SK284866B6 - Indole or 2,3-dihydroindole derivatives, pharmaceutical composition containing them and their use - Google Patents

Abstract

The present invention relates to indole and 2,3-dihydroindole derivatives having formula (I) any of its enantiomers or any mixture thereof, or an acid addition salt thereof, which are potent serotonin reuptake inhibitors and have 5-HT1A receptor antagonistic activity and are applicable for the treatment of disorders or disease like affective disorders, including depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive compulsive disorder.

Description

Field of the invention

The present invention relates to novel indole or 2,3-dihydroindole derivatives which are potent inhibitors of serotonin reuptake, pharmaceutical compositions containing these compounds and their use in the treatment of disorders or diseases responsive to inhibition of serotonin reuptake. The compounds of the invention also have 5-HT _1A receptor antagonistic activity and are considered to be particularly useful for the treatment of depression.

BACKGROUND OF THE INVENTION

Selective serotonin (SSR1) (or 5-HT) reuptake inhibitors such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram represent a significant step in the treatment of depression because they have less and less severe side effects compared to first generation antidepressants (tricyclic and non-selective) MAO inhibitors). The side effects associated with the first generation of antidepressants are such as to cause some patients to withdraw from treatment.

SSRIs and all other antidepressants currently available have serious drawbacks in that several weeks of treatment are required to produce a therapeutic effect. Late onset of action is a significant problem, especially in the treatment of patients with several depressions and potential suicides. Furthermore, one in three patients does not respond to SSR1.

Electrophysiological experiments in rats showed that sudden administration of SSR! reduces the firing of dorsal suture 5-HT neurons in rodent brain, while sustained treatment with SSR1 leads to normalization of the firing activity

5-HT neurons (Arborelius, L. et al., Naunyn-Schmiedeberg's Ar. Pharmacol. 1995, 352, 157; Gartside, SE et al., Br. J. Pharmacol. 1995, 115, 1064; Chaput, Y. et al. Naunyn-Schmideberg ' s Pharm. Pharmacol. 1986, 33, 342).

Furthermore, it has been reported that restoration of the 5-HT neuronal launch activity is linked to desensitization of somatodendric 5-HT _1A autoreceptors (Le Poul, E. et al., Naunyn-Schmiedeberg's Ar. Pharmacol. 1995, 352, 141; Invemizzi, R. et al. et al., Eur. J. Pharmacol., 1994, 260, 243).

It has been suggested that simultaneous administration of SSRIs and an agent causing in the rapid desensitization or inhibition of the _{5-HT] A} receptor mediated feed back mechanism would lead binding to a rapid onset of antidepressant effect (Artigas, F. et al, Trends Neurosci. 1996, 19, 378; De Vry, J. et al., Drug News Perspec. 1996, 9, 270).

The effect of the combined administration of a compound that inhibits serotonin reuptake and a 5-HT _1A receptor antagonist has been evaluated in several studies (Innis, RB, et al., Eur. J. Pharmacol., 1987, 143, pp. 195-204 and Gartside, SE , Br J. Pharacol, 1995, 115, 1064-1070 (Blier, P. et al., Trends Pharmacol. Sci., 1994, 15, 220). The studies found that antagonists of 5-HT, _A receptor antagonists inhibit the reduction of the batting caused by acute administration of serotonin reuptake inhibitors.

Treatment with pindolol (a known 5-HT _1A receptor and (3-adreno-receptor) antagonist and SSRI) was further evaluated in clinical trials.

A remarkable improvement in the patient's mood was recorded over a week. In addition, the combined administration of pindolol and SSRI has shown that it has a good effect on patients who have not responded to treatment with currently available antidepressants (Artigas F. et al., Ar. Gen. Psychiatry, 1994, 51, pp. 248-251 and Blier, P , et al., J. Clin. Psychopharmacol., 1995, 15, pp. 217-222).

Some patent applications have been filed covering the use of a combination of a 5-ΗΤ _1Λ antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A2-714 663).

EP-A1-529 462 describes 1,4-benzodioxane derivatives of the general formula

B-Q

wherein B is an optionally substituted indol-3-yl group and Q is C _n H _2n wherein n is 1, 2, 3, 4, 5 or 6. These compounds are said to have serotonin agonist and serotonin antagonist activity, such as as well as serotonin reuptake inhibitory activity and are useful as anxiolytics, antidepressants, antipsychotics, antihypertensives and cerebroprotective agents.

U.S. Pat. No. 5,002,948 to Perregaard et al. Discloses related indoles, indazoles, 2-indolones and their 2,3-dihydro derivatives of the formula

wherein X is -CH-, -CH ₂ -, -NH- or -CO-; and Ar is

wherein Y is O or S, Z is O, S or -CH ₂ - and n is 1, 2 or 3.

These compounds are full-length 5-HT _1A receptor ligands.

The object of the invention is to provide compounds with the inhibiting activity of serotonin reuptake and antagonist properties of the 5-HT, _A receptors. Such compounds can be used as medicaments with a rapid onset of action in the treatment of affective disorders such as depression.

It is a further object of the invention to provide a pharmaceutical composition comprising said compounds as active ingredients.

SUMMARY OF THE INVENTION

Thus, the invention includes, but is not limited to, the following compounds alone or in combination.

The present invention provides indole or 2,3-dihydroindole derivatives of formula (I)

their enantiomers or mixtures thereof, or their acid addition salts, wherein

X is -O-, -S-, or-CR ⁴ R ⁵ -; and

Y is -CR ⁶ R ⁷ -, -CR ⁶ R ⁷ -CR ⁸ R ⁹ - or -CR ⁶ = CR ⁷ -; or

X and Y together form -CR ⁴ = CR ⁵ -, or -CR ⁴ = CR ⁵ -CR ⁶ R ⁷ -;

Z is -O- or -S-;

W is N, C or CH;

A is a group selected from the group of formulas (II), (III) and (IV)

R ³ R ^{, J}

wherein the dotted line represents an optional bond;

R ^1, R ^2, R ^3, R ^12, R ^3, R ^14, R ^15, R ¹⁶ and R ¹⁷ are each independently hydrogen, halogen, trifluoromethyl, C _K4 -alkyl, C _{2nd 4} -alkenyl, C _{2nd 4-} alkynyl, C ₃ . ₇ -cycloalkyl, C1-6alkyl; _4- alkoxy, hydroxy, formyl, CO-C _1-4 alkyl, amino, C _1-4 alkyl; _4- alkylamino, (C ₁₄ ) ₂ -dialkylamino, CO-C ₁ . _4- alkylamino, C ₁ . ₄ alkoxycarbonylamino, aminocarbonylamino, C _M alkylamino-carbonylamino, (C _{M) 2} -dialkylaminokarbonylamino, nitro, cyano;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen or C 1-6 -alkyl; and

R ¹¹ is selected from hydrogen, C | _ ₄ -alkyl, _C2-.4 alkenyl, _{second 4-} alkynyl, C ₃ . ₇ -cycloalkyl, phenyl, naphthyl, phenyl-C _{first 4-} alkyl, naphthyl-C _1-4 -alkyl, CO-C ₁ . _4- alkyl and formyl.

In one embodiment of the invention, Z is -O- and the other substituents are as defined.

In another embodiment of the invention, Z is -S- and the other substituents are as defined.

In a third embodiment of the invention, A is a group of formula (II) and the other substituents are as defined.

In a fourth embodiment of the invention A is a group of formula (III) and the other substituents are as defined.

In a fifth embodiment of the invention, A is a group of formula (IV) and the other substituents are as defined.

Thus, in a particular embodiment of the invention, A is a group of formula (II) and Z is -O-, A is a group of formula (III) and Z is -O-, A is a group of formula (IV) and Z is -O-, A is a group of formula (II) and Z is -S-, A is a group of formula (III) and Z is -Sor A is a group of formula (IV) and Z is -S-.

In another embodiment of the present invention, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are selected from hydrogen or methyl.

Examples of compounds of the invention are:

3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole,

3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-bromo-1 H -indole, 3- [2- [4- (1,4) benzodioxan-5-yl) piperazin-l-yl] ethyl] -2-methyl-1 // - indole,

6-chloro-3- [2- [4- (2,2,5-trimethyl-2,3-dihydrobenzofuran-7-

-yl) piperidin-1-yl] ethyl] -1H-indole, 3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -4-chloro- 1 H -indole, 6-chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperidin-1-yl] ethyl] -1 H -indole, 6 chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) -l, 2,3,6-tetrahydro-l-pyridyl] ethyl] -lH-indole, 3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-fluoro-1 H -indole, 3- [2- [4- (1,4) -benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-methoxy-1 H -indole, 3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ] ethyl] -5-methyl-1 // - indole,

3- [2- [4- (l, 4-benzodioxan-5-yl) piperazin-l-yl] ethyl] -6-methyl-l // - indole,

3- [2- [4- (l, 4-benzodioxan-5-yl) piperazin-l-yl] -ethyl] -l // - indole;

3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -6-chloro-1 H -indole,

- (2- (4- (5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl) ethyl) -1H-indole,

6-chloro-3- [2- [4- (5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-indole,

6-chloro-3- [2- [4- (6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl) piperazin-1-yl] ethyl] - 1 H -indole, 6-chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) -piperazin-1-yl] ethyl] -1 H -indole .

