1-(4'-fluorophenyl)-3,5-substituted indoles useful in the treatment of psychic disorders and pharmaceutical compositions thereof

The present invention relates to novel indole derivatives which have interesting pharmacodynamic effects indicating pronounced activity in the treatment of psychic disorders, especially psychoses and, at the same time, a low degree of undesired side effects. Moreover, the invention relates to methods for the preparation of said indole derivatives, pharmaceutical compositions containing same, and methods for the treatment of psychic disorders, especially psychoses, by administering a therapeutically active amount of one of said derivatives to a living animal body, including human beings. The novel indole derivatives of the present invention are represented by the following formula: ##STR1## wherein R is phenyl, optionally substituted with halogen, lower alkyl or trifluoromethyl, or a hetero aromatic group, such as 2-thienyl, 3-thienyl, 2-furoyl, 3-furoyl, 2-thiazol, 2-oxazol, 2-imidazole, 2-pyridyl, 3-pyridyl or 4-pyridyl; R.sup.1 is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, trifluoromethyl, lower alkylsulfonyl, amino, lower alkylamino or lower di-alkylamino; "A" is nitrogen or carbon, and the dotted line indicates--when A is carbon--an optional bond; R.sup.2 is hydrogen, cycloalkyl, lower alkyl or lower alkenyl, optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid radical having from two to twenty-four carbon atoms inclusive, or R.sup.2 is the group ##STR2## wherein "n" is an integer of 2-6; X is oxygen or sulfur, or >C.dbd.X may constitute the group >CH.dbd. when Y is .dbd.N-- or .dbd.CH--; Y is oxygen, sulfur, CH.sub.2 or N R.sup.3, where R.sup.3 is hydrogen or lower alkyl, lower alkenyl or a cycloalkylmethyl group, said "cycloalkyl" having from three to six carbon atoms inclusive; Z is --(CH.sub.2).sub.m --, "m" being 2 or 3, or Z is --CH.dbd.CH-- or 1,2-phenylene optionally substituted with halogen or trifluoromethyl, or Z is --CO(or S)CH.sub.2 --; U is nitrogen or carbon, provided that when R.sup.1 is chloro, A is nitrogen and R.sup.2 is methyl or cyclohexyl, R may not be phenyl; as well as their pharmaceutically acceptable acid addition salts.

BACKGROUND OF THE INVENTION 
In the past, several indole derivatives being substituted at the nitrogen 
atom with a carboxylic acid radical have been found to possess analgetic 
and antiinflammatory properties. Recently it was suggested in German OLS 
No. 2811031 that also indoles having a phenylsubstituent at the nitrogen 
atom might have the desired analgetic or antiinflammatory effects, but no 
data were given for the 1-phenyl-5-chloro-3-methylpiperanzine-indole or 
1-phenyl-5-chloro-3-cyclohexyl-piperazine-indole actually disclosed in the 
specification. We have prepared the first-mentioned of these compounds (Lu 
23-015) and found that it was without interesting effects in the 
pharmacological testing carried out in our laboratories. 
In European Patent Application No. 80401005.6 some derivatives of 
tetrahydro-pyridinyl-indoles having at the 1-position either hydrogen or 
alkyl (1-3 C-atoms), were described as being neuroleptics. The 
pharmacological data given in the specification, however, indicate only 
weak to moderate neuroleptic activity. 
We have prepared one of these compounds, 
5-chloro-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyrid-4-yl)indol (Lu 
23-143) and found that it was almost inactive compared with the compounds 
of Formula I. 
It has now surprisingly been found that the novel indole derivatives of 
Formula I are potent dopaminergic antagonists in pharmacological tests, 
both in vivo and in vitro, as compared with wellknown neuroleptics 
commonly used in the treatment of psychoses; and especially very 
long-lasting effects - up to several days - were observed with many of the 
compounds of Formula I. Additionally, most of the the indoles of Formula I 
are strong 5-HT antagonists both periferically and centrally, which is 
considered to be important for the treatment of psychic disorders or 
cardiovascular diseases. 
The terms lower alkyl, lower alkoxy, lower alkylthio and lower alkysulfonyl 
designate such groups having from one to four carbon atoms inclusive. 
Exemplary of such groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 
sec.butyl, methoxy, ethoxy, propoxy, butoxy, methylthio, ethylthio, 
propylthio, methylsulfonyl, ethylsulfonyl, or the like. 
The term lower alkenyl designates alkenyl groups having from two to four 
carbon atoms, for example ethenyl, 1-propenyl, 2-butenyl, or the like. 
This invention also includes pharmaceutically acceptable salts of the 
compounds of Formula I formed with non-toxic acids. Such salts are easily 
prepared by methods known to the art. 
The base is reacted with either the calculated amount of organic or 
inorganic acid in an aqueous miscible solvent, such as acetone or ethanol, 
with isolation of the salt by concentration and cooling or an excess of 
the acid in aqueous immiscbile solvent, such as ethyl ether or chloroform, 
with the desired salt separating directly. 
Exemplary of such organic salts are those with maleic, fumaric, benzoic, 
ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, 
methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, 
citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, 
stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene 
sulfonic and theophylline acetic acids, as well as the 
8-halotheophyllines, for example 8-bromo-theophylline. Exemplary of such 
inorganic salts are those with hydrochloric, hydrobromic, sulfuric, 
sulfamic, phosphoric and nitric acids. Of course, these salts may also be 
prepared by the classical method of double decomposition of appropriate 
salts, which is wellknown to the art. 
