CA1077941A - Piperidine derivatives of indole - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

New piperidine derivatives of indole and their process of preparation are provided in formula (I)

Description

107~79~

The present invention is concerned with new piperidine derivatives of indole and their preparation.
The new derivatives of the invention, and the pharmacologically compatible salts thereof, have an anti-hypertensive action.
` According to the invention there are provided new plperidine derivatives of indole of the formula (I):-CH2 - O ~ (I) ,,, Rl ; .
wherein Rl and R2, which may be the same or different, are .:.
selected from the group consisting of hydrogen atoms and lower alkyl radicals, R3 is a hydrogen or halogen atom or a lower - ; alkyl or lower alkoxy radical and X is a straight-chain or ~; branched alkylene radical containing 2 or 3 carbon ,~ r,, ~
atoms, and the acid addition salts thereof with pharmacologic-. . .
ally compatible acids.

The lower alkyl radicals Rl, R2 and R3 can be straight-, ......
chained or branched and contain 1 to 6 and preferably 1 to 4 carbon atoms, The lower alkoxy radicals R3 may similarly contain 1 to 6 and preferably contain 1 to 4 carbon atoms, The halogen atom in the definition of R3 may be a fluorine, chlorine, bromine or iodine atom, with the latter being less preferred The substituent R3 may be in the ortho, meta or para position~
Examples of straight~chain or branched alkylene and alkylidene radicals containing 2 or 3 carbon atoms represented :

~ B`~ -1-,.;:

"- 1077941 by ,~ include ethylene, methylmethylene, propylene, dimethyl-methylene and methylethylene, ethylene and propylene being preferred.
According to another aspect of the invention there is provided a method of preparing a new piperidine derivative of formula (I), as defined above comprising reacting an indole -:
derivative of the formula (II):-~ X - Y

: ~ N ~ R2 (II) . Rl wherein Rl, R2 and X have the same meanings as above and Y is a reactive residue, with a piperidine derivative of the formula (III):-;'''''' `
' '.

H~CH~ - ~R3 (III) ~i' wherein R3 has the same meaning as above, or with an acid .. addition salt thereof, and, when Rl in general formula (II) represents a hydrogen atom, this is, if desired, replaced by a ;; lower al~yl radical subsequent to the condensation, and, if desired a free base of formula (I~ obtained is converted into a pharmacologically compatible salt.
: The reactive residue Y in the compound of formula (II) may be considered a leaving group in a SN substitution nucleo-. phillic reaction displaceably by an amino group' such leaving groups are well known and include, by way of example, a `~ chlorine or bromine atom or a mesyloxy or tosyloxy radical.

- 2 -;' ,, ''' ' ' : .

~0779~1 The reaction of the indole derivative (II) with the piperidine derivative (III) is preferably carried out in a solvent, for example, dioxan, isopropanol or N,N-dimethyl formamide, in the presence of an organic or inorganic base, for example, N-ethyl-diisopropylamine, triethylamine or potassium carkonate, or in the presence of an excess of the piperidine derivative (III), at a temperature offrom 20C. to the reflux temperature.
The compounds of general formula (II) are either known or can be easily prepared from known compounds. The compounds of general formula (III) are described in our simultaneously filed co-pending Canadian Patent Application ~o 264,608, Walter-Gunar Friebe et al, assigned to Boehringer Mannheim GmbH.

" . .
The subsequent introductlon of a lower alkyl radical as substituent Rl can be carried out by reaction of a compound of formula (I), in which Rl is a hydrogen atom, with an appropriate reactive lower alkyl compound, for example an alkyl halide, for example a bromide or iodide, according to known methods.
The pharmacologically compatible acid addition salts can be prepared in conventional manner, for example, by neutralisation of the compounds (I) with non-toxic inorganic or organic acids, for example hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid or succinic acid For the preparation of the pharmaceutical compositions it will be understood that the pharmacologically compatible salts should be pharmaceutically acceptable .: ',':

:, . .

, ~ - 3 -... ..