3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -4-methyl-177-indole,

3- [2- [4- (7-chloro-l, 4-benzodioxan-5-yl) piperazin-l-yl] ethyl] -6-chloro-l // - indole,

2- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl) -6-chloro-1H-indole,

- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-chloro-1 H -indole,

3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl) -6-chloro-2,3-dihydroindole,

6-chloro-3- [2- [4- (2,3-dihydrobenzofuran-7-yl) piperazin-l-yl] -ethyl] -l // - indole;

3- (2- (4- (1,4-benzodioxan-5-yl) -1,2,3,6-tetrahydro-1-pyridyl] ethyl) -6-chloro-1H-indole,

3- (2- (4- (1,4-benzodioxan-5-yl) piperidin-1-yl) ethyl] -6-chloro-1H-indole,

3- [2- [4- (1,4-Benzodioxin-5-yl) piperazin-1-yl] ethyl] -6-chloro-

- 1 H -indole,

3- [2- [4- (Benzofuran-7-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole; and

3- [2- [4- (1,3-benzodioxoan-4-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole,

6-chloro-3- [2- [4- (6-chloro-l, 4-benzodioxan-5-yl) piperazin-l-yl] -ethyl] -l // - indole;

5-chloro-3- [2- [4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-indole,

3- [2- [4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -5-fluoro-1 H -indole,

3- [2- [4- (benzothiophen-7-yl) piperazin-l-yl] ethyl] -5-chloro-l // - indole,

3- [2- [4- (benzothiopyran-8-yl) piperazin-l-yl] ethyl] -5-chloro-1 // - indole,

3- [2- [4- (benzothiopyran-8-yl) piperazin-l-yl] ethyl] -5-bromo-

- 1 // - indole,

3- [2- [4- (benzothiopyran-8-yl) piperazin-l-yl] ethyl] -6-chloro-l // - indole,

3- (2- (4- (1,4-benzodioxan-5-yl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl] -5-chloro-1 H -indole,

3- (2- (4- (1,4-benzodioxan-5-yl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl] -5-fluoro-1 H -indole,

3- (2- (4- (1,4-benzodioxan-5-yl) piperidin-1-yl) ethyl) -6-chloro-1H-indole,

3- (2- (4- (1,4-benzodioxan-5-yl) piperidin-1-yl) ethyl] -5-chloro-1 H -indole,

3- (2- (4- (1,4-benzodioxan-5-yl) -piperidin-l-yl] ethyl] -5-fluoro // - indole,

6-chloro-3- [2- [4- (2,3-dihydrobenzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -1H-indole,

3- [2- [4- (Benzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -6-chloro-1 H -indole,

3- [2- [4- (Benzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -5-bromo-1 H -indole,

3- [2- [4- (Benzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl-ethyl] -5-fluoro-1 H -indole, 3- [2- [4- ( benzofuran-7-yl) piperidin-l-yl] ethyl] -6-chloro-l // - indole,

3- [2- [4- (Benzofuran-7-yl) piperidin-l-yl] ethyl] -5-fluoro-l // - indole,

3- [2- [4- (Benzofuran-7-yl) piperidin-1-yl] ethyl] -5-bromo-1H-1-acetyl-3- [2- [4- (1,4-benzodioxan-4)] -yl) piperazin-1-yl] ethyl] -2,3-dihydro-1 H -indole,

- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-fluoro-1 H -indole,

1- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl) -6-chloro-177-indole,

- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -1H-indole,

- [2- [4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-indole,

3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-l-yl] ethyl] -2,3-dihydro-l / 7-indole.

3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -2,3-dihydro-5-fluoro-1 H -indole,

- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-chloro-2,3-dihydro-1H-indole,

3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-l-yl] ethyl] -L-butyl-1 // - indole,

-alyl-3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl) -1H-indole,

- [2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1-propargyl-1H-indole,

3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -2,3-dihydro-1-methyl-1H-indol,

3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -1-benzyl-2,3-dihydro-1 H -indole, 1-allyl-3- [2- [4- (l, 4-benzodioxan-5-yl) piperazin-l-yl] ethyl] -2,3-dihydro-l / Z-indol,

- acetyl-3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1H-indole,

- [2- [4- (Benzo-1,4-dithien-5-yl) piperazin-1-yl] ethyl] -5-chloro-1 H -indole,

3- [2- [4- (Benzo-1,4-dithian-5-yl) piperazin-1-yl] ethyl] -6-chloro-1 H -indole,

3- [2- [4- (Benzo-1,4-dithien-5-yl) piperazin-1-yl] ethyl] -5-fluoro-1 H -indole,

3- [2- [4- (Benzo-1-thia-4-oxan-5-yl) piperazin-1-yl] ethyl] -5-chloro-1 H -indole,

3- [2- [4- (Benzo-1-thia-4-oxan-5-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole; and

3- [2- [4- (Benzo-1-thia-4-oxan-5-yl) piperazin-1-yl] ethyl] -5-fluoro-1 H -indole or acid addition salts thereof.

The invention also relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent.

In another embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of a disorder or disease responsive to inhibition of serotonin reuptake and 5-HT _1A receptor antagonism.

In particular, the invention relates to the use of a compound of the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of effective disorders such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive-compulsive disorder.

In another embodiment, the present invention relates to a method of treating a disorder or disease of a living animal, including a human, that responds to inhibition of serotonin reuptake and 5-HT _1A receptor antagonism, comprising administering to said animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt.

In particular, the invention relates to a method of treating affective disorders such as depression, psychosis, anxiety disorder including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder, comprising, if necessary, administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt to an animal, including a human.

Due to their combined antagonism of 5-HT, _A receptors and inhibiting effect of serotonin reuptake, the compounds of the invention are considered particularly useful as medicaments with a rapid onset of action in the treatment of depression. The compounds may also be used to treat depression in patients who are immune to treatment with currently available antidepressants.

The compounds claimed in this invention are considered particularly useful for the treatment of depression requiring rapid antidepressant effect or depression that is resistant to other antidepressants.

The term halogen means fluorine, chlorine, bromine or iodine.

The term alkyl means a straight or branched chain of one or four carbon atoms, such as: methyl, ethyl, propyl, isopropyl and butyl.

The term alkenyl means a chain of two to four carbon atoms containing one double bond, such as: ethenyl, 1-, 2-propenyl, 2-, 3-propenyl, and the like.

The term alkynyl means a chain of two to four carbon atoms containing one triple bond, such as ethynyl, 1-, 2-propynyl, 2-, 3-propynyl, and the like.

The term cycloalkyl means cyclic alkyl of three to seven carbon atoms, including cyclopropyl, cyclobutyl, and the like.

Alkoxy is -O-alkyl, wherein alkyl is as defined.

Acyl means -CO-alkyl, wherein alkyl is as defined.

Alkylamino means -NH-alkyl and dialkylamino means -N- (alkyl) ₂ , wherein alkyl is as defined.

Acylamino means -NH-acyl, wherein acyl is as defined.

Alkoxycarbonylamino means alkyl-O-CO-NH-, wherein alkyl is as defined.

Alkylaminocarbonylamino means alkyl-NH-CO-NH-, wherein alkyl is as defined.

Dialkylaminocarbonylamino means (alkyl) ₂ -NH-CO-NH-, wherein alkyl is as defined.

Aryl) means an aromatic ring such as phenyl or naphthyl.

Arylalkyl means aryl-alkyl, wherein aryl and alkyl are as defined.

Examples of acid addition salts of the compounds of this invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, mandelic, mandelic acid , cinnamon, citracone, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic, as well as with 8-halo-thiophylins, for example with 8-bromothiophylline. Examples of inorganic acid addition salts of the present invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the present invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.

The compounds of the invention may further exist in unsolvate as well as solvate forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvate forms are considered equivalent to unsolvate forms for the purposes of the present invention.

Certain compounds of the invention contain chiral centers, and such compounds exist in the form of isomers (e.g., enantiomers). The present invention includes all such isomers and any mixtures thereof containing racemic mixtures.

Racemic forms can be resolved into the optical antipodes by known methods, for example, by separating their diastereomeric salts with optically active acids and liberating the optically active amine compounds by treatment with a base. Another method for resolving racemates into optical antipodes is based on optically active matrix chromatography. Thus, the racemic compounds of the invention can be resolved into their optical antipodes, for example by the crystallization of d- or 1- (tartrates, mandelanes or sulfogafuric acid esters) salts. The compounds of the invention may also be resolved by forming diastereomeric derivatives.

Methods which are well known in the art can be used to resolve optical isomers. Such methods include those described in J. Jacques, A. Collet and S. Wilen in "Enantiomers, Racemates and Resolution", John Wiley and Sons, New York, (1981).

Optically active compounds can also be prepared from optically active starting materials.

The compounds of the invention may be prepared by one of the following methods, including:

a) reduction of carbonyl groups of the compound of formula (V)

wherein R ¹ to R ¹ , R ¹² , R ¹⁴ to R ¹⁷ , X, Y, Z, W and the dashed line are determined;

b) alkylation of an amine of formula (VI)

wherein R ¹ to R ³ , X, Y, Z, W and the dotted line are defined with an agent of formula G-CH ₂ CH ₂ -A, wherein A is defined and G is a suitable leaving group such as halogen, mesilate or tosylate;

c) reductive alkylation of an amine of formula (VI)

(VI), wherein R ¹ to R ³ , X, Y, Z, W and the dotted line are as defined, with the reagent of formula B-CH ₂ -A, wherein A is as defined and B is either an aldehyde or a carboxylic acid group;

d) reduction of the double bond of the indoles of formula (VII)

wherein R ¹ to R ³ , X, Y, Z, W and the dashed line are defined and A 'is a group of formulas (II), (III) or (IV) as indicated, wherein the dashed line represents a bond, for purposes of obtaining the corresponding 2,3-dihydroindole derivatives;

e) reduction of the double bond of tetrahydropyridines of the general formula (VIII)

wherein R ¹ to R ³ , A, X, Y and Z are intended to yield the respective piperidine derivatives;

f) treating a compound of formula (I) wherein Y is -CR ⁶ = CR ⁷ - or wherein X and Y together form -CR ⁴ = CR ⁵ - or -CR ⁴ = CR ⁵ -CR ⁶ R ⁷ , with a reducing agent for the purpose of obtaining a double bond so as to obtain a corresponding reducing ring system;

g) reductively removing one or more substituents R ¹ -R ³ or R ¹² -R ¹⁷ in a compound of formula (I) wherein one or more of these substituents is selected from chlorine, bromine or iodine;

h) dialkylation of an amine of formula (IX)

(IX), wherein R 1 to R ³ , X, Y and Z are as defined, with an agent of formula (X)

( ^χ ).

wherein A is as defined and G is a suitable leaving group such as halogen, mesylate or tosylate;

i) dialkylating the amine of formula (XI) nh ₂

(XI) ₍ where A is intended, with an agent of formula (XII))

wherein R ¹ to R ³ , X, Y and Z are as defined and G is a suitable leaving group such as halogen, mesilate or tosilate, or

(j) alkylation or acylation of nitrogen atoms in an indole compound of general formula (ΧΙΠ)

wherein R ¹ to R ³ , X, Y, Z, W and the dotted line are defined and A is a group selected from the group of formula (III) or IV as indicated wherein R ¹¹ is hydrogen, with alkylating or acylating agents of formula R ¹¹ '-G, in which G is a suitable leaving group such as halogen, mesilate or tosilate, and R ¹¹ is other than hydrogen;

and then the compounds of formula (I) are isolated as the free bases or in the form of their acid addition salt.

The reduction according to method a) is preferably carried out in an inert organic solvent, for example diethyl ether or tetrahydrofuran in the presence of lithium aluminum hydride at reflux temperature. The starting compounds of formula (V) are generally prepared from compounds of formula (VI), 1,3-unsubstituted indoles and oxalyl chloride as described in the examples.

The alkylation according to method b) is preferably carried out in an inert organic solvent, for example in a suitable boiling alcohol or ketone, preferably in the presence of a base (potassium carbonate or triethylamine) at reflux temperature.

