SK952000A3 - Indole and 2,3-dihydroindole derivatives, their preparation and use - Google Patents

Description

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 reuptake inhibitors (SSRIs) (or 5-HT) 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 the 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 SSRIs.

Electrophysiological experiments in rats have shown that sudden administration of SSRI decreases the dorsal suture core 5-HT neuronal firing in rodent brain, while sustained treatment with SSRIs leads to normalization of the 5-HT neuron firing activity (Arborelius, L. et al., Naunyn-Schmiedeberg's Árch Pharmacol., 1995, 352, 157; Gartside, SE et al., Br. J. Pharmacol. 1995, 115, 1064; Chaput, Y. et al., Naunyn-Schmideberg's Ar. Pharmacol. 1986, 33, 342).

-2Ďalej, indicated that the recovery of the firing activity of 5-HT neurons is linked to desensitization of somatodendritic 5-HT autoreceptors _R (Le Poul, E. et al, Naunyn-Schmiedeberg's Arch. Pharmacol. 1995, 352, 141; Invernizzi, R. et al., Eur. J. Pharmacol., 1994, 260, 243).

It was believed that the simultaneous administration of SSRIs and an agent causing rapid desensitization or inhibition of the 5-HT 1A receptor mediated by the feedback mechanism would lead 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 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). In these studies, 5-HT 1A receptor antagonists were found to inhibit the decrease in evaporation caused by the acute administration of serotonin reuptake inhibitors.

Treatment with pindolol (a known 5-HT 1A receptor and β-adrenoreceptor 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-HT 1A 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 discloses 1,4-benzodioxane derivatives of the general formula

B-Q-N

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. 5,200,948, 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.

It is an object of the invention to provide compounds with effective serotonin reuptake inhibitory activity as well as antagonist properties at 5-HT _1A 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 the above compounds as active ingredients.

4. 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 the formula I

(d) their enantiomers or mixtures thereof, or their acid addition salts, where:

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

(H) (H1) (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, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, hydroxy, formyl, acyl , amino,

-5alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, nitro, cyano and aryl or arylalkyl, wherein the aryl may be substituted with halogen, trifluoromethyl, alkoxy, hydroxy, amino, alkylamino, nitro or cyano;

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

R ¹¹ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, acyl and formyl.

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

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

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

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

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

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 -S-, or 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 this 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-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] -1 / - / indole,

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

-66-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-1H-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-1-yl] ethyl] -1H-indole, 3- [2- [4- (1,4-benzodioxane) -5-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole, 3- [2- [4- (5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)] (piperazin-1-yl) ethyl] -1 H -indole, 6-chloro-3- [2- [4- (5-chloro-3,3-dimethyl-2,3-clihydrobenzofuran-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 _l 3-dihydrobenzofuran-7-yl) piperazin-1-yl ethyl] -1H-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-1H-indole, 1- (2- (4- (1,4-benzodioxane) 5-yl) piperazin-1-yl] ethyl] -5-chloro-1 / - / - 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-1-yl] ethyl] -1 H -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-1H-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-1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1H-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-1H-indole, 3- [2- [4- (benzothiophen-7-yl) piperazin-1-yl] ethyl] -5-chloro- 1H-indole, 3- [2- [4- (benzothiopyran-8-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole, 3- [2- [4- (benzothiopyran- 8-yl) piperazin-1-yl] ethyl] -5-bromo-1H-indole, 3- [2- [4- (benzothiopyran-8-yl) piperazin-1-yl] ethyl] -6- chloro-1H-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-1-yl) ethyl) -6-chloro-1H-indole,

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

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] -1-hindole,

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

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

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

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

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

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

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

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

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

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

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

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

3- (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-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] -1H-indole, 3- (2- [4- (benzo-1,4-dithien-5-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole, 3- [2- [4- (benzo-1,4-dithian-5-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole 3- [2- [4- (benzo-1,4-dithian-5-yl) piperazin-1-yl] ethyl] -5-fluoro-1H-indole, 3- [2- [4- (benzo) -1-thia-4-oxan-5-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole,

-83- [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-1H-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 preparation 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 disorders or diseases of living animals, including humans, that respond to inhibition of serotonin reuptake and antagonism of 5-HT _1A receptors, comprising administering to said animals a therapeutically effective amount of a compound of Formula I or a pharmaceutical an 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 an acid addition salt of an animal, including humans.