:, In the specification it will be understood that the qualification that the salts be "pharmaceutically acceptable"
means that the salts have the necessary physical characteristics, for example, stability, to render them suitable for formulation into pharmaceutical compositions. The qualification that the salts be "pharmacologically compatible" is to be understood, in the case of acid addition salts, as extending to salts of non-toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies, and similarly in the case of salts of the carboxylic acid group, the amine base or metal cation must similarly be non-toxic and have no adverse effects to the extent that such salts would be unsuitable for administra-r tion to living bodies Salts of compounds of formula (I~ which are not pharmaceutically acceptable and pharmacologically compatible form a useful aspect to the invention of the novel derivatives, : inasmuch as they can be readily converted, by conventional :
means, to different salts having the required physical and chemical characteristics to make them suitable for administra-::
tion in pharmaceutical compositions to living bodies.
The new compounds (I) of the invention and the salts thereof can be administered enterally and parenterally in liquid or solid form. Thus, the present invention also provides -~ pharmaceutical compositions comprising at least one of the new compounds, in admixture with a solid or liquid pharmaceutical diluent or carrier. For this purpose, there can be used the y . .
-~ conventional forms of administration, for example, tablets, capsules, dragées, syrups, solutions, suspensions and the like ~` 30 As injection medium, it is preferred to use water which con-; tains the additives usual in the case of injection colutions, ~ - 4 _ t,"
"' ' ' . ', .

for example, stabilising agents, solubilising agents and buffers.
Additives of this type include, for example, tartrate and cit-rate buffers, ethanol, complex formers (such as ethylene-diamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Liquid carrier materials for injection solutions must be sterile and are preferably placed into ampoules. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dis-persed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, mag-nesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols~.
. Compositions suitable for oral administration can, if desired, contain flavouring and sweetening materials.
The dosages to be administered will of course depend on the patient and must be decided by the patient's physician, Convenient units of dosage are dragées containing 25 mg of the compound of the invention, however the dosage unit may vary from 10 to 300 mg. It is recommended that use of the compound of the invention be introduced gradually, For example, in the case of dragées containing 25 mg of active ingredient, an initial treatment with 1 to 4 dragees daily may be suitable and this may be increased to 1 to 4 dragées four times daily ` in serious cases. Treatment after initial introduction is suitably maintained at 1 dragée two, three or four times daily.
:; The influence of different piperidine derivatives of .
indole of the invention on the average arterial blood pressure of hypertensive rats was determined and is described below to demonstrate the effectiveness of the compounds.

,''' Various piperidine derivatives of indole, of the invention were administered by probang to hypertensive rats as . a suspension in 1% methyl cellulose, in an amount of 10 ml of .~. :
liquid suspension per kg body weight of the rat.
- As a control there was separately administered .-:, 10 ml/kg of 1% methylcellulose solution; and as a comparison .
~- there was separately administered ~-methyl-Dopa a known anti-i hypertensive compound.
The results are tabulated below from which it will be observed that dosages of the compounds of the invention, ~ lower than a dosage of ~-methyl-Dopa are as effective or more .~. effective than the known ~-methyl-Dopa.

.. . .
..
:' Substance No. of Dosage Maximum blood pressure i; Rats (mg/kg) lowering (mm Hg) : .
. :
~ BM 16.010 5 50 -55 + 2 . . .
BM 16.139 10 25 -38 + 6 - BM 16.140 11 25 -25 + 7 ' BM 16.141 9 25 -12 + 3 ..
~ BM 16.142 12 10 -28 + 5 ....
.:. ..
, 20 BM 16,143 12 25 -34 + 7 BM 16.248 7 50 -27 + 8 ~;i, ' .
BM 16.249 7 25 -48 + ~0 . BM 16.250 7 25 -33 + 5 .: BM 16.287 7 50 -11 + 8 . BM 16.288 6 50 -4 + 4 ;........... BM 16.291 7 50 -8 + 5 . .:
BM 16.292 7 25 -5 + 4 . BM 16.293 7 25 -14 + 6 .;
, .,:, , , ~ ".
.,. - 6 -. " , ~ , , ~077941 Substance No. o~ Dosage Maximum blood pressure Rats (mg/kg) lowering (mm Hg) BM 16.294 7 25 -12 + 4 BM 16.295 7 50 -12 + 7 BM 16.296 7 50 -24 + 7 Control-10 ml 1%
methyl- 27 -2 + 3 cellulose i ~-Methyl-Dopa 8 150 -33 + 5 .