The arylpiperazine derivatives of formula (VI) are conveniently prepared from the corresponding arylamines according to the method described by Martin et al., J. Med. Chem., 1989, 32, 1052 or the method described by Kruse et al., Rec. Travel. Chim. Pays-Bas, 1988, 107, 303. The starting arylamines are either commercially available or are described in the literature.

Aryltetrahydropyridine derivatives of formula (VI) are known from the literature, U.S. Pat. 2,891,066, McElvain et al., J. Amer. Chem. Soc., 1959, 72, 3134. Preferably, the respective aryl bromide is lithiated with BuLi, followed by the addition of 1-benzyl-4-piperidone. Further treatment with acid gives N-benzyl-aryl-tetrahydropyridine. The benzyl group can be removed by catalytic hydrogenation or by treatment with, for example, ethyl chloroformate to give the corresponding ethyl carbamate, followed by acid or base hydrolysis. The starting aryl bromides are either commercially available or are described in the literature.

Agents of formula G-CH ₂ CH ₂ -A are either commercially available or can be prepared by methods known in the literature, for example, from the corresponding acetic acid derivatives by reduction to 2-hydroxyethyl derivatives and conversion of the hydroxy group to the G group by conventional methods.

Reductive alkylation according to method c) is performed according to standard methods known in the literature. The reaction can be carried out in two steps, ie, coupling the compound of formula (VI) and the reagent of formula B-CH ₂ -A by conventional methods with carboxylic acid chloride or using a coupling reagent, for example dicyclohexylcarbodiimide, followed by reduction of the resulting amide with lithium aluminum hydride. The reaction can also be carried out by a standard one-pot procedure. Carboxylic acids or aldehydes of formula _B-CH2 -A are either commercially available or described in the literature.

The reduction of the indole double bond according to method d) is conveniently carried out by treatment with diborane or a diborane precursor, for example with trimethylamine or dimethylsulfide complex in an inert solvent such as tetrahydrofuran or dioxane at a temperature from 0 ° C to reflux temperature followed by hydrolysis of borane derivatives acid catalyzed intermediates.

The reduction may optionally be performed by treatment with sodium cyanoborohydride in trifluoroacetic acid.

The reduction of the double bonds according to processes e) and f) is preferably carried out by hydrogenation in an alcohol in the presence of a noble metal catalyst such as platinum or palladium.

Removal of the halogen substituents according to method g) is conveniently accomplished by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst or by treatment with ammonium formate in an alcohol at an elevated temperature in the presence of a palladium catalyst.

The dialkylation of amines according to methods h) and i) is preferably carried out at elevated temperature in an inert solvent, for example chlorobenzene, toluene, N'-methylpyrrolidone, dimethylformamide or acetonitrile. The reaction may be carried out in the presence of a base such as potassium carbonate or triethylamine. The starting materials for methods h) and i) are commercially available or can be prepared from commercially available materials using traditional methods.

The N-alkylation according to method j) is carried out in an inert solvent such as an alcohol or a ketone at elevated temperature in the presence of a base such as potassium carbonate or triethylamine at reflux temperature. Preferably, a phase-transfer agent may be used.

The following examples illustrate the invention below. But they are not interpreted as limiting.

DETAILED DESCRIPTION OF THE INVENTION

The halogen-, methyl- or methoxy-substituted indoles used as described in Example 1 are commercially available.

The substituted 2- (1-indolyl) acetic acid used in Example 3 is prepared from the corresponding substituted indole and ethyl bromoacetate by conventional methods.

The substituted 3- (2-bromomethyl) indoles used in Example 2 were prepared from the corresponding 2- (1-indolyl) acetic acid ester by reduction to an alcohol with lithium aluminum hydride and further treated with tetra-bromomethane / triphenylphosphine according to standard literature methods.

The arylpiperazines used in Examples 1, 2 and 3 were prepared from the corresponding arylamines according to the method described by Martin et al., J. Med. Chem. 32, 1989, 1052 or the method described in Kruse et al., Rec. Travel. Chim. Pays-Bas, 107, 1988,303.

The starting arylamines are either commercially available or are described in the literature:

The synthesis of 5-amino-1,4-benzioxane is described in Dukas et al., Zh. Org. Khim. 3, 1967, 1121. The corresponding chlorinated derivatives are prepared in a similar manner.

The synthesis of 7-amino-2,3-dihydrobenzofuran is described in U.S. Pat. 4,302,592th

The synthesis of 7-aminobenzofuran is described by Van Wijngaarden et al., J. Med. Chem. 31,1988,1934.

The synthesis of 7-amino-benzo [b] thiophene is described by Boswell et al., J. Heterocycl. Chem. 5, 1968, 69.

7-Amino-2,3-dimethylbenzofuran and the corresponding 5-chloro and 5-methyl derivatives are prepared according to DE 3526510.

4-Amino-benzothiopyran is prepared according to European patent application EP 79683.

8- Amino-6-chloro-2,2-dimethylbenzopyran is prepared by conventional nitration of 6-chloro-2,2-dimethylbenzopyran (prepared according to Bolzoni et al., Angew. Chem. 90, 1978, 727-) followed by reduction of the obtained 8- nitro derivative. After

In a similar manner, 7-amino-5-chloro-3,3-dimethylbenzofuran is obtained from 5-chloro-3,3-dimethylbenzofuran (prepared according to European patent application EP 7719 800206). The corresponding dechlorinated derivatives are obtained by treatment with hydrogen gas in the presence of a noble metal catalyst according to standard procedures.

Aryltetrahydropyridine derivatives are known in the literature (US Patent Application No. 2,891,066 or McElvain et al., J. Amer. Chem. Soc., 72, 1959, 3134). Most preferably, the appropriate aryl bromide is lithiated with BuLi followed by the addition of 1-benzyl-4-piperidone. Subsequent treatment with mineral acid or trifluoroacetic acid affords N-benzylaryltetrahydropyrdine. The benzyl group may be removed by catalytic hydrogenation or by treatment of, for example, ethyl chloroformate to the corresponding ethyl carbamate, followed by acidic or alkaline hydrolysis. Appropriate piperidine derivatives can be obtained by reductive removal of the tetrahydropyridine ring double bond. All of these techniques are well known in the art. The starting aryl bromides are already described in the literature. In this way 4- (1,4-benzodioxan-5-yl) -1,2,3,6-tetrahydropyridines, 4- (2,3-dihydro-2-2-dimethylbenzofuran-7-yl) -1, are obtained. 2,3,6-tetrahydropyridines, 4- (2,3-dihydrobenzofuran-7-yl) -1,2,3,6-tetrahydropyridines, 4- (benzofuran-7-yl) -1,2,3, 6-tetrahydropyridines and corresponding piperidines.

Melting points were determined on a Bichi SMP-20 apparatus and are not corrected. Mass spectra were recorded on a Quattro MS-MS system from VG Biotech, Fisons Instruments. The MS-MS system was connected to an HP 1050 HPLC module system. A 20 to 50 μΐ sample (10 µg / ml) dissolved in 1% acetic acid / acetonitrile / water 1: 1 was fed via an automatic sample feeder with a flow rate 30 µl min ^-1 into Electrospray source. Spectra were recorded under two different set-up conditions. One set of data served to determine molecular weight (MH +) information (21 eV) and the other set to induce fragmentation (70 eV). The background was counting down. The relative intensities for the ions were obtained from the fragmentation record. If no intensity is given for the molecular ion (MH ⁺ ), this ion was present only in the first set of measurement conditions. 1 H NMR spectra of all new compounds were recorded at 250 MHz on a Bruker AC 250 or at 500 MHz on a Bruker DRX 500. Deuterated chloroform (99.8% D) was used as solvent. TMS was used as internal standard. The chemical shift was expressed in ppm. The following abbreviations are used for multiple NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet triplets, m = multiplet. The NMR signals associated with acidic protons were generally omitted. The water content of the crystalline compounds was determined by Karl Fischer titration. Basic processing in the processes involves extraction with the indicated organic solvent from the respective aqueous solution, drying of the combined organic extracts (anhydrous MgSO ₄ or Na ₂ SO ₄ ), filtration and evaporation of the solvent in vacuo. Kieselgel 60, 230-400 mesh ASTM was used for column chromatography.

Example 1

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-chloro-1 H -indole oxalate, (Compound 1a)

A solution of 5-chloroindole (5.0 g) in diethyl ether (130 mL) was cooled to 0 ° C under a nitrogen atmosphere followed by dropwise addition of a solution of oxalyl chloride (4.6 g) in diethyl ether (20 mL). After stirring for 16 h, the crystalline product 2- (5-chloro-1H-indol-3-yl) -2-oxoacetyl chloride (7.2 g) was collected by filtration.

A solution of this product (2.0 g) in dry tetrahydrofuran (250 mL) was added dropwise to a mixture of 1- (1,4-benzodioxan-5-yl) piperazine (1.2 g) and triethylamine (7.5 mL). in tetrahydrofuran (75 mL) at room temperature. The mixture was stirred for 16 h, followed by filtration and removal of the solvent in vacuo to give crude 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) -1,2-dioxoethyl). This is dissolved in tetrahydrofuran (25 mL) and added dropwise to a suspension of lithium aluminum hydride (2.1 g) in tetrahydrofuran at room temperature under a nitrogen atmosphere. At reflux for 3.5 h, the reaction was quenched with aqueous sodium hydroxide, followed by basic treatment with ethyl acetate, and the resulting oil purified by flash chromatography (eluent: heptane / ethanol / ethyl acetate / triethylamine 15: 2: 2: 1). It is recovered from acetone solution by addition of oxalic acid and recrystallized from methanol / tetrahydrofuran (1: 5) to give 0.8 g of the product of 1a, mp 224-228 ° C.

1 H NMR (DMSO-d ₆ ): 3.05 (t, 2H); 3.10 to 3.50 (m, 10H);

4.15 to 4.30 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.10 (d, 1H); 7.30 (s, 1H); 7.40 (d, 1H); 7.65 (s, 1H);

11.15 (s, 1H); MS m / z (%): 398 (MH < ^{+ &gt};, 9%), 233 (100%), 221 (29%), 218 (19%), 178 (59%).

The following compounds were prepared analogously: 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-bromo-1 H -indole oxalate, (compound 1b), mp 236-240 ° C.

1 H NMR (DMSO-d ₆ ): 3.10 (t, 2H); 3.15 to 3.45 (m, 10H);

4.15 to 4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.20 (d, 1H); 7.30 (s, 1H); 7.35 (d, 1H); 7.80 (s, 1H);

11.20 (s, 1H). MS m / z (%): 444 (MH < ^{+ &gt};, 5%), 442 (5%), 233 (80%), 224 (21%), 222 (22%), 221 (25%), 218 (23). %), 190 (19%), 70 (100%).

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -2-methyl-1H-indole oxalate, (compound 1c), m.p. 205-208 ° C.