The compounds of Formula I as well as the pharmaceutically acceptable acid 
addition salts thereof may be administered both orally and parenterally, 
for example in the form of tablets, capsules, powders, syrups or solutions 
for injection. 
Of the indoles of Formula I, those wherein R.sup.1 is chlorine, fluorine, 
trifluoromethyl, methyl, nitro or amino in the 5-position, R is phenyl 
substituted with fluorine in the 4'-or the 2'-position, R.sup.2 is methyl, 
hydroxyethyl or 3-hydroxypropyl, and A is as defined above, have shown 
especially favourable effects in the pharmacological testing, and also 
have few undesired side effects. 
The invention moreover relates to a method for the preparation of the novel 
indoles of Formula I, which comprises 
(a) reacting an indole derivative of the following formula: 
##STR3## 
wherein R.sup.1 and R are as defined above, with a 4-piperidone of the 
formula: wherein R.sup.2 is as defined above, 
or 
(b) reducing a compound of the following formula: 
##STR4## 
wherein R.sup.1, R and R.sup.2 are as defined above, or 
(c) reacting a compound of the following formula: 
##STR5## 
wherein R.sup.1, R.sup.2 and A are as defined above, with a compound of 
formula: 
EQU R-hal 
wherein R is as defined above and "hal" is halogen, in the presence of a 
metal catalyst, or 
(d) reacting a compound of the following formula: 
##STR6## 
wherein R.sup.1, R and A are as defined above, with a lower alkyl halide 
or an epoxide of formula 
##STR7## 
wherein R is hydrogen, methyl or ethyl, or 
(e) reducing a compound of the following formula: 
##STR8## 
wherein R.sup.1, R and A are as defined above and R.sup.4 is hydrogen, 
lower alkyl (1-3 C-atoms) or lower alkoxy (1-3 C-atoms), or 
(f) heating a compound of the following formula: 
##STR9## 
wherein R.sup.1 and R as defined above, with a piperazine of formula: 
wherein R.sup.2 is as defined above, 
##STR10## 
or 
(g) reducing a compound of the following formula: 
##STR11## 
wherein R.sup.1, R and R.sup.2 are as defined above, with a suitable 
reducing agent, whereupon the indole of Formula I is isolated in the form 
of the free base or a pharmaceutically acceptable acid addition salt 
thereof, and if the group R.sup.2 contains one or two hydroxyl groups, if 
desired, acylating such a hydroxy group with a reactive derivative of an 
aliphatic carboxylic acid having from two to twenty-four carbon atoms, and 
isolating the ester formed as the free base or a pharmaceutically 
acceptable acid addition salt thereof. 
In method (a) the reaction is performed under strong acidic conditions by 
heating. Trifluoroacetic acid or HCl in ethanol are preferred as acid 
catalysts. The starting compounds of Formula II are conveniently prepared 
according to procedures described in the litterature, e.g. by reduction of 
R substituted isatins or oxindoles by a method described by H. Sirowej et 
al, in Synthesis 1972, 84, according to the following reaction scheme: 
##STR12## 
Isatins and oxindoles are prepared by a Fiedel-Craft ring closure under 
standard conditions from N-oxalylchloro- or N-(2-chloroacetyl) 
diphenylamines respectively. The compounds of Formula II may alternatively 
be prepared by arylation of N-unsubstituted indoles according to the 
method described by M.A. Khan and E.K. Rocha, Chem.Pharm.Bull. 25 (11), 
3110-3114 (1977). An alternative way of obtaining the intermediates of 
Formula II is that from an indoxyl-2-carboxylic ester as outlined below: 
##STR13## 
In method (b) the reduction is preferably carried out at low hydrogen 
pressures (3 ato.) in the presence of platinum or palladium on carbon 
black. 
In method (c) the arylation is preferably carried out at about 
160.degree.-210.degree. C. in aprotic polar solvents as e.g. 
N-methyl-2-pyrrolidone or hexamethylphosphoric triamide with K.sub.2 
CO.sub.3 as base and copper as a catalyst. In method (e) the reduction is 
preferably carried out with LiAlH.sub.4 in THF or diethylether or with 
diborane in THF. 
Method (f) is a two step procedure in which compound VII first is 
decarboxyalkylated in the presence of an inorganic salt as e.g. LiCl or 
MgCl.sub.2 in a polar solvent as e.g. diglyme, hexamethylphosphoric 
triamide or N-methyl-2-pyrrolidone at elevated temperatures 
(120.degree.-150.degree. C.). Finally, the appropriate piperazine is added 
and the temperature raised to about 200.degree. C. and kept there until 
the corresponding indoxyle has disappeared according to TLC analysis. The 
compounds of Formula VII are conveniently prepared according to the 
procedures reported by P.C. Unangst and M.E. Carethers, J.Heterocyclic 
Chem. 21, 709 (1984). 
In method (g) diborane in THF is conveniently used as a reducing agent. The 
compounds of Formula VIII are prepared from the corresponding 
R-substituted isatins according to the following reaction scheme: 
##STR14## 
The methods of the invention shall be illustrated in the following by some 
examples, which may not be construed as limiting:

EXAMPLE 1 
(Method a) 
1-(4'-Fluorophenyl)-5-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H 
-indole, hydrochloride (Lu 20-089). 
1-(4'-fluorophenyl)-5-methyl-1H-indole (4.5 g) and 1-methyl-4-piperidone (5 
g) were dissolved in 25 ml of acetic acid and added dropwise to 50 ml of 
trifluoroacetic acid kept almost at the boiling point. The mixture was 
gently refluxed for another 1/2 h. Excess trifluoroacetic acid was 
evaporated and the reaction mixture was added to 50 ml of 6 M HCl and 50 
ml of ether. The precipitated title compound was filtered off and dried. 