BM lb. 010 = 3-[2-(4-Phenoxymethyl-piperidino)-ethyl]-indole BM 16.139 = 3-~2-[4-(3-Methyl-phenoxymethyl)-piperidino]-ethyl~-indole ; BM 16.140 = 3- f2-[4-(2-Chloro-phenoxymethyl)-piperidino-ethyl~-indole BM 16.141 = 3-~2-[4-(4-Chloro-phenoxymethyl)-piperidino]-; ethyl~-indole " BM 16.142 = 3- ~2-[4-(2-Methoxy-phenoxymethyl)-piperidino]-ethyl}-indole BM 16.143 = 3- ~-[4-(4-Fluoro-phenoxymethyl)-piperidino]-. . .
ethyl3-indole , BM 16.248 = 1-Methyl-3-[2-(4-phenoxymethyl-piperidino)-ethyl]-indole ` BM 16.249 = 2-Methyl-3-[2-(4-phenoxymethyl-piperidino)-ethyl]-indole BM 16.250 = 3-[3-(4-Phenoxymethyl-piperidino)-propyl]-indole BM 16.287 = 3-~2-[4-(2-Methyl-phenoxymethyl)-piperidino]-ethyl}-indole BM 16.288 = 3- ~2-[4-(2-Bromophenoxymethyl)-piperidino]-ethyl~-indole , BM 16.291 = 3-~2-[4-(4-Methyl-phenoxymethyl)-piperidino]-ethyl}-indole , BM 16.292 = 3- ~2-[4-(3-Chloro-phenoxymethyl)-piperidino]-ethyl~-indole BM 16.293 = 3-~2-[4-(3-Methoxy-phenoxymethyl)piperidino]-; ethyl~-indole BM 16,294 = 3-~2-[4-(4-Methoxy-phenoxymethyl)-piperidino]-ethyl~-indole BM 16.295 = 3-~2-[4-(2-Fluoro-phenoxymethyl)-piperidino]-ethyl3-indole BM 16.296 = 3-~2-[4-(2-n-Butoxy-phenoxymethyl)-piperidino]-ethyl~-indole ., , ,:, , :
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~;;"' 10779~1 Having thus generally described the invention, reference will now be made to the following Examples, illustrat-ing the invention. It wiLl be understood that different products of the invention will be obtained by appropriate variation of the starting materials.
Example 1

3-[2-(4-Phenoxymethylpiperidino)-ethyl]-indole .
A mixture of 8.96 g. (0,04 mol) 3-(2-bromoethyl)-indole, 7.65 g. (0.04 mol) 4-phenoxymethylpiperidine, 7,76 g.
(0.06 mol) N-ethyl-diisopropylamine and 100 ml. dioxan is heated under reflux for 9 hours. After cooling, the reaction mixture is filtered, the filtrate is evaporated in a vacuum and the residue is taken up in diethyl ether, washed with water, dried over anhydrous sodium sulphate and evaporated. After recrystal-lisation from isopropanol/ligroin, there are obtained 5.55 g.
3-[2-(4-phenoxymethyl)-piperidino)-ethyl]-indole (41% of theory); m.p. 113 - 114C.
; By the addition of excess ethereal hydrogen chloride solution to the isopropanolic solution, there is obtained the ; 20 hydrochloride; m.p. 213C.
The following compounds are obtained in an analogous manner:

`~ product and starting Yield m.p. C. (solvent materials %used for recryst-allisation) ,.., ; 3-~2-[4-(2-bromophenoxymethyl)-33101 - 102 ; piperidino]-ethyl~-indole from (isopropanol) 3-(2-bromoethyl)-indole and 4-(2-bromophenoxymethyl)-piperidine 3- ~2-[4-(2-chlorophenoxymethyl)- 37 113 - 114 piperidino~-ethyl~-indole from (diethyl ether) 3-(2-bromoethyl)-indole and 4-(2-chlorophenoxymethyl)-piperidine .";
g _ .
, .