1 H NMR (DMSO-d ₆ ): 2.35 (s, 3H); 2.95 to 3.15 (m, 4H);

3.15 to 3.45 (m, 8H); 4.15 to 4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 6.95 (t, 1H); 7.00 (t, 1H); 7.25 (d, 1H); 7.50 (d, 1H); 10.85 (s, 1H). MS m / z (%): 378 (MH < ^{+ &gt};, 5%), 233 (9%), 221 (7%), 218 (5%), 158 (100%).

6-Chloro-3- [2- [4- (2,2,5-trimethyl-2,3-dihydro-benzofuran-7-yl) -piperidin-1-yl] -ethyl] -1 H -indole fumarate, (Compound 1d) mp 232-237 ° C.

1 H NMR (DMSO-d ₆ ): 1.40 (s, 6H); 1.65-1.85 (m, 4H);

2.20 (s. 3H); 2.30 (t, 2 H); 2.60 (t, 2 H); 2.70 to 2.85 (m, 3H); 2.90 (s, 3H); 3.10 to 3.30 (m, 2H); 6.60 (s, 2 H); 6.70 (s, 1H); 6.80 (s, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (s, 1H). MS m / z (%): 423 (MH < ^{+ &gt};, 11%), 258 (100%), 178 (14%), 70 (41%).

3- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -4-chloro-1H-indole oxalate, (compound le), m.p. 210-218 C.

1 H NMR (DMSO-d ₆ ): 3.10-3.50 (m, 12H); 4.10 to 4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.00 (d, 1H); 7.05 (t, 1H); 7.30 to 7.40 (m, 2H); 11.40 (s, 1H). MS m / z (%): 398 (MH < ^{+ &gt};, 10%), 233 (100%), 221 (47%), 218 (18%), 180 (25%), 178 (84%).

6-Chloro-3- (2- (4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperidin-1-yl) ethyl] -1 H -indole oxalate, (compound 1f), m.p. 190-193 ° C.

1 H NMR (DMSO-d ₆ ): 1.40 (s, 6H); 1.75 to 1.95 (m, 4H);

2.50 to 2.70 (m, 2H); 2.70 to 2.80 (m, 1H); 2.85-3.05 (m, 6H); 3.25 to 3.40 (m, 2H); 6.75 (t, 1H); 6.95 (d, 1H);

6.95 to 7.10 (m, 2H); 7.25 (s, 1H); 7.40 (s, 1H); 7.55 (d,

IH); 11.00 (s, 1H). MS m / z (%): 409 (MH < ^{+ &gt};, 6%), 244 (100%), 232 (9%), 178 (16%).

6-Chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) -l, 2,3,6-tetrahydro-l-pyridyl] ethyl] -l / 7 -indole oxalate (compound 1 g), m.p. 200-204 ° C.

1 H NMR (DMSO-d ₆ ): 1.40 (s, 6H); 2.70 to 2.80 (m, 2H); 3.00 (s, 2 H); 3.15 (t. 2H); 3.30 (t, 2 H); 3.35 to 3.50 (m, 2H); 3.85 to 4.00 (m, 2H); 6.35 (s, 1H); 6.85 (t, 1H); 7.00 (d, 1H); 7.05 to 7.15 (m, 2H); 7.30 (s, 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.15 (s, 1H). MS m / z (%): 407 (MH < ^{+ &gt};, 2%), 207 (8%), 180 (33%), 178 (100%).

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl) -5-fluoro-1H-indole oxalate (compound 1h), m.p. 224 to 226 ° C.

1 H NMR (DMSO-d ₆ ): 3.10 (t, 2H); 3.10 to 3.50 (m, 10H);

4.15 to 4.35 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 6.95 (t, 1H); 7.30 (s, 1H); 7.30 to 7.50 (m, 2H); 11.10 (s, 1H). MS m / z (%): 382 (MH < ^{+ &gt};, 9%), 233 (78%), 221 (30%), 218 (22%), 190 (20%), 162 (97%), 70 (100%). %).

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-methoxy-1H-indole hemioxalate (compound li), m.p. 189-196 C.

1 H NMR (DMSO-d ₆ ): 3.00 (t, 2H); 3.05 to 3.30 (m, 10H);

3.80 (s, 3H); 4.15 to 4.35 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.70 to 6.80 (m, 2H); 7.10 (s, 1H); 7.15 (s, 1H); 7.25 (d, 1H); 10.70 (s, 1H). MS m / z (%): 394 (MH < ^{+ &gt};, 7%), 233 (79%), 218 (21%), 190 (21%), 174 (61%), 70 (100%).

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-methyl-1H-indole hemifumarate, (compound 1j), m.p. 147-154 C.

1 H NMR (DMSO-d 6): 2.40 (s, 3H); 2.60 to 2.80 (m, 6H); 2.85 (t, 2H); 2.95 to 3.15 (m, 4H) 4.15-4.30 (m, 4H) 6.45 (d, 1H) 6.50 (d, 1H) 6.60 (s, 1H) 6.70 (t, 1H); 6.90 (d, 1H); 7.10 (s, 1H); 7.20 (d, 1H); 7.30 (s, 1H); 10.65 (s, 1H).

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -6-methyl-177-indole hemifumarate, (Compound 1k), m.p. 204-207 ° C .

1 H NMR (DMSO-d ₆ ): 2.35 (s, 3H); 2.60 to 2.80 (m, 6H);

2.90 (t, 2 H); 2.95 to 3.15 (m, 4H); 4.10 to 4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 6.80 (d, 1H); 7.05 (s, 1H); 7.10 (s, 1H); 7.40 (d, 1H); 10.60 (s, 1H).

6-Chloro-3- [2- [4- (7-chloro-1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1 H -indole oxalate, (compound 11), with temperature mp 237-238 ° C.

1 H NMR (DMSO-d ₆ ): 3.00 to 3.15 (m, 2H); 3.15 to 3.40 (m, 10H); 4.20 (s, 4H); 6.50 (d, 1H); 6.65 (d, 1H); 7.00 (dd, 1H); 7.25 (d, 1H); 7.40 (d, 1H); 7.60 (d, 1H); 10.95 (s, 1H). MS m / z (%): 432 (MH < ^{+ &gt};, 3%), 267 (42%), 252 (12%), 224 (10%), 178 (27%), 70 (100%).

6-Chloro-3- [2- [4- (6-chloro-1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1 H -indole oxalate, (compound 1m), with temperature mp 216-217 ° C.

1 H NMR (DMSO-d ₆ ): 2.60 (t, 2H); 2.85 (t, 2 H); 3.10 (b, 4H); 3.30 (s, 4H); 4.15 to 4.30 (m, 4H); 6.15 (d, 1H); 6.35 (d, 1H); 7.00 (dd, 1H); 7.20 (d, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.95 (s, 1H). MS m / z (%): 432 (MH < ^{+ &gt};, 2%), 267 (47%), 252 (16%), 224 (16%), 178 (30%), 70 (100%).

5-Chloro-3- (2- [4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl-ethyl] -1 H -indole oxalate, (Compound 1n), m.p. 134-138 ° C .

1 H NMR (DMSO-d ₆ ): 2.65-2.80 (m, 6H); 2.90 (t, 2 H); 3.00 to 3.25 (m, 6H); 4.50 (t, 2 H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 7.05 (d, 1H); 7.25 (s, 1H);

7.35 (d, 1H); 7.60 (s, 1H); 11.05 (s, 1H). MS m / z (%): 382 (MH < ^{+ >} ), 217 (39%), 205 (17%), 178 (38%), 143 (11%), 70 (100%).

6-Chloro-3- [2- [4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1 H -indole oxalate (compound lo), m.p. 205-207 C.

1 H NMR (DMSO-d ₆ ): 2.60-2.75 (m, 6H); 2.90 (t, 2 H); 3.00 to 3.20 (m, 6H); 4.50 (t, 2 H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.80 (d, 1H); 6.95 (d, 1H); 7.20 (s, 1H);

7.35 (s, 1H); 7.55 (d, 1H); 10.95 (s, 1H). MS m / z (%): 382 (MH < ^{+ >} ), 217 (33%), 202 (18%), 70 (100%).

3- (2- (4- (2,3-Dihydrobenzofuran-7-yl) piperazin-1-yl) ethyl] -5-fluoro-1H-indole oxalate, (Compound 1p), m.p. 145-149 C.

1 H NMR (DMSO-d ₆ ): 2.65-2.85 (m, 6H); 2.90 (t, 2 H); 3.00 to 3.20 (m, 6H); 4.50 (t, 2 H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 6.90 (t, 1H); 7.25 (s, 1H);

7.25 to 7.35 (m, 2H); 10.95 (s, 1H). MS m / z (%): 366 (MH < ^{+ &gt};, 4%), 217 (31%), 205 (18%), 174 (16%), 162 (81%), 70 (100%).

3- [2- [4- (Benzothiophen-7-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole oxalate (compound 1q), m.p. 175.2-176.6 ° C .

1 H NMR (DMSO-d ₆ ): 3.10 (m, 2H); 3.26 (m, 2 H); 3.38 to

3.36 (m. 6H); 7.05 (d, 1H); 7.09 (d, 1H); 7.33 (s, 1H); 7.40 to 7.37 (m, 3H); 7.47 (d, 1H); 7.62 (d, 1H); 7.69 (s, 1H), 7.76 (d, 1H). MS m / z (%): 398.1 (MH ⁺ , 1.1% ( ³⁷ Cl)). 396.1 (MH ⁺ , 2.8% ( ³⁵ Cl)), 230.9 (1005), 177.8 (58%), 69.8 (50.8%).

3- [2- [4- (Benzothiopyran-8-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole, (comp. 1r), mp 152-153 ° C.

1 H NMR (CDCl 3): 2.08 (m, 2H); 2.75 (m, 6H); 2.83 (m, 2 H); 2.98 (m, 4H); 3.05 (m, 2 H); 6.80 (d, 1H); 6.99 to 6.94 (m, 2H); 7.08 (s, 1H); 7.14 (d, 2 H); 7.26 (d, 1H); 7.59 (s, 1H); 8.00 (s, 1H). MS m / z (%): 412.3 (MH ⁺ , 100% ( ³⁵ Cl)), 414.5 (MH ⁺ , 63% ( ³⁷ Cl)), 247.1 (23.7%).

3- [2- [4- (Benzothiopyran-8-yl) piperazin-1-yl] ethyl] -5-bromo-1 H -indole. (compound 1 s), m.p. 166-167 ° C.

1 H NMR (CDCl 3): 2.04 (m, 2H); 2.75 (m, 6H); 2.82 (m, 2 H); 2.98 (m, 4H); 3.05 (m, 4 H); 6.81 (d, 1H); 6.98 - 6.93 (m, 2H); 7.05 (s, 1H); 7.21 (d, 2 H); 7.26 (d, 1H); 7.76 (s, 1H); 8.02 (s, 1H). MS m / z (%): 458.4: (MH ⁺ , 21.7% ( ⁸¹ Br)), 456.3 (MH ⁺ , 23.9% ( ⁷⁹ Br)), 232.0 (58.7) %); 143.1 (100%).