Because of their combined 5-HT 1A receptor antagonism and serotonin reuptake inhibitory effect, the compounds of this invention are considered particularly useful as drugs 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 a 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, etc.

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, etc.

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

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

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

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

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

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

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

Aryl means an aromatic ring such as phenyl or naphthyl.

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

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, lactic acid, lactic acid. , cinnamon, citracone, aspart, stear, palmitic, itacon,

-10-glycol, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic, as well as with 8-halo-thiophylenes, for example with 8-bromo-thophyllin. Examples of inorganic acid addition salts of the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the 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 may be resolved into their optical antipodes, for example, by fractional crystallization of d- or I- (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 the carbonyl groups of the compound of formula V

wherein R ¹ to R ³ , R ¹² , R ¹⁴ to R ¹⁷ , X, Y, Z, W and the dashed line are as defined above;

b) Alkylation of an amine of formula VI

W NH 1 / (VI) wherein R ¹ to R ³ , X, Y, Z, W and the dashed line are as defined above, with the reagent of formula G-CHaChh-A, wherein A is as defined above and G is a suitable leaving group, such as halogen, mesylate or tosilate;

c) Reductive alkylation of an amine of formula VI

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

-12 (VII)

d) Reduction of the indole double bond of formula VII

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

e) Reduction of the tetrahydropyridine double bond of formula VIII

wherein R ¹ to R ³ , A, X, Y and Z are as defined above in order to obtain the respective piperidine derivatives;

f) Treatment of a compound of formula I wherein Y is -CR ⁶ = CR ⁷ -, or wherein X and Y taken together form -CR ⁴ = CR ⁵ - or -CR ⁴ = CR ⁵ -CR ⁶ R ⁷ , s a reducing agent to obtain a double bond to provide the appropriate reducing ring system;

g) Reductive removal of 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) Dialkylating the amine of formula IX

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

wherein A is as defined above and G is a suitable leaving group halogen, mesilate or tosilate;

i) Dialkylating the amine of formula XI

wherein A is as defined above, with an agent of formula XII

G (IX) (X) such as (XI) (XII) wherein R ¹ to R ³ , X, Y and Z are as defined above and G is a suitable leaving group such as halogen, mesylate or tosilate, or

j) Alkylation or acylation of nitrogen atoms in an indole compound of formula XIII

wherein R ¹ to R ³ , X, Y, Z, W and the dotted line are as defined above and A is a group selected from the group of formula III or IV as above wherein R ¹¹ is hydrogen, by salkylating or acylating agents of formula R ^11- G, wherein G is a suitable leaving group such as halogen, mesylate or tosilate, and R ¹¹ is as defined above except 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 below.

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-15Bas, 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 appropriate aryl bromide is lithiated with BuLi followed by addition of 1-benzyl-4-piperidone. Further treatment with acid affords N-benzyl-aryltetrahydropyridine. The benzyl group may be removed by catalytic hydrogenation or 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.

G-CH ₂ CH ₂ -A reagents 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 the 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 may 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 agent, for example dicyclohexylcarbodiimide, followed by reduction of the resulting amide with lithium aluminum hydride. The reaction can also be carried out using 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. However, 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 tetrahydrofuran / 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-nitroderivative. 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 addition of 1-benzyl-4-piperidone. Subsequent treatment with mineral acid or trifluoroacetic acid affords N-benzyl-aryltetrahydropyrdine. 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 is obtained

- 18-Tetrahydropyridines, 4- (2,3-dihydro-2-2-dimethylbenzofuran-7-yl) -1,2,3,6-tetrahydropyridines, 4- (2,3-dihydrobenzofuran-7-yl) -1,2 , 3,6-tetrahydropyridines, 4- (benzofuran-7yl) -1,2,3,6-tetrahydropyridines and the corresponding piperidines.