Yield: 3.1 g (43%). M.p.262.degree.-266.degree. C. 
In a corresponding manner the following tretrahydropyridin-4-ylindoles were 
prepared: 
5-Fluoro-1-(4'-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H 
-indole, hydrochloride. (Lu 21-018). M.p.256.degree. C. 
1-(4'-Fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoro 
methyl-1H-indole, oxalate. (Lu 21-120). M.p. 228.degree.-229.degree. C. 
1-(4'-Fluorophenyl)-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- 
indole. (Lu 22-135). M.p. 168.degree.-170.degree. C. 
1-(3'-Fluorophenyl)-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- 
indole, maleate. (Lu 24-004). M.p. 216.degree.-217.degree. C. 
1-(2'-Fluorophenyl)-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- 
indole, maleat. (Lu 24-003). M.p. 208.degree. C. 
3-(1-(2-Hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(4'-trifluoromethyl 
phenyl-1H-indole, fumarate. (Lu 24-012). M.p. 174.degree.-175.degree. C. 
1-(4'-Fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 
hydrochloride. (Lu 23-083). M.p. 268.degree.-270.degree. C. 
1-(4'-Fluorophenyl)-5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, 
maleate. (Lu 23-133). M.p. 204.degree.-205.degree. C. 
5-Chloro-1-(4'-fluorophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridi 
n-4-yl)-1H-indole, hydrochloride. (Lu 23-146). M.p. 280.degree.-282.degree. 
C. 
5-Chloro-1-(4'-fluorophenyl)-3-(1,2,3,6-tetrahydropridin-4-yl)-1H-indole. 
(Lu 23-147). M.p. 105.degree.-107.degree. C. 
1-(4'-fluoropheynl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5 
-nitro-1H-indole. (Lu 23-150). M.p. 151.degree.-152.degree. C. 
1-(4'-Fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H 
-indole. (Lu 23-155). M.p. 128.degree.-130.degree. C. 
1-(4'-Fluorophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl) 
-5-trifluoromethyl-1H-indole. (Lu 23-156). M.p. 140.degree.-141.degree. C. 
5-fluoro-1-(4'-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. 
(Lu 23-159). M.p. 75.degree.-77.degree. C. 
5-fluoro-1-(4'-flurophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin 
-4-yl)-1H-indole, oxalate. (Lu 23-160). M.p. 180.degree.-184.degree. C. 
5-fluoro-1-(4'-fluorophenyl)-3-(1-(2-propyl)-1,2,3,6-tetrahydropyridin-4-yl 
)-1H-indole, fumarate. (Lu 23-167). M.p. 190.degree.-195.degree. C. 
1-(4'-Fluorophenyl)-3-(1-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridin-4-yl) 
-5trifluoromethyl-1H-indole. (Lu 23-171). M.p. 159.degree.-161.degree. C. 
5-Fluor-1-(4'-fluorophenyl)-3-(1-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridi 
n-4-yl)-1H-indole, oxalate. (Lu 23-175). M.p. 173.degree.-175.degree. C. 
EXAMPLE 2 
(method b) 
1-(4'-Fluorophenyl)-3-(1-methyl-4-piperidyl)-5-trifluoromethyl-1H-indole, 
oxalate. (Lu 21.degree.-131). 
Compound Lu 21-120, oxalate (2.5 g) is dissloved in ethanol (200 ml), and 
PtO.sub.2 (0.2 g) is added. Hydrogenation is continued for 3h at 3 atm. 
The catalyst was then filtered off, ethanol evaporated and the title 
compound crystallized from acetone/ether. Yield: 1.2 g (48%). M.p. 
251.degree.-252.degree. C. 
In a corresponding manner were also prepared: 
1-(4'-Fluorophenyl)-3-(1-(2--imidazolidinon-1-ylethyl)-4-piperidyl)-1H-indo 
le. (Lu 23-086). M.p. 174.degree.-175.degree. C. 
1-(4'-Fluorophenyl)-3-(1-(1-pyrrolidin-2-onylethyl)-4-piperidyl)-5-trifluor 
omethyl-1H-indole, fumarate. (Lu 23-158). M.p. 240.degree.-241.degree. C. 
5-Chloro-1-(4'-fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-4-piperidyl) 
-1H-indole, maleate. (Lu 23-174). M.p. 155.degree.-160.degree. C. 
EXAMPLE 3 
(Method c) 
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-pyridin-3-yl-1H-indol 
e. (Lu 24-016). 
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro--1H-indole (4.5 g), 
3-bromopyridin (6.0 g), CuBr (4.5 g) and K.sub.2 CO.sub.3 (8.0 g) were 
heated under stirring at 160.degree. C. for 2.5 h. After cooling the 
reaction mixture was poured into diluted NH.sub.4 OH (500 ml) and 
extracted with ethyl acetate (2.times.300 ml). The combined organic phases 
were dried (MgSO.sub.4) and the solvent evaporated. The title compound was 
obtained by recrystallization from acetone. Yield: 3.4 g (58%). M.p. 
175.degree.-177.degree. C. 
In a corresponding manner were also prepared: 
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-pyridin-2-yl-1H-indol 
e. (Lu24-015). M.p. 134.degree. C. 
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(2-thiazolo-1H-indole 
. (Lu24-022). M.p. 204.degree.-206.degree. C. 
5-Chloro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(3-thienyl)-1H-indol 
e, maleate. (Lu 24-001). M.p. 168.degree.-170.degree. C. 