3- [2- [4- (Benzothiopyran-8-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole (compound lt), mp 178-179 ° C.

1 H NMR (CDCl ₃ ): 2.07 (m, 2H); 2.75 (m, 6H); 2.83 (m, 2 H); 2.98 (m, 4H); 3.04 (m, 4H); 6.80 (d, IH); 6.98 - 6.92 (m, 2H); 7.04 (s, 1 H); 7.08 (d, IH); 7.33 (s, 1 H); 7.52 (d, IH); 7.95 (s, 1 H). MS m / z (%): 412.3: (MH ⁺ , 31.8% ( ³⁵ Cl)), 247.3 (81.8%), 232.0 (63.9%); 178.1 (63.6%); 143.1 (100%).

3- [2- [4- (Benzofuran-7-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole (compound lu), m.p. 202-204 ° C.

1 H NMR (DMSO-d ₆ ): 2.65-2.85 (m, 6H); 2.90 (t, 2 H);

3.20 to 3.40 (m, 4H); 6.60 (s, 1 H); 6.80 (d, IH); 6.90 (d, IH); 7.00 (d, IH); 7.05 to 7.30 (m, 3H); 7.40 (d, IH); 7.55 (d, IH); 7.95 (d, IH); 11.00 (s, 1 H). MS m / z (%): 380 (MH + 4%), 215 (100%), 200 (12%); 178 (36%); 172 (20%).

- [2- [4- (1,4-Benzodioxan-5-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -6-chloro-1H-indole oxalate, (compound lv ), m.p. 240-247 ° C.

1 H NMR (DMSO-d ₆ ): 2.70 (s, 2H); 2.90 (t, 2 H); 3.10 (t. 2H); 3.20 to 3.70 (m, 4H); 3.80 (s, 2 H); 4.25 (s. 4H); 5.85 (s, 1 H); 6.75 (t, 1 H); 6.80 (d, 2 H); 7.05 (d, IH); 7.30 (s, 1 H); 7.40 (s, 1 H); 7.60 (d, IH); 11.10 (s, 1 H). MS m / z (%): 395 (MH < ^{+ &gt};, 1%), 178 (100%).

6-Chloro-3- [2- [4- (2,3-dihydrobenzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -1H-indole oxalate, (Compound 1x) mp 211-214 ° C.

1 H NMR (DMSO-d ₆ ): 2.75 (s, 2H); 3.05 to 3.15 (m, 2H);

3.20 (t, 2 H); 3.25 to 3.50 (m, 4H); 3.85 (s, 2 H); 4.55 (t, 2 H); 6.30 (s, 1 H); 6.85 (t, 1 H); 7.00 (d, IH); 7.10 (d, IH);

7.15 (d, IH); 7.30 (s, 1 H); 7.40 (s, 1 H); 7.60 (d, IH); 11.10 (s, 1 H). MS m / z (%): 379 (MH < ^{+ &gt};, 3%), 178 (100%).

3- [2- [4- (Benzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -6-chloro-1H-indole hemifumarate, (Compound ly), s mp 214-220 ° C.

1 H NMR (DMSO-d 6): 2.65 (s, 2H); 2.75-2.85 (m, 4H);

2.90 to 3.00 (m, 2H); 3.10 to 3.50 (m, 3H); 6.55 (s. 2H);

6.90-7.00 (m, 2H); 7.15 to 7.30 (m, 3H); 7.35 (s, 1 H);

7.50 to 7.60 (m, 2H); 8.00 (s, 1 H); 10.90 (s, 1 H). MS m / z (%): 377 (MH < ^{+ &gt};, 25%), 178 (73%), 143 (22%).

3- [2- [4- (Benzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -5-bromo-1H-indole oxalate, (Compound 1z), s mp 185-194 ° C.

1 H NMR (DMSO-d ₆ ): 2.90 (s, 2H); 3.10 to 3.20 (m, 2H);

3.25 to 3.55 (m, 4H); 3.95 (s, 2 H); 6.60 (s, 1 H); 7.00 (s, 1 H); 7.20 (d, IH); 7.20 to 7.45 (m, 4H); 7.60 (d, IH); 7.80 (s, 1 H); 8.05 (s, 1 H); 11.20 (s, 1 H). MS m / z (%): 423 (MH < ^{+ >} ( ^sl Br), 22%), 421 (MH < ^{+ >} ( ⁷⁹ Br), 20%), 224 (70%), 222 (72%), 143 (33%). ).

3- [2- [4- (Benzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -5-fluoro-1 H -indole hemioxalate, (compound 1aa), s mp 176-179 ° C.

1 H NMR (DMSO-d ₆ ): 2.75 (s, 2H); 2.90 to 3.25 (m, 6H); 3.65 (s, 2 H); 6.60 (s, 1 H); 6.85 to 6.95 (m, 1H); 7.00 (s, 1 H); 7.20 to 7.40 (m, 5H); 7.60 (d, IH); 8.00 (s, 1 H); 11.00 (s, 1 H). MS m / z (%): 361 (MH < ^{+ &gt};, 12%), 162 (100%), 115 (13%).

3- [2- [4- (Benzofuran-7-yl) piperidin-1-yl] ethyl] -6-chloro-1H-indole hemifumarate, (compound 1bb), mp 245-250 ° C.

1 H NMR (DMSO-d ₆ ): 1.85-2.00 (m, 4H); 2.75 (t, 2 H);

2.90 (t, 2 H); 3.05 (tt, 1 H); 3.25 (d, 2 H); 6.55 (s. 2H); 6.95 (s, 1 H); 7.00 (d, IH); 7.15 to 7.25 (m, 3H); 7.40 (s, 1 H);

7.50 (d, IH); 7.55 (d, IH); 8.00 (s, 1H); 10.95 (s, 1 H). MS m / z (%): 379 (MH < ^{+ &gt};, 5%), 214 (10%), 178 (20%), 143 (100%).

- [2- [4- (Benzofuran-7-yl) piperidin-1-yl] ethyl] -5-fluoro-1H-indole oxalate (compound Icc), mp 191-194 ° C. H NMR (DMSO-d _s): 2.05 to 2.25 (m, 4H); 3.05 to 3.20 (m, 4H); 3.20 to 4.40 (m, 3H); 3.60 to 3.70 (m, 2H); 6.90 to 7.00 (m, 2H); 7.15 to 7.25 (m, 2H); 7.35 to 7.45 (m, 3H); 7.55 (d, IH); 8.00 (s, 1 H); 11.05 (s, 1 H). MS m / z (%): 363 (MH < ^{+ &gt};, 5%), 214 (9%), 161 (10%), 143 (24%).

3- [2- [4- (Benzofuran-7-yl) piperidin-1-yl] ethyl] -5-bromo-1H-indole oxalate, (compound 1dd), m.p. 153-157 ° C.

1 H NMR (DMSO-d ₆ ): 2.05-2.20 (m, 4H); 3.05 to 3.20 (m, 4H); 3.20 to 3.40 (m, 3H); 3.70 (d, 2 H); 6.95 (s, 1 H);

7.15 to 7.25 (m, 3H); 7.30 to 7.40 (m, 2H); 7.55 (d, IH);

7.80 (s, 1 H); 8.00 (s, 1 H); 11.20 (s, 1 H). MS m / z (%): 423 (MH < ^{+ &gt};, 36%), 224 (27%), 202 (45%), 143 (27%), 117 (18%).

Example 2 3- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -1 H -indole hemifumarate, (Compound 2a)

A mixture of 3- (2-bromomethyl) -1 H -indole (1.5 g), 1- (1,4-benzodioxan-5-yl) piperazine (1.2 g), potassium carbonate (1.9 g) and potassium iodide (0.1 g) in methyl isobutyl ketone (100 mL) was refluxed for 16 h. Standard work-up with ethyl acetate gave an oil which was purified by flash chromatography (eluent: heptane / ethanol / ethyl acetate / triethylamine 15: 2: 2: 1). The fumarate salt is obtained from the ethanol solution by the addition of fumaric acid. Recrystallization from ethanol gave hemifumarate 2a (0.9 g), mp 204-207 ° C.

1 H NMR (DMSO-d 6): 2.60-2.80 (m, 6H); 2.90 (t, 2 H); 2.95 to 3.10 (m, 4H); 4.15 to 4.30 (m, 4H); 6.50 (d, IH);

6.55 (d, IH); 6.60 (s, 1 H); 6.75 (t, 1 H); 7.00 (t, 1 H); 7.10 (t, 1 H); 7.20 (s, IH); 7.35 (d, IH); 7.55 (d, IH); 10.75 (s, 1 H). MS m / z (%): 364 (MH < ^{+ &gt};, 5%), 233 (57%), 218 (21%), 190 (19%), 144 (54%), 70 (100%).

- Ac-ethyl-3- [2- [4- (1,4-benzodioxan-4-yl) piperazin-1-yl] ethyl] -2,3-dihydro-1 H -indole (compound 2b), mp 119-120 ° C.

1 H NMR (DMSO-d ₆ ): 1.90 (d, 1H); 2.20 (s, 4H); 2.95 to 3.30 (m, 1H); 3.40 to 3.50 (m, 1H); 3.75 to 3.85 (m, 1H);

4.20-4.30 (m, 4H); 6.45 (dd, IH); 6.55 (dd, IH); 6.75 (t, 1 H); 7.00 (t, 1 H); 7.20 (t, IH); 7.30 (d, IH); 8.05 (d, IH). MS m / z (%): 408 (MH < ^{+ &gt};, 54%), 233 (17%), 178 (100%), 119 (20%).

Example 3

3- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole hemifumarate, (compound 3a)

A mixture of 2- (6-chloro-1H-indol-3-yl) acetic acid (2.0 g), 1- (1,4-benzodioxan-5-yl) piperazine (3.6 g); N-dicyclohexylcarbodiimide (2.4 g) and 4-dimethylaminopyridine (0.2 g) in dry tetrahydrofuran (100 mL) were stirred at room temperature under nitrogen for 16 h.

Filtration and standard work-up with methylene chloride gave an oil which was purified by flash chromatography (eluent: ethyl acetate / heptane / methanol 16: 3: 1) to give 3- [2- (4- (1,4-benzodioxan-5-yl) piperazine). 1-yl] -2-oxoethyl] -6-chloro-1 H -indole as an oil (2.0 g).