Melting points were determined on a Buchi 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 modular system. A 20 to 50 µL sample (10 µg / mL) dissolved in 1% acetic acid / acetonitrile / water 1: 1 was fed via an automatic sample feeder with 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 (ΜΙ-Γ), 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-1H-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] -5-chloro-1 H -indole as a solid product. This product was 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. After reflux for 3.5 h, the reaction is quenched with aqueous sodium hydroxide, followed by basic treatment with ethyl acetate. The resulting oil was purified by flash chromatography (eluent: heptane / ethanol / ethyl acetate / triethylamine 15: 2: 2: 1). The oxalate salt is obtained from acetone solution by addition of oxalic acid and recrystallized from methanol / tetrahydrofuran (1: 5) to give 0.8 g of the product of compound 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, IH); 6.55 (d, IH); 6.75 (t, 1 H); 7.10 (d, IH); 7.30 (s, 1 H); 7.40 (d, IH); 7.65 (s, 1 H); 11.15 (s, 1 H); 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-1H-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, IH); 6.60 (d, IH); 6.75 (t, 1 H); 7.20 (d, IH); 7.30 (s, 1 H); 7.35 (d, IH); 7.80 (s, 1 H); 11.20 (s, 1 H). MS m / z (%): 444 (MH < ^{+ &gt};, 5%), 442 (5%), 233 (80%), 224 (21%), 222 (22%), 221 (25%), 218 (23). %), 190 (19%), 70 (100%).

-203- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -2-methyl-1H-indole oxalate, (compound

1c), mp 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, IH); 6.60 (d, IH); 6.75 (t, 1H); 6.95 (t, IH); 7.00 (t, 1 H);

7.25 (d, IH); 7.50 (d, IH); 10.85 (s, 1 H). MS m / z (%): 378 (MH < ^{+ &gt};, 5%), 233 (9%), 221 (7%), 218 (5%), 158 (100%).

6-Chloro-3- [2- [4- ( _2L 2,5-trimethyl-2,3-dihydrobenzofuran-7-yl) piperidin-1-yl] ethyl] -1Hindole fumarate, (compound 1d), with temperature 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, IH); 6.80 (s, 1 H); 7.00 (d, IH); 7.20 (s, IH); 7.35 (s, 1 H); 7.55 (d, 1H); 10.95 (s, 1 H). 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 1e), m.p. 218 ° C.

¹ H NMR (DMSO-d 6): 3.10-3.50 (m, 12H); 4.10 to 4.30 (m, 4H); 6.50 (d, IH); 6.60 (d, IH); 6.75 (t, 1 H); 7.00 (d, IH); 7.05 (t, 1 H); 7.30 to 7.40 (m, 2H); 11.40 (s, 1 H). MS m / z (%): 398 (MH < + >, 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] -1H-indole oxalate, (compound 1f), with temperature mp 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 to 3.05 (m, 6H); 3.25 to 3.40 (m, 2H); 6.75 (t, 1 H); 6.95 (d, 1H); 6.95 to 7.10 (m, 2H); 7.25 (s, 1H); 7.40 (s, 1H); 7.55 (d, 1H); 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) -1,2,3,6-tetrahydro-1-pyridyl] ethyl] -1H- indole oxalate (compound 1 g), m.p. 200-204 ° C.