3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1-(2-thienyl)-1H-indole 
, maleate. (Lu 24-014). M.p. 206.degree.-208.degree. C. 
EXAMPLE 4 
(methods c and e) 
5-Chloro-1-(4'-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H 
-indole, hydrobromide. (Lu 22-117). 
5-Chloro-3-(1-carbethoxy-1,2,3,6-tetrahydropyridin-4-yl)-lH-indole (10 g), 
1,4-fluoroiodobenzene (15 g), CuBr (10 g) and K.sub.2 CO.sub.3 (15 g) in 
HMPA (50 ml) were heated (180.degree.-200.degree. C.) while stirring for 
3h. After cooling the reaction mixture was poured into H.sub.2 O (1 ltr.) 
and ethylenediamine (100 ml). The crude product was obtained by extraction 
twice with ether/ethyl acetate (2:1). The combined organic phases were 
dried (MgSo.sub.4) and the solvents were evaporated. The pure 
5-chloro-1-(4'-fluorophenyl)-3-(1-carbethoxy-1,2,3,6-tetrahydropyridin-4-y 
l)-1H-indole was obtained by column chromatography on silica gel (eluent 
30% ether in dichloromethane). Yield: 8.9 g (68%). M.p. 
120.degree.-122.degree. C. The carbethoxy compound then obtained (3 g) was 
dissolved in dry THF (50 ml) and LiAlH.sub.4 pellets (2 g) were added. The 
mixture was refluxed for lh, cooled and H.sub.2 O/THF added to destroy 
excess LiAlH.sub.4 . The precipitate was filtered off and THF evaporated. 
The remaining oil was dissolved in acetone and the title compound 
precipitated as a hydrobromide salt. Yield: 2.4 g (75%). M.p. 258.degree. 
C. 
In a corresponding manner were also prepared: 
5-Chloro-1-(4'-fluorophenyl)-3-(1-isobutyl-1,2,3,6-tetrahydropyridin-4-yl)- 
1H-indole, hydrobromide. (Lu 22-134). M.p. 285.degree.-286.degree. C. 
5-Fluro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2-thiazolo)-1H-indol 
e, fumarate. (Lu 24-013). M.p. 190.degree.-194.degree. C. 
EXAMPLE 5 
(method d) 
5-Fluoro-2-(4'-fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetr 
ahydropyridin-4-yl)-1H-indole, oxalate. (Lu 21-046) 
5-Fluoro-1-(4'-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole 
(2g) prepared as described in Example 1; l-chloroethyl-2-imidazolidinon (2 
g), K.sub.2 CO.sub.3 (3 g) and a small crystal of K1 were refluxed in 
methyl isobytyl ketone (50 ml) for 16 h. The reaction mixture was poured 
into H.sub.2 O and CH.sub.2 Cl.sub.2 (200 ml) was added. The organic phase 
was separated, dried (MgSO.sub.4) and the solvents evaporated. The crude 
product was dissolved in acetone and precipitated as an oxalate salt. 
Yield: 1.2 g (36%). M.p. 186.degree.-189.degree. C. 
In a corresponding manner the following indoles were prepared: 
1-(4'-Flurophenyl)-3-(4-(2-imidazolidinon-1-ylethyl)-1-piperazino)-5-triflu 
oromethyl-1H-indole, dihydrobromide. (Lu 23-001). M.p. 
262.degree.-263.degree. C. 
1-(4'-Fluorophenyl)-3-(4-(1-pyrrolidin-2-onylethyl)-1-piperazino)-5-trifluo 
romethyl-1H-indole. (Lu 22-133). M.p. 224.degree.-227.degree. C. 
1-(4'-Fluorophenyl)-5-nitro-3-(1-pyrrolidin-2-onylethyl)-1,2,3,6-tetrahydro 
pyridin-4-yl)-1H-indole, hydrochloride (Lu 23-024). M.p. 
263.degree.-265.degree. C. 
1-(4'-Fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropyr 
idin-4-yl)-1H-indole, hydrochloride. (Lu 23-075). M.p. 
259.degree.-262.degree. C. 
1-(4'-Fluorophenyl)-5-nitro-3-(1-(2-oxazolidinon-3-ylethyl)-1,2,36-tetrahyd 
ropyridin-4-yl)-1H-indole, maleate (Lu 23-134). M.p. 
128.degree.-130.degree. C. 
1-(4'-Fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropri 
din-4-yl)-5-nitro-1H-indole. (Lu 23-142). M.p. 177.degree.-179.degree. C. 
5-Chloro-1-(4'-fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetr 
ahydropyridin-4-yl)-1H-indole. (Lu 23-148). M.p. 138.degree.-140.degree. C. 
1-(4'-Fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropri 
din-4-yl)-5-trifluoromethyl-1H-indole. (Lu 23-157). M.p. 
164.degree.-165.degree. C. 
1-(2'-Fluorophenyl)-3-(1-(2-imidazolidinon-1-ylethyl)-1,2,3,6-tetrahydropri 
din-4-yl)-5-nitro-1H-indole, maleate. (Lu 24-024). M.p. 200.degree. C. 
EXAMPLE 6 
(Method e) 
1-(4'-Fluorophenyl)-3-(1-pyrrolo-2-ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5 
-trifluoromethyl-1H-indole. maleate. (Lu 23-172). 
1-(4'-Fluorophenyl)-3-(1-pyrrolo-2-aceto)-1,2,3,6-tetrahydropyridin-4-yl)-5 
-trifluoromethyl-1H-indole (2.5g) was refluxed with LiAlH.sub.4 (1g)indry 
THF (50ml) for 1.5h. After cooling H.sub.2 O/THF was added to destroy 
excess of LiAlH.sub.4. The precipitate was filtered off and THF 
evaporated. The remaining oil was dissolved in 2-propanol and the title 
compound precipitated as a maleate. Yield: 1.3 g (42%). M.p. 