The oil was dissolved in tetrahydrofuran (25 mL) and added dropwise to a suspension of lithium aluminum hydride (0.9 g) in dry tetrahydrofuran (50 mL) at room temperature, followed by heating to boiling for 3 hours. Quenching with 2M aqueous sodium hydroxide and standard work-up affords 3a free base as an oil (1.9 g). The hemifumarate salt, compound 3a (1.0 g), is obtained from an ethanol solution by the addition of filmaric acid, m.p. 215-216 ° C.

1 H NMR (DMSO-d 6): 2.60 to 2.85 (m, 6H); 2.85 to 2.95 (m, 2H); 2.95 to 3.10 (m, 4H); 4.10 to 4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 7.00 (dd, 1H); 7.25 (d, 1H); 7.40 (d, 1H); 7.55 (d, 1H); 10.95 (s, 1H). MS m / z (%): 398 (MH < ^{+ &gt};, 10%), 234 (13%), 233 (100%), 178 (12%).

The following compounds were prepared analogously: 3- [2- [4- (5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1 H -indole hemifumarate (compound 3b), mp 210-212 ° C.

1 H NMR (DMSO-d ₆ ): 1.40 (s, 6H); 2.55 to 2.75 (m, 6H);

2.80 to 3.00 (m, 4H); 3.05 to 3.20 (m, 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.80 (d, 1H); 6.95 (t, 1H); 7.05 (t, 1H); 7.15 (d, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.70 (s, 1H). MS m / z (%): 410 (MH < ^{+ &gt};, 18%), 281 (32%), 279 (100%), 144 (39%).

6-Chloro-3- [2- [4- (5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-indole hemifumarate, (compound 3c) ), m.p. 130-132 ° C.

H NMR (DMSO-d _s): 1.25 (s, 6H); 2.55 to 2.70 (m, 6H); 2.85 (t, 2 H); 3.00 to 3.20 (m, 4H); 4.25 (s, 2 H); 6.60 (s, 1H); 6.65 (s, 1H); 6.85 (s, 1H); 7.00 (d, 1H); 7.20 (s, 1H);

7.35 (s, 1H); 7.55 (d, 1H); 10.90 (s, 1H). MS m / z (%): 446 (8%), 444 (MH < + >, 11%), 281 (34%), 280 (16%), 279 (100%), 178 (15%).

6-Chloro-3- [2- [4- (6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl) piperazin-1-yl] ethyl] -1 / -indole fumarate, (compound 3d), m.p. 224-225 ° C.

1 H NMR (DMSO-d ₆ ): 1.30 (s, 6H); 1.70 (t, 2 H); 2.60 to

2.75 (m, 8H); 2.90 (t, 2 H); 2.95 to 3.10 (m, 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.70 (d, 1H); 7.00 (d, 1H); 7.20 (s, 1H);

7.35 (s, 1H); 7.55 (d, 1H); 10.95 (s, 1H). MS m / z (%): 458 (MH < ^{+ &gt};, 11%), 295 (32%), 293 (100%), 259 (11%), 178 (14%).

6-Chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-indole fumarate, (compound 3e), with temperature mp 165-167 ° C.

1 H NMR (DMSO-d ₆ ): 1.40 (s, 6H); 2.65 to 2.80 (m, 6H);

2.90 (t, 2 H); 2.95 (s, 2 H); 3.00 to 3.20 (m, 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.70 (t, 1H); 6.75 (d, 1H); 7.00 (d, 1H);

7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H). MS m / z (%): 410 (MH < ^{+ &gt};, 6%), 245 (67%), 209 (39%), 178 (8%), 127 (51%), 45 (100%).

- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -6-chloro-1 H -indole oxalate, (compound 3f), m.p. 235 ° C.

1 H NMR (DMSO-d ₆ ): 2.85 (s, 4H); 2.95 to 3.15 (m, 6H);

4.15 to 4.30 (m, 4H); 4.40 (t, 2 H); 6.45 to 6.55 (m, 3H); 6.70 (t, 1H); 7.05 (d, 1H); 7.45 (d, 1H); 7.55 (d, 1H); 7.70 (s, 1H). MS m / z (%): 398 (MH < ^{+ &gt};, 45%), 218 (100%), 178 (50%).

- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl) -5-chloro-1H-indole oxalate, (compound 3g), m.p. 234-235 ° C.

1 H NMR (DMSO-d ₆ ): 2.85 (s, 4H); 2.95 to 3.15 (m, 6H);

4.15 to 4.30 (m, 4H); 4.45 (t, 2 H); 6.40 to 6.50 (m, 2H);

6.55 (d, 1H); 6.70 (t, 1H); 7.15 (d, 1H); 7.50 (s, 1H); 7.55 to 7.65 (m, 2H). MS m / z (%): 398 (MH < ^{+ &gt};, 44%), 218 (100%), 178 (62%).

1- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-fluoro-1H-indole oxalate, (compound 3h), m.p. 230-231 ° C.

H NMR _{(DMSO-d '):} 2.90 (s, 4H); 2.95 to 3.20 (m, 6H);

4.15 to 4.30 (m, 4H); 4.45 (t, 2 H); 6.40 to 6.50 (m, 2H);

6.55 (d, 1H); 6.75 (t, 1H); 7.00 (t. 2H); 7.30 (d, 1H); 7.50 (s, 1H); 7.50 to 7.55 (m, 1H). MS m / z (%): 382 (MH < ^{+ >} ), 218 (63%), 162 (100%).

1- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -1ZZ-indole oxalate, (compound 3i), mp 225-229 ° C. 1 H NMR _(DMSO-d6): 2.95 (s, 4H), 3.05 to 3.20 (m, 6H), 4.10 4.30 (m, 4H), 4.45 (t, 2H) 6.40 to 6.50 (m, 2H);

6.55 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.40 (s, 1H); 7.55 (t, 2H). MS m / z (%): 364 (MH < ^{+ &gt};, 100%), 218 (85%), 146 (80%).

1- (2- (4- (2,3-Dihydrobenzofuran-7-yl) piperazin-1-yl) ethyl) -1H-indole oxalate, (compound 3j), m.p. 223-226 ° C.

1 H NMR (DMSO-d ₆ ): 2.85 (s, 4H); 3.00 (t, 2 H); 3.05 to

3.20 (m, 6H); 4.40 (t, 2 H); 4.50 (t, 2 H); 6.45 (d, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 7.00 (t, 1H); 7.15 (t, 1H); 7.40 (d, 1H); 7.55 (dd, 2 H). MS m / z (%): 348 (MH < ^{+ &gt};, 38%), 231 (50%), 201 (100%), 174 (25%), 162 (41%), 146 (98%).

Example 4

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -2,3-dihydro-1H-indole sesquioxalate, (Compound 4a)

A solution of compound 2a (16 g) in trifluoroacetic acid (200 mL) was treated in portions with sodium borohydride (2 x 2.9 g, 1.5 hour intervals) at room temperature followed by stirring for 2.5 hours at room temperature. Pour the reaction mixture into ice and basify with aqueous sodium hydroxide, followed by standard work-up. The resulting oil was purified by flash chromatography (eluent: heptane / ethyl acetate / ethanol / triethylamine 15: 2: 2: 1) to give the title base as a yellow oil (13.8 g). The title oxalate is obtained from the free base (1.4 g) as a crystalline material from ethanol by adding oxalic acid (0.9 g), m.p. 145-150 ° C.

1 H NMR (DMSO-d ₆ ): 1.75-1.85 (m, 1H); 2.05 to 2.15 (m, 1H); 2.95 to 3.30 (m, 12H); 3.60 (t, 1H); 4.20 (d, 4H);

6.50 (d, 2 H); 6.60 (d, 2 H); 6.75 (t, 1H); 6.95 (t, 1H); 7.10 (d, 1H). MS m / z (%): 366 (MH < ^{+ &gt};, 10%), 221 (10%), 178 (14%), 150 (20%), 118 (100%).

The following compounds were prepared analogously:

3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -2,3-dihydro-5-fluoro-1H-indole hemioxalate, (compound 4b), s mp 201-205 ° C.

1 H NMR (DMSO-d ₆ ): 1.60-1.80 (m, 1H); 1.95 to 2.10 (m, 1H); 2.60 to 3.30 (m, 12H); 3.35 (t, 1H); 4.20 (d, 4H);

6.35 to 6.55 (m, 3H); 6.15 to 6.25 (m, 2H); 6.90 (d, 1H). MS m / z (%): 384 (MH < ^{+ &gt};, 32%), 178 (28%), 150 (12%), 136 (100%).

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl) -5-chloro-2,3-dihydro-1 H -indole oxalate, (compound 4c), with temperature mp 153-157 ° C.

1 H NMR (DMSO-d ₆ ): 1.70-1.85 (m, 1H); 2.05 to 2.20 (m, 1H); 2.85 to 3.05 (m, 2H); 3.05 to 3.35 (m, 10H); 3.60 (t, 2 H); 4.15 to 4.30 (m, 4H); 6.45 to 6.60 (m, 3H); 6.75 (t, 1H); 6.95 (dd, 1H); 7.10 (d, 1H). MS m / z (%): 400 (MH +, 39%), 178 (39%), 152 (100%).

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl) -6-chloro-2,3-dihydro-1H-indole oxalate, (compound 4d), at a temperature of mp 185-188 ° C.

1 H NMR (DMSO-d ₆ ): 1.75-1.85 (m, 1H); 2.00 to 2.10 (m, 1H); 2.90 to 3.30 (m, 12H); 3.60 (t, 1H); 4.15 to 4.30 (m, 4H); 6.45 (s, 1H); 6.50 (d, 1H); 6.55 (t, 2 H); 6.75 (t, 1H); 7.05 (d, 1H). MS m / z (%): 400 (MH < ^{+ &gt};, 14%), 221 (52%), 180 (22%), 152 (100%).

Example 5

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl] -1-butyl-1H-indole oxalate, (Compound 5a)

A solution of compound 2a (1.0 g) in dry tetrahydrofuran (50 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.14 g) in tetrahydrofuran (25 mL) at room temperature. After stirring for 30 minutes, a solution of 1-bromobutane (0.85 g) in dry tetrahydrofuran (10 mL) was added dropwise. Stirring for 1 hour followed by standard treatment with ethyl acetate gave an oil which was purified by flash chromatography (eluent: heptane / ethyl acetate / triethylamine 15: 3: 2). The resulting oil was converted to the title oxalate salt (0.7 g) from acetone by addition of oxalic acid, m.p. 168-174 ° C.

1 H NMR (DMSO-d 6): 0.90 (t, 3H); 1.25 (qv, 2H); 1.70 (qv, 2H); 3.05 (t, 2 H); 3.15 to 3.40 (m, 8H); 4.10 (t. 2H); 4.15 to 4.30 (m, 4H); 6.55 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.15 (t, 1H); 7.25 (s, 1H); 7.45 (d, 1H); 7.60 (d, 1H). MS m / z (%): 420 (MH < ^{+ &gt};, 33%), 233 (39%), 200 (100%), 158 (36%).