1~7941 product and starting Yield m.p, C, (solvent) materials %used for recryst-allisation) 3-~2-[4-(3-chlorophenoxymethyl)-51133 - 135 piperidino]-ethyl~-indole ~rom (ethyl acetate) 3-(2-bromoethyl)-1ndole and ~-(3-chlorophenoxymethyl)-piperidine 3-~2-[4-(4-chlorophenoxymethyl)-32141 - 142 piperidino]-ethyl1-indole from ~diethyl ether) 3-(2-bromoethyl)-indole and 4-(4-chlorophenoxymethyl)-piperidine 3-~2-[4-(2-fluorophenoxymethyl)-48120 - 121 piperidino]-ethyl~-indole from (ethyl acetate) 3-(2-bromoethyl)-indole and 4-(2-fluorophenoxymethyl)-piperidine 3-~2-[4-(4-fluorophenoxymethyl)-36130 - 131 piperidino]-ethyl~-indole from (diethyl ether) 3-(2-bromoethyl)-indole and 4-(4-fluorophenoxymethyl)-piperidine 3-{2-[4-(2-methoxy-phenoxymethyl)- 32 107 - 108 piperidino]-ethyl~-indole from (isopropanol) 3-(2-bromoethyl)-indole and 4-(2-methoxy-phenoxymethyl)-piperidine 3-~2-[4-(3-methoxy-phenoxymethyl~- 38 100 - 102 piperidino]-ethyl~-indole from (ethyl acetate) 3-(2-bromoethyl)-indole and 4-(3-methoxy-phenoxymethyl)-piperidine 3- ~2-[4-(4-methoxy-phenoxymethyl)- 44 120 - 121 piperidino]-ethyl~-indole from (ethyl acetate) 3-(2-bromoethyl)-indole and 4-(4-methoxy-phenoxymethyl)-piperidine 3-~2-[4-(2-n-butoxy-phenoxymethyl)- 35 90 - 91 piperidino]-ethyl}-indole from 3- (ethyl acetate) (2-bromoethyl)-indole and 4-(2-n-butoxy-phenoxymethyl)-piperidine 3-~2-[4-(2-methyl-phenoxymethyl)-41102 - 103 piperidino]-ethyl~-indole from (isopropanol) 3-(2-bromoethyl)-indole and 4-(2-methyl-phenoxymethyl)-piperidine 3- - [ 4-(3-methyl-phenoxymethyl)- 32 98 - 100 piperidino]-ethyl}-indole from (diethyl ether) 3-(2~bromoethyl)-indole and 4-(3-methyl-phenoxymethyl)-piperidine .

., ':

:. -- 10 --. :, , , :. .

` ~07794~1 product and starting Yield m,p. C. (solvent materials %used for recryst-allisation) 3-~2-[4-(4-methyl-phenoxymethyl)- 58 130 - 132 piperidino]-ethyl3-indole from (ethyl acetate) 3-(2-bromoethyl)-indole and 4-(4-methyl-phenoxymethyl)-piperidine l-methyl-3-[2-(4-phenoxymethyl-43 89 - 90 piperidino)-ethyl]-indole from (isopropanol) 1-methyl-3-(2-bromoethyl)-indole and 4-phenoxymethyl-piperidine 2-methyl-3-[2-(4-phenoxymethyl-45hydrochloride piperidino)-ethyl]-indole from 214 - 216 2-methyl-3-(2-bromoethyl)-indole , and 4-phenoxymethyl-piperidine (1sopropanol) 3-[3-(4-phenoxymethyl-piperidino)- 43 hydrochloride propyl]-indole from 3-(3-tosyloxy- 222 - 224 propyl)-indole and 4-phenoxymethyl- (methanol) ,. piperidine .

Example 2 l-Methyl-3-[2-(4-phenoxymethylpiperidino)-ethyl]-indole . _ ~
To a solution of 0,1 g, ferric nitrate and 1,25 g, sodium in 250 ml, liquid ammonia are added 9,0 g, (0,027 mol) 3-[2-(4-phenoxymethylpiperidino)-ethyl]-indole (prepared as described in Example 1), After stirring for 1 hour, there is added dropwise a solution of 3.9 g. (0.038 mol) methyl iodide in 50 ml, diethyl ether, followed by stirring for 3 hours at reflux temperature. After the addition of 5.3 g, ammonium chloride, the ammonia is left to evaporate off overnight.
The residue is extracted with diethyl ether and purified by chromatography on silica gel, using chloroform/methanol (9:1 v/v). The first eluate is evaporated and the residue is re-crystallised from isopropanol to give 4.9 g. 1-methyl-3-[2-(4-phenoxymethyl-piperidino)ethyl]-indole (52% of theory), m.p. 89 - 90C, 1~77941 Example 3 Preparation of pharmaceutical compositions.
Composition:
25 g, active material according to the present invention 150 g. lactose 100 g. polyvinylpyrrolidone solution (5% in water) 5 g. magnesium stearate 15 g, sodium amylopectin glycolate The active material is carefully mixed with the lactose in a kneader, thoroughly moistened with the polyvinyl-pyrrolidone solution and the resultant mass passed through a sieve with a mesh size of 1.9 mm. The resultant granulate is dried and freed from coarse components by passing through a sieve with a mesh size of 1.2 mm. and freed from fines by pass-ing through a sive with a mesh size of 0.6 mm.
The granules thus obtained can be filled directly into hard gelatine capsules (180 mg./capsule~ and administered ' in this form.
,~ - The granules can also be mixed with the magnesium stearate and sodium amylopectin glycolate and pressed into ~ tablets. T'he diameter of the tablets is 8 mm., the weight is 5" ~ 200 mg., the hardness is 2.0 kg. and the content of active ~ ; ., ~ material is 25 mg./tablet.