194.degree.-195.degree. C. 
In a corresponding manner were also prepared: 
1-(4'-Fluorophenyl)-3-(1-(2-methyl-1-imidazole-2-ethyl)-1,2,3,6-tetrahydrop 
yridin-4-yl)-5-trifluoromethyl-1H-indole, difumarate. (Lu 23-173). M.p. 
189.degree.-191.degree. C. 
1-(4'-Fluorophenyl)-3-(1-(1-imidazole-2-ethyl)-1,2,3,6-tetrahydropyridin-4- 
yl)-5-trifluoromethyl-1H-indole, dimaleate. (Lu 24-002). M.p. 
165.degree.-167.degree. C. 
EXAMPLE 7 
(method f) 
1-(4'-Fluorophenyl)-3-(4-methylpiperazio)-5-trifluoromethyl-1H-indole, 
dihydrochloride. (Lu 21-123). 
2-Carboxymethyl-1-(4'-fluorophenyl)-5-trifluoromethylindolin-3-on (15 g) 
and MgCl.sub.2.sup.. 6H.sub.2 O (30 g) in HMPA (100 ml) were heated under 
N.sub.2 at 120.degree.-140.degree. C. for 1 h and finally at 150.degree. 
C. for another 1/2 h. 1-Methylpiperazin (25 ml) was added and the mixture 
was refluxed under N.sub.2 at an oil bath temperature of 200.degree. C. 
for 16 h. The mixture was cooled and poured into 1 ltr. of H.sub.2 O and 
extracted with ether (3.times.200 ml). The combined ether extracts were 
washed with 0.5 M HCl (3.times.300 ml). The acidic H.sub.2 O phase was 
made alkaline and reextracted with ether (2.times.200 ml). The combined 
organic phase was dried (MgSO.sub.4) and the ether evaporated. The 
remaining oil was dissolved in acetone and the title compound precipitated 
as a dihydrochloride. Yield: 6.7 g (35%). M.p. 245.degree.- 247.degree. C. 
In a corresponding manner the following 3-piperazinoindoles were prepared: 
1-(4'-Flurophenyl)-3-(4-(2-hydroxyethyl)-piperazino)-5-trifluoromethyl-1H-i 
ndole. (Lu 21-152). M.p. 164.degree. C. 
1-(4'-Fluorophenyl)-3-piperazino-5-trifluoromethyl-1H-indole. (Lu 21-153). 
M.p. 168.degree.-170.degree. C. 
1-(4'-Fluorophenyl)-3-(4-isopropyl-piperazino)-5-trifluoromethyl-1H-indole, 
dihydrochloride. (Lu 23-016). M.p. 278.degree.-280.degree. C. 
5-Chloro-3-(4-methylpiperazino)-1-phenyl-1H-indole. (Lu 23-015). M.p. 
174.degree.-175.degree. C. 
EXAMPLE 8 
(method g) 
1-(4'-Fluorophenyl)-5-methyl-3-(1-methyl-4-piperidyl)-1H-indole, 
hydrobromide. (Lu 21-037). 
To 14 g of Mg turnings was added 4-chloro-1-methylpiperidine (35 g) in dry 
THF (500 ml). The mixture was refluxed for 1 hour and filtered under 
N.sub.2 into an ice cooled solution of 1-(4'-fluorophenyl)-5-methylisatin 
(60 g) in dry THF (500 ml). The mixture was heated to reflux and poured 
into H.sub.2 O (1 ltr.) saturated with NH.sub.4 Cl and extracted with 
ether (2.times.300 ml). The combined organic phases were dried 
(MgSO.sub.4), the ether evaporated yilding 48.5 g (58%) of 
1-(4'-fluorophenyl-3-hydroxy-5-methyl-3-(1-methyl-4-piperidyl)indolin-2-on 
. M.p. 177.degree.-179.degree. C. // To a suspension of LiAlH.sub.4 (1 g) 
in dry THF (100 ml) was added 2.5 g of the above prepared indolin-2-on. 
The mixture was refluxed for 1 hour, excess of LiAlH.sub.4 destroyed by 
addition of H.sub.2 O / THF, and filtered; and 2 M HCl (500 ml) was added 
to the filtrate and gently heated. The H.sub.2 O phase was made alkaline 
and the product extracted with ether (2.times.300 ml). The combined ether 
phases were dried (MgSO.sub.4) and the ether evaporated. The remaining oil 
was dissolved in acetone and 
1-(4'-fluorophenyl)-5-methyl-3-(1-methyl-4-piperidyl)indolin-2-on was 
precipitated as an oxalate. Yield: 2.0 g (66%). M.p. 222.degree. C. To a 
solution of B.sub.2 H.sub.6 in THF (100 ml) kept under N.sub.2 at 
0.degree. C. was added 11.0 g of the oxalate salt prepared as above. The 
mixture was heated slowly to 50.degree. C. and kept there for 2 hours. It 
was finally poured onto ice (1 ltr.) and extracted with ether (2.times.200 
ml). The combined ether phases were dried (MgSO.sub.4) and the ether 
evaporated. The remaining oil was dissolved in 2-propanol and the title 
compound precipitated as a hydrobromide salt. Yield: 3.7 g (36%). M.p. 
254.degree.-256.degree. C. 