The following compounds were prepared analogously:

-alyl-3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl-ethyl] -1 H -indole oxalate, (compound 5b), mp 187-190 ° C.

1 H NMR (DMSO-d 6): 3.05 (t, 2H); 3.10 to 3.40 (m, 10H);

4.20 (d, 4H); 4.75 (d, 2 H); 5.05 (d, 1H); 5.15 (d, 1H); 5.90 to 6.05 (m, 1H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.15 (t, 1H); 7.25 (s, 1H); 7.40 (d, 1H); 7.60 (d, 1H). MS m / z (%): 404 (MH < ^{+ &gt};, 38%), 233 (38%), 184 (43%), 120 (29%).

3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl) ethyl) -1-propargyl-1H-indole oxalate (compound 5c), m.p. 168-172 ° C.

¹ H NMR (DMSO-d ₆ ): 3.00-3.30 (m, 12H); 3.40 (t, 1H);

4.25 (d, 4H); 5.05 (d, 2 H); 6.50 (d, 2 H); 6.55 (d, 1H); 7.10 (t, 1H); 7.20 (t, 1H); 7.30 (s, 1H); 7.50 (d, 1H); 7.65 (d, 1H). MS m / z (%): 402 (MH < ^{+ &gt};, 52%), 233 (50%), 182 (57%), 167 (100%).

Example 6 3- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -2,3-dihydro-1-methyl-1 H -indole oxalate, (Compound 6a )

A solution of compound 4a (1.5 g) in dry tetrahydrofuran (50 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.21 g) in tetrahydrofuran (25 mL) at room temperature. After stirring for 30 minutes, a solution of iodomethane (0.75 g) in dry tetrahydrofuran (25 mL) was added dropwise. Stirring for 1 hour followed by standard treatment with ethyl acetate gave an oil which was purified by flash chromatography (eluent: heptane / ethyl acetate / triethylamine 15: 3: 2). The resulting oil was converted to the title oxalate salt (0.3 g) from acetone by addition of oxalic acid, mp 155-165 ° C.

1 H NMR (DMSO-d ₆ ): 1.75-1.85 (m, 1H); 2.05 to 2.15 (m, 1H); 2.70 (s, 3H); 2.90 to 3.25 (m, 12H); 3.40 (t, 1H);

4.15 to 4.30 (m, 4H); 6.45 to 6.55 (m, 3H); 6.65 (t. 3H);

6.75 (t, 1H); 7.05 (t, 1H); 7.10 (d, 1H). MS m / z (%): 380 (MH < ^{+ &gt};, 4%), 178 (4%), 132 (53%).

The following compounds were prepared analogously: 3- (2- (4- (1,4-Benzodioxan-5-yl) piperazin-1-yl-ethyl) -1-benzyl-2,3-dihydro-1H-indole oxalate, ( compound 6b), m.p. 158-165 ° C.

1 H NMR (DMSO-d ₆ ): 1.75-1.85 (m, 1H); 2.10 to 2.20 (m, 1H); 2.90 to 3.30 (m, 12H); 3.45 (t, 1H); 4.15 to 4.25 (m, 5H); 4.35 (d, 1H); 6.50 (d, 1H); 6.55 (d, 1H); 6.65 to 6.70 (m, 2H); 6.75 (t, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.30 (t, 1H); 7.35 (s, 4H). MS m / z (%): 456 (MH < ^{+ &gt};, 19%), 236 (25%), 178 (100%), 130 (11%).

- Al y 1-3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl) -2,3-dihydro-1 H -indole oxalate, (compound 6c), s mp 133-136 ° C.

1 H NMR (DMSO-d ₆ ): 1.75-1.85 (m, 1H); 2.10 to 2.20 (m, 1H); 2.95 to 3.35 (m, 12H); 3.50 (t, 1H); 3.65 (dd, 1H);

3.75 (dd, 1H); 4.25 (d, 4H); 5.15 (d, 1H); 5.30 (d, 1H); 5.85 to 5.95 (m, 1H); 6.50 (d, 1H); 6.55 (d, 2 H); 6.65 (t, 1H);

6.75 (t, 1H); 7.00 (t, 1H); 7.10 (d, 1H). MS m / z (%): 406 (MII ^< ^{+ &gt};, 15%), 178 (178%), 158 (24%), 130 (31%), 117 (20%).

Example 7

-Acetyl 3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1 H -indole oxalate, (Compound 7a)

A mixture of 2a (2.0 g), tetrabutylammonium acid sulfate (0.2 g), sodium hydroxide (1.0 g) and methylene chloride (40 mL) was stirred for 10 minutes, followed by dropwise addition of acetyl chloride solution (0). , 97 g) in methylene chloride at room temperature. After stirring for 1 hour, water is added followed by basic work-up. The resulting oil was purified by flash chromatography (eluent: heptane / ethyl acetate / ethanol / triethylamine 17: 1: 1) to give a yellow oil which was converted to the title oxalate salt (0.75 g) from acetone by addition of oxalic acid, temperature mp 199-202 ° C.

H NMR (DMSO-d _s): 2.65 (s, 3H); 3.05 (t, 2 H); 3.15 (s, 10H); 4.20 (d, 2 H); 4.25 (d, 2 H); 6.50 (d, 1H); 6.55 (d, 1H);

6.75 (t, 1H); 7.30 to 7.40 (m, 2H); 7.70 (d, 1H); 7.80 (s, 1H); 8.35 (d, 1H). MS m / z (%): 406 (MH < ^{+ &gt};, 28%), 233 (44%), 218 (39%), 144 (100%).

Pharmacological tests

The affinity of the compounds for the 5-HT, _A receptors was determined by measuring the inhibition of binding of a radioactive ligand at 5-HT _IA receptor, as described in the following tests:

Inhibition of ³ H-5-CT binding to human 5-HT _1A receptors

In this way, the ability of the drug to inhibit the binding of ³ H-5-carboxamidotryptamine ( ³ H-5-CT) to cloned human 5-HT _1A receptors stably expressed in transfected HeLa cells (HA7) (Fargin, A. et al., J. Biol. Chem., 1989, 264, 14848) determined in vitro. The quantitative assay is performed as a modification of the method described by Harrington, MA et al., J. Pharmacol. Exp. Thcr., 1994, 268, 1098. Human 5-HT _1A receptors (40 gg cell homogenate) were incubated for 15 minutes at 37 ° C in 50 mM Tris buffer at pH 7.7 in the presence of ³ H-5-CT. Non-specific binding was determined including 10 μΜntertergoline. The reaction was terminated by rapid filtration through Unifilter GF / B filters on a Tomtec Cell Harveste (cell harvester). Filters were calculated in a Packard Top Counter. The results are shown in Table 1.

Table 1

Compound No. Inhibition of ³ H-5-CT binding IC ₅₀ (nM) la 17 lb 7.2 lc 2.5 ld 55 le 11 lf 6.1 ig 2.8 lh 4.6 when 6.9 ij 14 Ik 2.0 11 12 lm 99 ln 8.2 2 2.9 2b 13 lv 0.81 3a L2 3b 3.6 3d 21 4d 14 pindolol * 100

Table 1 * Compound

The compounds of the invention were also tested for their effect on serotonin reuptake in the following assay.

Inhibition of ³ H-5-HT uptake into rat brain synaptosomes

Using this method, the ability of drugs to inhibit the accumulation of ³ H-5-HT into whole rat brain synaptosomes was determined in vitro. The assay was performed as described by Hyttel, J., Psychopharmacology, 1978, 60, 13. The results obtained are shown in Table 2.

Table 2

Compound No. Inhibition of Serotonin IC ₅₀ Feedback (nM) la 5.0 lb 2.8 lc 45 ld 36 le 0.25 lf 5.9 Ig 3.8 lh 1.7 when 6.8 U 3.5 lk 18 11 7.7 lm 57 ln 2.1 lv 0.85 2 3.5 2b 12 3a 5.3 3b 8.3 3d 15 4d 4.3 paroxetine * 0.29

Table 2 * compound shown

5-HT | _And antagonist activity of some compounds of the invention was determined in vitro in cloned 5-HT _1A receptors stably expressed in transfected HeLa cells (ΗΑ7). In this assay, 5-HT _1A antagonist activity was determined by measuring the ability of the compounds to antagonize 5-ovanú induced inhibition of forskolin-induced cAMP accumulation. The assay was performed as a modification of the method described by Pauwels, PJ et al., Biochem. Pharmacol., 1993, 45, 375. The results obtained are shown in Table 3.

Compound No. Antagonism Inhibition of cAMP-induced forskolin by IC accumulation. _n la 2900 lb 5000 le 2400 lf 1800 Ig 1800 ih 280 when 620 Li are 980 lk 580 ln 1900 lo 3200 lt 5900 lu 2000 lv 3300 lx 3000 2 160 2b 250 3a 500 3c 2600 3d 2300 4c 890 6a 100

most preferably from 0.1 to 50 mg of the active compound of the invention.

Compound No. Antagonism Inhibition of cAMP-induced forskolin by IC ₅₀ accumulation pindolol * 270

Table 3: * compound shown

Claims (19)