-21 ¹ H-NMR (DMSO-de): 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, 1 H); 6.85 (t, 1 H); 7.00 (d, IH); 7.05 to 7.15 (m, 2H); 7.30 (s, 1 H); 7.40 (s, 1 H); 7.60 (d, IH); 11.15 (s, 1 H). 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. 224-226 ° 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, IH); 6.60 (d, IH); 6.75 (t, 1 H); 6.95 (t, IH); 7.30 (s, 1 H); 7.30 to 7.50 (m, 2H); 11.10 (s, 1 H). MS m / z (%): 382 (MH +, 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-1 H -indole hemioxalate, (compound 1i), 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, IH); 6.55 (d, IH); 6.70 to 6.80 (m, 2H); 7.10 (s, 1 H); 7.15 (s, 1 H);

7.25 (d, IH); 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 1 j), 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, 2 H); 2.95 to 3.15 (m, 4H); 4.15 to 4.30 (m, 4H); 6.45 (d, IH); 6.50 (d, IH); 6.60 (s, 1 H); 6.70 (t, IH); 6.90 (d, IH); 7.10 (s, 1 H); 7.20 (d, IH); 7.30 (s, 1 H); 10.65 (s, 1 H).

3- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -6-methyl-1H-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, IH); 6.50 (d, IH); 6.60 (s, 1 H); 6.70 (t, IH);

6.80 (d, IH); 7.05 (s, 1 H); 7.10 (s, 1 H); 7.40 (d, IH); 10.60 (s, 1 H).

6-Chloro-3- [2- [4- (7-chloro-1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1H-indole oxalate, (Compound 11) 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, IH); 6.65 (d, IH); 7.00 (dd, IH); 7.25 (d, IH); 7.40 (d, IH); 7.60 (d, IH); 10.95 (s, 1 H). 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] -1H-indole oxalate (compound 1m), m.p. 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, IH); 6.35 (d, IH); 7.00 (dd, IH); 7.20 (d, IH); 7.35 (d, IH);

7.55 (d, IH); 10.95 (s, 1 H). 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] -1H-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, 1 H); 6.65 (d, IH); 6.75 (t, 1 H); 6.85 (d, IH); 7.05 (d, IH); 7.25 (s, 1 H); 7.35 (d, IH); 7.60 (s, 1 H); 11.05 (s, 1 H). 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] -1H-indole oxalate (compound 1o), m.p. 205-207 ° C C.

¹ H NMR (DMSO-d 6): 2.60 to 2.75 (m, 6H); 2.90 (t, 2 H); 3.00 to 3.20 (m, 6H); 4.50 (t, 2 H); 6.60 (s, 1 H); 6.65 (d, IH); 6.75 (t, 1 H); 6.80 (d, 1H); 6.95 (d, IH); 7.20 (s, IH); 7.35 (s, 1 H); 7.55 (d, IH); 10.95 (s, 1 H). 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, 1 H); 6.65 (d, IH); 6.75 (t, 1 H); 6.85 (d, IH); 6.90 (t, IH); 7.25 (s,

-231 H); 7.25 to 7.35 (m, 2H); 10.95 (s, 1 H). 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, IH); 7.09 (d, IH); 7.33 (s, 1 H); 7.40 to 7.37 (m, 3H); 7.47 (d, IH); 7.62 (d, IH); 7.69 (s, 1H); 7.76 (d, 1H). MS m / z (%): 398.1 (MH ⁺ , 1.1% ( ³⁷ CI)), 396.1 (MH ⁺ , 2.8% ( ³⁵ CI)),

230.9 (1005), 177.8 (58%), 69.8 (50.8%).

3- [2- [4- (Benzothiopyran-8-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole (compound 1 r), 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, IH); 6.99 to 6.94 (m, 2H); 7.08 (s, 1 H); 7.14 (d, 2 H); 7.26 (d, IH); 7.59 (s, 1 H); 8.00 (s, 1 H). 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-1H-indole (compound 1s), 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, IH); 6.98 - 6.93 (m, 2H); 7.05 (s, 1 H); 7.21 (d, 2 H); 7.26 (d, IH); 7.76 (s, 1H), 8.02 (s, 1H). MS m / z (%): 458.4: (MH ⁺ , 21.7% (, ¹ 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 1t), m.p. 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, 1H); 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%).

