-1,2,3,6-
tetrahydropyridyl)-butyl~-S-hydroxymethyl;ndole, m.p
178.
Example 20
HCl is passed into a boiling solution of 4.04 9
of 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-5-carboxylic acid ;n 50 ml of absolute ethanol for
Z hours. The mixture is bo;led for a further hour and
worked up ;n the customary manner to give ethyl 3-C4-(4-
30 phenyl-1,2~3,6-tetrahydropyridyl)-butyl~-indole-5-
carboxylate. Rf 0.65 (silica gel; 8:2 CH2Clz/CH30H).
The follow;ng are obta;ned analogously by esteri-
f;cat;on:
methyl 3-C4-(4-phenyl-1,Z"3,6-tetrahydropyridyl)-bu~yl~-
35 indole-2-carboxylate,
methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydroPYridYl)-butYl]-
indole-4-carboxylate,
methyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
~57S~7 26474-48
33 ~
indole-5-carboxylate,
methyl 3 C4-(4-phenyl-1,2,3,6-tetrahydroPyridyl)-butyl]
indole-6-carboxylate,
methyl 3-C4-(4-phenyl-1,.,3,6-tetrahydropyridyl)-butyl~-
indoLe-7-carboxylate,
ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-2-carboxylate,
ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-4-carboxylate,
1û ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-6-carboxylate,
ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
in~ole-7-carboxylate,
methyl 3-C4-t4-phenyL-1,2,3,6-tetrahydropyridyl)-butyl~-
5-methoxy;ndole-6-carboxylate,
ethyl 3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
5-methoxyindole-6-carboxylate,
methyl 3-C4-~4~phenyl-1,2,3,6-tetrahydropyridyl)-butyl~-
5-hydroxyindole-6-carboxylate,
ethyl 3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-bu~yl~-
5-hydroxyindole-6-carboxylate,
methyl 3-C4-~4-phenyl-1,2~3~6-tetrahydropyridyl)-butyl~-
7-chloroindole-4-carboxylate, hydrochloride, m.p. 219-221
ethyl 3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
7-chloro;ndole-4-carboxylate and
butyl 3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-
indole-5-carboxylate.
Example 21
4.04 9 of 3-C4-(4-phenyl-1,2,3,6-tetrahydropyrid-
yl)-butyl~-;ndole-5-carboxylic acid are dissolved in 30
ml of chloroform, the solution ;s saturated with HCl gas,
1.8 9 of thionyl chloride are added dropwise and the mix-
ture is boiled for 2 hours. After evaporation, 30 ml of
toluene are added and the mixture is evaporated again.
The residue is dissolved in 20 ml of chloroform, this
solution is added dropwise, with stirring, to a saturated
solution of ammonia in 50 ml of chloroform, the mixture
is stirred for 2 hours at 20 and is filtered, and the
r ! . ,~7 ~.~57597
filtrate is concentrated. Working up in the customary
manner gives 3-[4 (4-phenyl-1,2,3,6-tetrahydropyr;dyl)-
butyl]-indole~5-carboxamide, m.p. 207-208.
The following are obtained analogously from the
acids by reacting the la~ter with SOCl2 and then with
ammonia or the corresponding amines:
3 C4-(4-phenyl 1,2,3,6-tetrahydropyridyl)-butyl~-indole-
2-carboxamide,
3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl] indole-
2-carboxylic acid N~me`thylamide and
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl~-indole-
2-carboxylic acid N,N-dimethylamide. Rf û.72 (sllica
gel, 8:2 CH2Cl2/CH30H).
Example 22
0.02 mol of concentrated ammonia (D = 0.9) is
added dropwise at ZO to a solution of 4.18 9 of methyl
3-C4-t4-phenyl-1,2,3,6-tetrahydropyr;dyL)-butyl~-indole-
5-carboxylate in 30 ml of dimethylformamide. The mixture
is st;rred for a further hour at 20 and worked up ;n
the customary manner to give 3-C4-(4-phenyl-1,2,3,6-
tetrahydropyridyl)-butyl~-indole-5-carboxamide, m.p. 207-
208.
Example 23
A m;xture of 37.3 9 of 3-C4-t4-phenyl-1,2,3,6-
tetrahydropyridyl)-butyl~-5-carbamoylindole, 27.1 9 of
NaOH, 525 ml of water and 450 ml of diethylene glycol
monoethyl ether ;s boiled with stirring for 16 hours.
The mixture is cooled, worked up in the customary manner
and acidified to give 3-C4-(4-phenyl-1,2,3,6-tetrahydro-
pyridyl)-butyl~-indole-5-carboxylic acid, m~p. 284-285.
Example 24
4.5 9 of 3-C4-(4-phenyl-1,2,396-tetrahydropyrid-
yl)-2-thiabutyl]-5-methoxy-6-ethoxycarbonylindole are
boiled with 20 ml of water and 100 ml of 2N ethanolic
KOH for 30 minutes, and the mixture is worked up in the
customary manner to give 3-[4-(4-phenyl-1,2~3~6-tetra-
hydropyridyl)-2-thiabutyl]-5-methoxyindole-6-carboxylic
acid, m.p. 16B-171.