PATENT CLAIMS Some of the compounds of the invention were also tested for their in vivo effect on _{5-HT-receptor} assay described in C. Sanchez et al, Eur. J. Pharmacol., 1996, 315, p. 245. In this assay, the antagonist effects of the test compounds were determined by measuring the ability of the test compounds to inhibit 5-HT syndrome induced by 5-MeO-DMT. The compounds of the invention have significant activity as inhibitors of serotonin feedback and have antagonistic effect at 5-HT) _receptors. Thus, the compounds of the invention are believed to be useful in the treatment of diseases and disorders responsive to inhibition of serotonin feedback and antagonist activity at 5-HT _1A receptors. Diseases responsive to serotonin feedback inhibition are well known in the art and include affective disorders such as depression, psychosis, anxiety disorder including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and the like. As explained, the antagonistic activity of the compounds of the invention on 5-HT _1A receptors will paralyze the negative feedback mechanism induced by inhibition of serotonin feedback, and it is therefore expected to improve the effect of the compounds of the invention to inhibit serotonin reuptake. Thus, the compounds as claimed herein are particularly useful as medicaments with a rapid onset of action in the treatment of depression. The compounds may also be used to treat depressions that do not respond positively to currently available SSR1. Pharmaceutical compositions The pharmaceutical compositions of the invention may be prepared by conventional methods known in the art. For example: Tablets may be prepared by mixing the active ingredient with a conventional excipient and / or solvent and then compressing the mixture in a conventional tabletting machine. Examples of excipients or solvents are: corn starch, potato starch, magnesium stearate, gelatin, lactose, resins and the like. Any other excipients or supplements generally used for such purposes as dyes, essences, preservatives, etc., may be used provided that they are compatible with the active ingredients Solutions for injections may be prepared by dissolving the active ingredient and possible supplements in a portion of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution, and filling into the desired ampoules or vials. Any suitable supplement conventionally used in the art may be added, such as a flexible agent, preservatives, antioxidants, etc. The pharmaceutical compositions of the invention or those made in accordance with the invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc. or parenterally in the form of solutions for injection. Methods known in the art and any pharmaceutically acceptable carriers, diluents, vehicles or other additives normally used in the art may be used to prepare such compounds. Usually, the compounds of the invention are administered in unit dosage forms containing said compounds in an amount of about 0.01 to 1000 mg. The total daily dose is usually in the range of 0.05 to 500 mg and What is claimed is: 1. An indole or 2,3-dihydroindole derivative of the general formula (I) ^: their enantiomers or mixtures thereof, or their acid addition salts, wherein X is -Ο-, -S- or -CR ⁴ R ⁵ -; and Y is -CR ⁶ R ⁷ -, -CR ⁶ R ⁷ -CR ⁸ R ⁹ - or -CR ^e = CR ⁷ -; or X and Y together form -CR ⁴ = CR ⁵ - or -CR ⁴ = CR ⁵ -CR ⁶ R ⁷ -; Z is -O- or -S-; W is N, C or CH; A is a group selected from the group of formulas (II), (III) and (IV) wherein the dotted line represents an optional bond; R ^1, R ^2, R ^3, R ^12, R ^13, R ^14, R ^15, R ¹⁶ and R ¹⁷ are each independently hydrogen, halogen, trifluoromethyl, C _M alkyl, C _{2nd 4} -alkenyl, C _{2nd 4-} alkynyl, C ₃ . ₇ -cycloalkyl, C 1-6 alkyl; ₄ alkoxy, hydroxy, formyl, CO-C _{first 4} alkyl, amino, C ₁ _ ₄ alkylamino, (C _{first 4) 2} dialkylamino, CO-C _M -alkylamino, C _{first 4} alkoxycarbonylamino, aminocarbonylamino, C _{first 4} -alkylamino-carbonylamino, (C _{first 4) 2} -dialkylaminokarbonylamino, nitro, cyano; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen or C 1-6 alkyl; and R ¹¹ is selected from hydrogen, C 1. ₄ -alkyl, C _{2nd 4} -alkenyl, C _{2nd 4-} alkynyl, C ₃ . _7- cycloalkyl, phenyl, naphthyl, phenyl-C 1-6 -alkyl, naphthyl-C ₁ . _4- alkyl, C ₀ -C ₁ . _4- alkyl and formyl. Indole or 2,3-dihydroindole derivatives according to claim 1, wherein Z is -O-. The indole or 2,3-dihydroindole derivatives of claim 1, wherein Z is -S-. The indole or 2,3-dihydroindole derivatives of claim 1, wherein A is a group of formula (II). The indole or 2,3-dihydroindole derivatives of claim 1, wherein A is a group of formula (III). The indole or 2,3-dihydroindole derivatives of claim 1, wherein A is a group of formula (IV). The indole or 2,3-dihydroindole derivative according to claim 2, wherein A is a group of formula (II). The indole or 2,3-dihydroindole derivative according to claim 2, wherein A is a group of formula (III). The indole or 2,3-dihydroindole derivative according to claim 2, wherein A is a group of formula (IV). The indole or 2,3-dihydroindole derivative according to claim 3, wherein A is a group of formula (II). The indole or 2,3-dihydroindole derivative according to claim 3, wherein A is a group of formula (III). The indole or 2,3-dihydroindole derivative according to claim 3, wherein A is a group of formula (IV). Indole or 2,3-dihydroindole derivatives according to claims 1 to 12, wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are selected from hydrogen or methyl. 14. The indole or 2,3-dihydroindole derivative according to claim 1, selected from the group consisting of: 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-chloro-1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-bromo-1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -2-methyl-1H-indole, 6-chloro-3- [2- [4- (2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl) piperidin-1-yl] ethyl] -1H-indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-l-yl] ethyl] -4-chloro-1 // - indole, 6-chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperidin-1-yl] ethyl] -1H-indole, 6-chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) -1,2,3,6-tetrahydro-1-pyridyl] ethyl] -1H- indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-fluoro-1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-methoxy-1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-methyl-1H-indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -6-methyl-1H-indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-l-yl] -ethyl] -l // - indole; 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-l-yl] ethyl] -6-chloro-1 // - indole, 3- [2- [4- (5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-indole, 6-chloro-3- [2- [4- (5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-indole, 6-chloro-3- [2- [4- (6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl) piperazin-1-yl] ethyl] 1 H -indole, 6-chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -4-methyl-1H-indole, 3- [2- [4- (7-chloro-1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole, 2- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -6-chloro-1 H -indole, 1- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-chloro-1H-indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -6-chloro-2,3-dihydroindole, 6-chloro-3- [2- [4- (2,3-dihydrobenzofuran-7-yl) piperazine-l-yljetyl] -1 // - indole; 3- (2- (4- (1,4-benzodioxan-5-yl) -1,2,3,6-tetrahydro-1-pyridyl] ethyl) -6-chloro-1H-indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperidin-1-yl) ethyl] -6-chloro-1 H -indole, 3- (2- (4- (1,4-benzodioxin-5-yl) piperazin-1-yl) ethyl] -6-chloro-1 H -indole, 3- [2- [4- (Benzofuran-7-yl) piperazin-1-yl] ethyl] -6-chloro-1 H -indole and 3- (2- (4- (1,3-benzodioxoán-4-yl) piperazin-l-yl] ethyl] -6-chloro-1 // - indole, 6-chloro-3- [2- [4- (6-chloro-1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1H-indole, 5-chloro-3- [2- [4- (2,3-dihydrobenzofuran-7-yl) piperazin-l-yl] -ethyl] -l // - indole; 3- (2- (4- (2,3-dihydrobenzofuran-7-yl) piperazin-l-yl] ethyl] -5-fluoro-l // - indole, 3- [2- [4- (benzothiophen-7-yl) piperazin-l-yl] ethyl] -5-chloro-l // - indole, 3- [2- [4- (benzothiopyran-8-yl) piperazin-l-yl] ethyl] -5-chloro-1/7-indole. 3- [2- [4- (benzothiopyran-8-yl) piperazin-l-yl] ethyl] -5-bromo-1 // - indole, 3- [2- [4- (benzothiopyran-8-yl) piperazin-l-yl] ethyl] -6-chloro-1 // - indole, 3- (2- (4- (1,4-benzodioxan-5-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl) -5-chloro-1H-indole, 3- (2- (4- (1,4-benzodioxan-5-yl) -1,2,3,6-tetrahydropyridin-1-yl) ethyl] -5-fluoro-1H-indole, 3- (2- (4- (1,4-benzodioxan-5-yl) -piperidin-l-yl] ethyl] -6-chloro-l // - indole, 3- (2- (4- (1,4-benzodioxan-5-yl) -piperidin-l-yl] ethyl] -5-chloro-1 / Z-indol, 3- (2- (4- (1,4-benzodioxan-5-yl) piperidin-1-yl-ethyl) -5-fluoro-1H-indole, 6-chloro-3- [2- [4- (2,3-dihydrobenzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -1H-indole, 3- [2- [4- (Benzofuran-7-YLJ-1,2,3,6-tetrahydropyridine-l-yl] ethyl] -6-chloro-l // - indole, 3- [2- [4- (Benzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -5-bromo-1 H -indole, 3- [2- [4- (Benzofuran-7-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -5-fluoro-1H-indole, 3- [2- [4- (Benzofuran-7-yl) piperidin-l-yl] ethyl] -6-chloro-l // - indole, 3- [2- [4- (Benzofuran-7-yl) piperidin-l-yl] ethyl] -5-fluoro-l // - indole, 3- [2- [4- (Benzofuran-7-yl) piperidin-1-yl] ethyl] -5-bromo-1H-indole, 1-acetyl-3- [2- [4- (1,4-benzodioxan-4-yl) piperazin-1-yl] ethyl] -2,3-dihydro-1 H -indole, 1- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -5-fluoro-1 H -indole, 1- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -6-chloro-1 H -indole, 1- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl) -1 H -indole, 1- (2- (4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl) ethyl] -1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -2,3-dihydro-1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -2,3-dihydro-5-fluoro-1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl) -5-chloro-2,3-dihydro-1H-indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -1-butyl-1H-indole, 1-allyl-3- [2- [4- (l, 4-benzodioxan-5-yl) piperazin-l-yl] -ethyl] -l // - indole; 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-l-yl] ethyl] -L-propargyl-1 // - indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl) -2,3-dihydro-1-methyl-1 H -indole, 3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl) -1-benzyl-2,3-dihydro-1H-indole, 1-Allyl-3- (2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl) ethyl] -2,3-dihydro-1H-indole, 1-Acetyl-3- [2- (4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1 H -indole, 3- [2- [4- (benzo-l, 4-dithiane-5-yl) piperazin-l-yl] ethyl] -5-chloro-l // - indole, 3- [2- [4- (Benzo-1,4-dithian-5-yl) -piperazin-1-yl] -ethyl] -6-chloro-1 H -indole, 3- [2- [4- (benzo-l, 4-dithiane-5-yl) piperazin-l-yl] ethyl] -5-fluoro-l // - indole, 3- [2- [4- (Benzo-1-thia-4-oxan-5-yl) piperazin-1-yl] ethyl] -5-chloro-1 H -indole, 3- [2- [4- (Benzo-1-thia-4-oxan-5-yl) piperazin-1-yl] ethyl] -6-chloro-1 H -indole and 3- [2- [4- (Benzo-1-thia-4-oxan-5-yl) piperazin-1-yl] ethyl] -5-fluoro-1 H -indole or acid addition salts thereof. A pharmaceutical composition comprising a compound of claims 1 to 14 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent. Indole or 2,3-dihydroindole derivatives according to claims 1 to 14, or pharmaceutically acceptable acid addition salts thereof, for use in the treatment of disorders or diseases of animals, including humans, that respond positively to inhibition of serotonin reuptake and 5-HT _1A receptor antagonism . The indole or 2,3-dihydroindole derivatives of claim 16, wherein the disease or disorder is an affective disorder including depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, and obsessive-compulsive disorder. Use of a compound according to claims 1 to 14 or a pharmaceutically acceptable acid addition salt for the preparation of a medicament for the treatment of diseases or disorders responsive to the inhibition of serotonin reuptake and 5-HT _1A receptor antagonism. The use of a compound according to claim 16, wherein the disease or disorder is an affective disorder including depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, and obsessive-compulsive disorder.