EXAMPLE 9 
5-Amino-1-(4'-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- 
indole, fumarate. (Lu 23-149) 
1-(4'-Fluorophenyl)-3-(methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-in 
dole (Lu 22-135) (10 g) in 90% ethanol (150 ml) was heated to reflux and 
dil. HCl (2 ml) and Fe-powder (5 g) were added within 0.5 hour. Reflux was 
continued for another hour. The reaction mixture was filtered, cooled down 
and subsequently poured into 1 liter of NH.sub. 4 Oh and extracted with 
ethyl acetate (2.times.400 ml). The combined organic phases were dried 
(MgSO.sub.4) and the solvent evaporated. The remaining oil and purified by 
column chromatography on silica gel (eluted with ethyl acetate/methanol 
1:1 containing 2% of triethylamine). The title compound was finally 
precipitated as a fumarate from ethanol/acetone (1:1). Yield 4.2 g (34%). 
M.p. 128.degree.-134.degree. C. 
EXAMPLE 10 
1-(4'-Fluorophenyl)-3-(4-(2-(pyrrolidin-2-thion-1-yl)-ethyl)-1-piperazino)- 
5-trifluoromethyl-1H-indole (Lu23-018). 
The pyrrolidonyl indole derivative (Lu 22-133) (2.8 g) prepared in Example 
4 and p-methoxyphenylthionophosphine sulfide dimer (2.0 g) (Lawesson 
reagent) were heated in HMPA (25 ml) at 110.degree. C. for 1 hour. The 
reaction mixture was poured into H.sub.2 O (500 ml) and K.sub.2 CO.sub.3 
(10 g) added. The product was extracted with ether containing 10% of ethyl 
acetate (2.times.200 ml). The combined organic phases were dried 
(MgSO.sub.4), the solvents evaporated and the resulting crystalline 
product was recrystallized from ethanol yielding 2.1 g (73%) of the title 
compound. M.p. 199.degree.-201.degree. C. 
EXAMPLE 11 
3-(4-(1-Acetyloxyethyl)-1-piperazino)-1-(4'-fluorophenyl)-5-trifluoromethyl 
-1H-indole. (Lu 23-161). 
1-(4'Fluorophenyl)-3-(4-(2-hydroxyethyl)-1-piperazino)-5-trifluoromethyl-1H 
-indole (Lu 21-152) (5 g) was heated to reflux in acetone (50 ml). 
Acetylchloride (2 ml) was added slowly. Refluxing was continued for 1.5 h. 
The solvent was evaporated and the remaining oil was extracted with 
CH.sub.2 Cl.sub.2 (2.times.200 ml) from NH.sub.4 OH at Ph 10. The combined 
organic phases were dried (MgSO.sub.4) and the solvent evaporated. The 
title compound precipitated from ether. Yield: 3.7 g (72%). M.p. 
129.degree.-131.degree. C. 
In a corresponding manner the following esterified indole derivatives were 
prepared: 
3-(4-(1-decanoyloxyethyl)-1-piperazino)-1-(4'-fluorophenyl)-5-trifluorometh 
yl-1H-indole. (Lu 23-162). M.p. 71.degree.-73.degree. C. 
1-(4'-Fluorophenyl)-3-(4-(l-oleyloxyethyl)-1-piperazino)-5-trifluoromethyl- 
1H-indole, dihydrochloride. (Lu 23-163). M.p. 158.degree.-162.degree. C. 
The compounds of Formula I were tested according to reliable and well 
recognized pharmacological tests as follows: 
1. Methylphenidate antagonism 
The inhibiting effect of test substances on the methylphenidate-induced 
gnawing in mice is determined as described by Pedersen and Christensen 
(1972). The test substance is given i.p. in different doses, while 
methylphenidate is given s.c. in the dose 60 mg/kg, 1/2, 2 or 24 hours 
after injection of test substance. Per dose of the test substance is used 
3.times.2 mice (8, 18-25 g). The results are given in fractions: 0/3, 1/3, 
2/3 and 3/3, where 0,1,2 and 3 are the number of pairs, which has not been 
gnawing on receipt of the test substance. 
Ref: 
Pedersen, V. and Christensen, A.V.: Acta pharmacol. et toxicol. 31, 
488-496, 1972. 
2. Catalepsy 
Evaluation of catalepsy is made according to Arnt (1983). The rat is placed 
on a vertical wire mesh (mesh diameter 12 mm) and considered as cataleptic 
if it remains immobile for more than 15 seconds. The number of cataleptic 
rats in each dose group is determined every hour, 1-6 hours and 24 hours 
following peroral administration of test compound. The maximal numbers of 
cataleptic rats in each of at least 3 dose groups, each consisting of at 
least 4 rats, is recorded. These numbers are used for calculation of 
ED.sub.50 values by log-probit analysis. 
Ref.: 
Arnt, J.: European J. Pharmacol. 90, 47-55, 1983. 
3. Quipazine inhibition 
Quipazine and a number of other compounds, which increase 5-HT.sub.2 
receptor activity in the CNS, induce a characteristic rapid shake (twitch) 
of the head. This response is inhibited by 5-HT.sub.2 receptor antagonists 
(Vetulani et al. 1980, Arnt et al. 1984). 
The test compound or saline is injected subcutaneously 2 hours before 
subcutaneous injection of quipazine hemimalecate (15umol/kg). At least 3 
dose groups, each consisting of at least 4 rats, are used. The rats are 
individually placed in observation cages (12.times.25 cm) and the number 
of head twitches are counted 30-40 min after quipazine administration. 
Inhibition of head twitches is expressed in per cent of the number of head 
twitches in the control group. ED 50 values are calculated by log-probit 
analysis. 