597
s
,., ` --,3~ --
The following are obtained analogously by saponi-
fying the corresponding methyl or ethyl esters:
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
indole-4-carboxylic acid,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl~-
indole-5-carboxylic acid, m~p. 184-189,
3~C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
indole-6-carboxylic acid,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl~-
indole-7-carboxylic acid,
3-C4-t4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl]-
5-hydroxyindole-6-carboxylic acid,
3-C4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl~-
7-chloroindole-4-carboxylic acid,
3-C4-(4-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-5-carboxylic acid,
3-C4-(4-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-5-carboxylic acid,
3-C4-~3-m-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-5-carboxylic acid,
3-C4-~3-m-hydroxyphenyl 1,2,3,6-tetrahydropyridyl)-2-
th;abutyl]-indole-6-carboxylic acid,
3-C4-~3-p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-5-carboxylic acid,
3-C4-~3 p-hydroxyphenyl-1,2,3,6-tetrahydropyridyl)-2-
thiabutyl]-indole-6-carboxylic acid,
3-C4-(4-phenylpiperidino)-2-thiabutyl~-indole-5-carboxy-
lic acid,
3-C4-(4-phenylpiperidino)-2-thiabutyl]-indole-6-carboxy-
3û lic acid,
3-C4-(4-m-hydroxyphenylpiperidino)-2-thiabutyl~-indole-
5-carboxylic acid,
3-C4-~4-m-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
6-carboxylic acid,
3-C4-(4-p-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
5-carboxylic acid,
3-~4-(4-p-hydroxyphenylpiperidino)-2-thiabutyl]-indole-
6-carboxylic acid,
5759~ ~
3-C4-(3-m-hYdroxyphenylpiperidino)-2-thiabutyl]-indole
5-carboxylic acid,
3-C4-(3-m-hydroxyphenylpiperidino)-2-thiabutyl]-indole
6-carboxylic acid,
3-c4-(3-m-hydroxyphenylpiperidino)-2-thiabutyl]-7-chlor
indole-4-carboxyl;c acid,
3-C4-(3-p-hydroxyphenylpiperidino)-2-thiabutyl]~7-chloro-
indole-5-carboxylic acid and
3-C4-(3-p-hydroxyphenylpiperidino)-2-th;abutyL]-7-chloro-
;ndole-6-carboxylic acid.
Example 25
In analogy to Example 1, the following are obtained from
the corresponding starting materials of formula II and III:
3-L3-(4-phenyl-1,2,3,6-tetrahydropyridyl)-propyl7-4-hydroxy-
methyl-indole, m.p. 164 - 168
2-hydroxymethyl-3-L4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-
butyl7-5-methoxylnclole~ m.p. 145 - 146
2-hydroxymethyl-3-L4-(LI-phenyl-1~2~3,6-tetrahydropyridyl)-
buty~7-6-methoxyLnloLe.
Example 26
In analogy to Example 3, there are obtainecl from the
corresponding oxo-carboxylic acids:
3-/2-(4-phenyl-1,2,3,6-tetrahydropyridyl)-ethyl7-irldole-
6-carboxylic acid, m.p. ~240
3-L3-(4-phenyl-1,2,3,6-tetrahydropyridyl)-propyl7-indole-4-
carboxylic acid, m.p. 268 - 271
3-L4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl7-5-hydroxy-
indole-6-carboxylic acid
3-L4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl7-6-hydroxy-
indole-5-carboxylic acid
3-L4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl7-5-
hydroxy-indole-6-carboxylic acid
3-L4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-2-thiabutyl7-
6-hydroxy-indole-5-carboxylic acid.
" ~57597
i 7
~xample 27
In analogy to Example 8 there is obtained from 1~(2-mercap-
toethyl)-3-m-hydroxyphenyl-piperidine and 5-hydroxy-
methyl-gramine:
3-L4-(3-m-hydroxyphenyl-piperidino)-2-thiabutyl7-5-
hydroxymethyl-indole.
Example 28
A solution of 1.5 9 of diisobutylaluminiumhydride in 15 ml
of toluene is added with cooling and stirring to a suspen-
sion of 3.9 9 oF 2-hydroxymethyl-3-L4-(4-phenyl-1,2,3,6-
tetrahydropyridyl)-butyl7-6-methoxy-indole in 400 ml
of toluene. rhe mixture is warrned to room temperature,
refluxed for 3 hours with stirring, cooled and worked
up in the osual manner. 2-Hydroxymethyl-3-L4-(4-phenyl-
l,2,3,6-tetrallyclropyrldyl)-butyl7-6-hydroxy-indole is
obtainecl.
From the corresponcling 5-methoxy compound there is obtained
analogous:ly:
2-hydroxymethyl-3-L4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-
butyl7-5-hydroxy-indole.
57597
The examples below relate to pharmaceutical for-
mulations conta;ning amines of the formula I or acid
addition salts thereof:
Example A: Tablets
A mixture of 1 kg of 3-C4-(4-phenyl 1,2,3,6-
tetrahydropyridyl)-butyl]-indole-50carboxamide, 4 kg of
lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1
kg of magnesium stearate is compressed in the customary
manner to g;ve tablets, so that each tablet contains 10
mg of active compound.
Example 0: Coated tablets
Tablets are compressed analogously to ~xample A
and are then coated in a customary manner with a coating
composed of sucrose, potato starch, talc, tragacanth and
colorant.
Example C: Capsules
2 kg of 3-C4-~4-phenyl-1,2,3,6-tetrahydropyridyl)-
butyl~-indole-5-carboxylic acid are filled into hard
gelatine capsules in a customary manner, so that each
capsule conta;ns 20 mg of the act;ve compound.
Example D: Ampoules
A solut;on of 1 kg of 3-C4-~4-phenyl-1,2,3,6-
tetrahydropyridyl)-butyl~-5-methoxyindole 6-carboxylic
acid hydrochloride in 60 litres of twice distilled water
is filtered under sterile conditions and is filled into
ampoules, which are lyophilised under sterile conditions
and closed in a sterile manner. Each ampouLe contains
10 mg of active compound.
Tablets, coated tablets, capsules and ampoules
containing one or more of the other active compounds of
the formula I and/or physiologically acceptable acid
addition salts thereof can be obtained analogously.