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Claims (44)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the preparation of a piperidine derivative of indole of the formula (I):- (I) in which R1 and R2, which may be the same or different, are selected from the group consisting of hydrogen atoms and lower alkyl radicals, R3 is a hydrogen or halogen atom or a lower alkyl or lower alkoxy radical and X is a straight-chained or branched alkylene radical containing 2 or 3 carbon atoms, and of the pharmacologically compatible acid addition salts thereof, comprising reacting an indole derivative of the formula (II) :- (II) in which R1, R2 and X are as defined above and Y is a reactive residue, with a piperidine derivative of the formula (III):- (III) in which R3 is as defined above, or with an acid addition salt thereof, whereafter, when a product is obtained in which R1 is a hydrogen atom, it is if desired, subsequently alkylated and, if desired, a free base of formula (I) is converted into a salt by neutralisation with a non-toxic inorganic or organic acid to produce a pharmacologically compatible acid addition salt.

2. A process according to claim 1, wherein the reacting is carried out in a solvent.

3. A process according to claim 2, wherein the reacting is carried out in the presence of an organic or inorganic base or of an excess of the piperidine derivative (III).

4. A process according to claim 1, 2 or 3, wherein the reacting is carried out at a temperature of from 20°C to reflux temperature.

5. A process according to claim 1, wherein a product of formula (I) in which R1 is a hydrogen atom is alkylated with a lower alkyl halide to produce a product of formula (I), in which R1 is a lower alkyl group.

6. A process according to claim 1, wherein a free base of formula (I) is converted into a pharmaceutically acceptable, pharmacologically compatible acid addition salt by neutralisation with a non-toxic inorganic or organic acid.

7. A process according to claim 1, in which R1 and R2 are selected from the group consisting of hydrogen atoms and lower alkyl radicals of 1 to 4 carbon atoms, and R3 is a hydrogen, fluorine, chlorine or bromine atom or a lower alkyl or lower alkoxy radical of 1 to 4 carbon atoms.

8. A process according to claim 1, for preparing 3-[2-(4-phenoxymethylpiperidino)-ethyl]-indole comprising reacting 3-(2-bromoethyl)-indole with 4-phenoxymethylpiperidine.

9. A process according to claim 1, for preparing 3-{2-[4-(2-bromophenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(2-bromophenoxymethyl)-piperidine.

10. A process according to claim 1, for preparing 3-{2-[4-(2-chlorophenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(2-chlorophenoxymethyl)-piperidine.

11. A process according to claim 1, for preparing 3-{2-[4-(3-chlorophenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(3-chlorophenoxymethyl)-piperidine.

12. A process according to claim 1, for preparing 3-{2-[4-(4-chlorophenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(4-chlorophenoxymethyl)-piperidine.

13. A process according to claim 1, for preparing 3-{2-[4-(2-fluorophenoxymethyl)-piperidino]-ethyl} indole comprising reacting 3-(2-bromoethyl)-indole with 4-(2-fluorophenoxymethyl)-piperidine.

14. A process according to claim 1, for preparing 3-{2-[4-(4-fluorophenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(4-fluorophenoxymethyl)-piperidine.

15. A process according to claim 1, for preparing 3-{2-[4-(2-methoxyphenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(2-methoxyphenoxymethyl)-piperidine.

16. A process according to claim 1, for preparing 3-{2-[4-(3-methoxyphenoxymethyl)-piperidino]-ethyl}indole comprising reacting 3-(2-bromoethyl)-indole with 4-(3-methoxyphenoxymethyl)-piperidine.

17. A process according to claim 1, for preparing 3-{2-[4-(4-methoxyphenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(4-methoxyphenoxymethyl)-piperidine.