Ref.: 
Vetulani, J., B.B. Beduarczyk, K. Reichenberg and A. Rokost: 
Neuropharmacology 19, 155-158, 1983. 
Arnt, J., J. Hyttel and J.-J. Larsen: Acta pharmacol. et toxicol. 55, 
363-372, 1984. 
4. .sup.3 H-spiroperidol bindings 
The affinity of compounds to dopamine (DA) D-2 receptors and 
serotomin.sub.2 (5-HT.sub.2) receptors was determined by in vitro receptor 
binding technique. Binding of .sup.3 H-spiroperidol to DA D-2 receptors in 
rat striatal membranes and to 5-HT.sub.2 receptors in rat cortical 
membranes was determined as described in detail by Arnt et al. (1984). 
Ref.: 
Arnt, J., J. Hyttel and J.-J. Larsen: Acta pharmacol. et toxicol. 55, 
363-372, 1984. 
TABLE 1 
__________________________________________________________________________ 
Pharmacology of Indoles 
MePh Catalep. 
Qvipaz. 
.sup.3 H-Spiroperidol bindings 
Antg. ED50(po) 
inh. DA-2 5-HT.sub.2 
Compound ED50(ip) 
(.mu.mol/kg) 
ED50(sc) 
receptors 
No. (.mu.mol/kg) 
1-6 h 
24 h 
(.mu.mol/kg) 
IC.sub.50 /10.sup.-9 M 
__________________________________________________________________________ 
Lu 20-089 
0.18 0.43 
6.5 0.12 0.34 1.8 
Lu 21-018 
0.58 2.00 
&gt;6.9 
0.15 0.74 3.0 
Lu 21-037 
2.10 
Lu 21-046 
48.1 0.23 
Lu 21-120 
0.08 0.32 
0.35 
0.03 0.61 3.1 
Lu 21-123 
0.09 0.08 
0.62 
0.035 1.7 6.7 
Lu 21-131 
0.60 0.59 
2.2 
Lu 21-152 
0.11 0.17 
0.28 
0.023 2.8 7.4 
Lu 21-153 
2.0 7.1 16.0 
0.37 3.7 6.7 
Lu 22-117 
0.06 0.09* 
&gt;0.37* 
0.052 1.2 0.66 
Lu 22-133 
0.82 0.66* 
1.7* 
0.15 1.9 
Lu 22-134 
1.7 2.7* 
&gt;2.7* 
2.5 5.3 
Lu 22-135 
0.10 0.078 
&gt;0.89* 
0.009 1.1 1.9 
Lu 23-001 
0.22 1.2 2.6 0.047 6.6 18 
Lu 23-011 
0.12* 0.55 
&gt;1.8 
0.041 0.38 
Lu 23-015 
8.8 12.0 
&gt;15 0.062 12.0 3.9 
Lu 23-018 
53.0 1.2 2.9 
Lu 23-024 
0.65 6.8* 
&gt;10* 5.3 
Lu 23-075 
19* 0.18 
Lu 23-083 
1.3* 9.4 &gt;14 0.15 1.8 
Lu 23-086 
&gt;98* 0.036 42 2.9 
Lu 23-133 
18* 11.0 
&gt;11 5.9 
Lu 23-134 
9.0* 1.1 &gt;8.8 2.8 15 
Lu 23-142 
2.6* 6.7 
Lu 23-143 
72.0* &gt;18* 
&gt;18* 
4.5 
Lu 23-146 
0.73* 1.0* 
Lu 23-147 
&gt;99* 
Lu 23-148 
&gt;91* 
Lu 23-149 
0.45* 
Lu 23-150 
0.07* 0.21 4.7 10 
Lu 23-155 
3.8* 
Lu 23-156 
0.07* &lt;0.19* 
1.1* 
0.03 19 15 
Lu 23-157 
0.37* 0.49* 
2.6* 
0.12 
Lu 23-158 
2.9* 0.11 
Lu 23-159 
47* 
Lu 23-160 
3.4* 5.2* 11 34 
Lu 23-161 
0.05* 0.09* 
0.18* 
Lu 23-162 
1.7* 
Lu 23-163 
1.1* 
Lu 23-167 
2.7* 2.7* 
&gt;11.0* 
Lu 23-171 
0.11* 
Lu 23-172 
&gt;70* &gt;0.55 31 
Lu 23-173 
0.77* 1.8* &gt;7.1 42 60 
Lu 23-174 
&gt;72* 0.49 20 6.6 
Lu 23-175 
0.32* 0.68* 11 6.7 
Lu 24-001 
2.6 0.19 8.8 
Lu 24-002 
0.45* &gt;0.45 
Lu 24-003 
0.09* 6.0 14 
Lu 24-004 
1.1* 
Lu 24-012 
&gt;20* 
Lu 24-013 
&gt;20* 
Lu 24-014 
&gt;22* 
Lu 24-015 
3.8* 
Lu 24-016 
&gt;30* 
Lu 24-022 
Lu 24-024 
Clorpromazine 
23 70 0.38 24 30 
Cis(Z)Flupentixol 
0.14 2.4 19 0.042 3.2 13 
Haloperidol 
0.11 1.0 0.99 8.2 58 
Tefludazine 
0.06 0.61 
0.9 0.06 19 8.6 
__________________________________________________________________________ 
*ED50 from sc administration 
LD.sub.50 i.v. mice was determined for Lu 21-152 and Lu 22-135 to be 147 
.mu.mol/kg and 276 .mu.mol/kg respectively which indicates a comparatively 
low acute toxicity as compared with known neuroleptics such as 
chlorpromazine, cis(Z)-flupentixol and tefludazin having values between 
120-180 .mu.mol/kg. 
The compounds of Formula I and the non-toxic acid addition salts thereof 
may be administered to animals such as dogs, cats, horses, sheeps or the 
like, including human beings, both orally and parenterally, and may be 
used for example in the form of tablets, capsules, powders, syrups or in 
the form of the usual sterile solutions for injection. - Results upon 
administration to human beings have been very gratifying. 
Most conveniently the compounds of Formula I are administered orally in 
unit dosage form such as tablets or capsules, each dosage unit containing 
the free amine or a non-toxic acid addition salt of one of the said 
compounds in a amount of from about 0.10 to about 100 mg, most preferably, 
however, from about 5 to 50 mg, calculated as the free amine, the total 
daily dosage usually ranging from about 1.0 to about 500 mg. The exact 
individual dosages as well as daily dosages in a particular case will, of 
course, be determined according to established medical principles under 
the direction of a physician. 
When preparing tablets, the active ingredient is for the most part mixed 
with ordinary tablet adjuvants such as corn starch, potato starch, talcum, 
magnesium stearate, gelatine, lactose, gums, or the like. 
When the compound of Formula I is an ester, preferably a decanoic acid 
ester, palmitic acid ester or a behenic acid ester, the composition may 
advantageously be an oily solution for injection, and such solutions often 
have a very prolonged effect when compared with the corresponding 
unesterified compound. 
Typical examples of formulas for composition containing 
1-(4'fluorophenyl)-3-(4-(2-hydroxyethyl-1-piperazinyl)-5-trifluoromethylin 
dole (called Lu 21-152 for short) as the active ingredient, are as follows: 
______________________________________ 
(1) Tablets containing 5 milligrams of Lu 21-152 
calculated as the free base: 
Lu 21-152 5 mg 
Lactose 18 mg 
Potato starch 
27 mg 
Saccharose 58 mg 
Sorbitol 3 mg 
Talcum 5 mg 
Gelatine 2 mg 
Povidone 1 mg 
Magnesium stearate 
0.5 mg 
(2) Tablets containing 50 milligrams of Lu 21-152 
calculated as the free base: 
Lu 21-152 50 mg 
Lactose 16 mg 
Potato starch 
45 mg 
Saccharose 106 mg 
Sorbitol 6 mg 
Talcum 9 mg 
Gelatine 4 mg 
Povidone 3 mg 
Magnesium stearate 
0.6 mg 
(3) Syrup containing per milliliter: 
Lu 21-152 10 mg 
Sorbitol 500 mg 
Tragacanth 7 mg 
Glycerol 50 mg 
Methyl-paraben 
1 mg 
Propyl-paraben 
0.1 mg 
Ethanol 0.005 ml 
Water ad 1 ml 
(4) Solution for injection containing per milliliter: 
Lu 21-152 50 mg 
Acetic acid 17.9 mg 
Sterile water 
ad 1 ml 
(5) Solution for injection containing per milliliter: 
Lu 21-152 10 mg 
Sorbitol 42.9 mg 
Acetic acid 0.63 mg 
Sodium hydroxide 
22 mg 
Sterile water 
ad 1 ml 
______________________________________ 
Any other pharmaceutical tableting adjuvants may be used provided that they 
are compatible with the active ingredient, and additional compositions and 
dosage forms may be similar to those presently used for neuroleptics, such 
as chlorpenthixol, flupentixol or fluphenazine. 
Also combinations of the compounds of Formula I as well as their non-toxic 
acid salts with other active ingredients, especially other neuroleptics, 
thymoleptics, tranquilizers, analgetics or the like, fall within the scope 
of the present invention. 
As previously stated, when isolating the compounds of Formula I in the form 
of an acid addition salt the acid is preferably selected so as to contain 
an anion which is non-toxic and pharmacologically acceptable, at least in 
usual therapeutic doses. Representative salts which are included in this 
preferred group are the hydrochlorides, hydrobromides, sulphates, 
acetates, phosphates, nitrates, methanesulphonates, ethane-sulphonates, 
lactates, citrates, tartrates or bitartrates, pamoates and maleates of the 
amines of Formula I. Other acids are likewise suitable and may be employed 
if desired. For example: fumaric banzoic, ascorbic, succinic, salicylic, 
bismethylenesalicylic, propionic gluconic, malic, malonic, mandelic, 
cannamic, citraconic, stearic, palmitic, itaconic, glycolic, 
benzenesulphonic, and sulphamic acids may also be employed as acid 
addition saltforming acids. 
When it is desired to isolate a compound of the invention in the form of 
the free base, this may be done according to conventional procedure as by 
dissolving the isolated or unisolated salt in water, treating with a 
suitable alkaline material, extracting the liberated free base with a 
suitable organic solvent drying the extract and evaporating to dryness or 
fractionally distilling to effect isolation of the free basic amine. 
The invention also comprises a method for the alleviation, palliation, 
mitigation or inhibition of the manifestations of certain 
physiological-psychological abnormalies of animals, including psychoses, 
by administering to a living animal body, including human beings, an 
adequate quantity of a compound of Formula I or a non-toxic acid addition 
salt thereof. An adequate quantity would be from about 0.001 mg to about 
10 mg per kg of body weight in each unit dosage, and from about 0.003 
milligrams to about 7 milligrams/kg of body weight per day. 
It is to be understood that the invention is not limited to the exact 
details of operation or exact compound or compositions shown and 
described, as obvious modifications and equivalents will be apparent to 
one skilled in the art.