18. A process according to claim 1, for preparing 3-{2-[4-(2-n-butoxyphenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(2-n-butoxyphenoxymethyl)-piperidine.

19. A process according to claim 1, for preparing 3-{2-[4-(2-methylphenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(2-methylphenoxymethyl)-piperidine.

20. A process according to claim 1, for preparing 3-{2-[4-(3-methylphenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(3-methylphenoxymethyl)-piperidine.

21. A process according to claim 1, for preparing 3-{2-[4-(4-methylphenoxymethyl)-piperidino]-ethyl}-indole comprising reacting 3-(2-bromoethyl)-indole with 4-(4-methylphenoxymethyl)-piperidine.

22. A process according to claim 1, for preparing 1-methyl-3-[2-(4-phenoxymethylpiperidino)-ethyl]-indole comprising react-ing 1-methyl-3-(2-bromoethyl)-indole with 4-phenoxymethyl-piperidine.

23. A process according to claim 1, for preparing 2-methyl-3-[2-(4-phenoxymethylpiperidino)-ethyl]-indole comprising reacting 2-methyl-3-(2-bromoethyl)-indole with 4-phenoxymethyl-piperidine.

24. A process according to claim 1, for preparing 3-[3-(4-phenoxymethylpiperidino)-propyl]-indole comprising reacting 3-(3-tosyloxypropyl)-indole with 4-phenoxymethyl-piperidine.

25. A process according to claim 5, for preparing 1-methyl-3[2-(4-phenoxymethylpiperidino)-ethyl]-indole comprising reacting 3-[2-(4-phenoxymethylpiperidino)-ethyl]-indole with methyliodide.

26. A piperidine derivative of indole of formula (I):- (I) wherein R1 and R2, which may be the same or different, are select-ed from the group consisting of hydrogen atoms and lower alkyl radicals, R3 is a hydrogen or halogen atom or a lower alkyl or lower alkoxy radical and X is a straight-chained or branched alkylene radical containing 2 or 3 carbon atoms;
and the pharmacologically compatible salts thereof, whenever pre-pared by the process of claim 1, or by an obvious chemical equiva-lent.

27. A pharmaceutically acceptable, pharmacologically compatible acid addition salt of piperidine derivative of indole of formula (I) as defined in claim 1, whenever prepared by the process of-claim 6, or by an obvious chemical equivalent.

28. 3-[2-(4-Phenoxymethylpiperidino)-ethyl] indole, when-ever prepared by the process of claim 8, or by an obvious chemical equivalent.

29. 3-{2-[4-(2-Bromophenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 9, or by an obvious chemical equivalent.

30. 3-{2-[4-(2-Chlorophenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 10, or by an obvious chemical equivalent.

31. 3-{2-[4-(3-Chlorophenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 11, or by an obvious chemical equivalent.

32. 3-{2-[4-(4-Chlorophenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 12, or by an obvious chemical equivalent.

33. 3-{2-[4-(2-Fluorophenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 13, or by an obvious chemical equivalent.

34. 3-{2-[4-(4-Fluorophenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 14, or by an obvious chemical equivalent.

35. 3-{2-[4-(2-Methoxyphenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 15, or by an obvious chemical equivalent.

36. 3-{2-[4-(3-Methoxyphenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 16, or by an obvious chemical equivalent.

37. 3-{2-[4-(4-Methoxyphenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 17, or by an obvious chemical equivalent.

38. 3-{2-[4-(2-n-Butoxyphenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 18, or by an obvious chemical equivalent.

39. 3-{2-[4-(2-Methylphenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 19, or by an obvious chemical equivalent.

40. 3-{2-[4-(3-Methylphenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 20, or by an obvious chemical equivalent.

41. 3-{2-[4-(4-Methylphenoxymethyl)-piperidino]-ethyl}-indole, whenever prepared by the process of claim 21, or by an obvious chemical equivalent.

42. 1-Methyl-3-[2-(4-phenoxymethylpiperidino)-ethyl]-indole, whenever prepared by the process of claim 22 or 25, or by an obvious chemical equivalent.

43. 2-Methyl-3-[2-(4-phenoxymethylpiperidino)-ethyl]-indole, whenever prepared by the process of claim 23, or by an obvious chemical equivalent.

44. 3-[3-(4-Phenoxymethylpiperidino)-propyl]-indole, when-ever prepared by the process of claim 24, or by an obvious chemical equivalent.