-243- [2- [4- (Benzofuran-7-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole, (compound 1 µ), 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, 1H); 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 < ^{+ &gt};, 4%), 215 (100%), 200 (12%); 178 (36%); 172 (20%).

3- [2- [4- (1,4-Benzodioxan-5-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -6-chloro-1H-indole oxalate (compound 1v) ), 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, 1H); 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] -1Hindole oxalate, (Compound 1x), s 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 1y), with temperature mp 214-220 ° C.

¹ H NMR (DMSO-d 6): 2.65 (s, 2H); 2.75 to 2.85 (m, 4H); 2.90 to 3.00 (m, 2H); 3.10 to 3.50 (m, 3H); 6.55 (s. 2H); 6.90 to 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), with temperature mp 185-194 ° C.

-25 ¹ H-NMR (DMSO-de): 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, 1H); 7.00 (s, 1H); 7.20 (d, IH); 7.20 to 7.45 (m, 4H); 7.60 (d, IH);

7.80 (s, 1 H); 8.05 (s, 1H); 11.20 (s, 1 H). MS m / z (%): 423 (MH < ^{+ >} ( ⁸¹ 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-1H-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, 1 H); 10.95 (s, 1 H). MS m / z (%): 379 (MH < ^{+ &gt};, 5%), 214 (10%), 178 (20%), 143 (100%).

3- [2- [4- (Benzofuran-7-yl) piperidin-1-yl] ethyl] -5-fluoro-1H-indole oxalate (compound 1cc), m.p. 191-194 ° C.

¹ H NMR (DMSO-d 6): 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, 1H); 7.15 to 7.25 (m, 3H); 7.30 to 7.40 (m, 2H); 7.55 (d, 1H); 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%).

-26Example 2

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

A mixture of 3- (2-bromomethyl) -1H-indole (1.5 g), 1- (1,4-benzodioxan-5-yl) piperazine (1.2 g), potassium carbonate (1.9 g) and iodide potassium (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%).

-Acety 1-3- (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), of dicyclohexylcarbodiimide (2.4 g) and 4-dimethylaminopyridine (0.2 g) in dry tetrahydrofuran (100 ml) were stirred at room temperature under nitrogen atmosphere for 16 hours. Filtration and standard treatment with methylene

-27 chloride yields an oil which is purified by flash chromatography (eluent: ethyl acetate / heptane / methanol 16: 3: 1) to give 3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] - 2-oxoethyl] -6-chloro-1H-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 a ethanol solution by the addition of fumaric 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, IH); 6.50 (d, IH); 6.60 (s, 1H); 6.70 (t, IH); 7.00 (dd, IH); 7.25 (d, IH); 7.40 (d, IH); 7.55 (d, IH); 10.95 (s, 1 H). 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 _I, 2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1 / - / - 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, 1 H); 6.65 (d, IH); 6.80 (d, IH); 6.95 (t, IH); 7.05 (t, 1 H); 7.15 (d, IH); 7.35 (d, IH); 7.55 (d, IH); 10.70 (s, 1H). MS m / z (%): 410 (MH +, 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.

¹ H NMR (DMSO-d 6): 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, 1 H); 6.65 (s, 1 H); 6.85 (s, 1 H); 7.00 (d, IH); 7.20 (s, IH); 7.35 (s, 1 H); 7.55 (d, IH); 10.90 (s, 1 H). MS m / z (%): 446 (8%), 444 (MH < ^{+ &gt};, 11%), 281 (34%), 280 (16%), 279 (100%), 178 (15%).

-286-Chloro-3- [2- [4- (6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl) piperazin-1-yl] ethyl] -1H-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, 1 H); 6.65 (d, IH); 6.70 (d, 1H); 7.00 (d, IH); 7.20 (s, IH); 7.35 (s, 1 H); 7.55 (d, IH); 10.95 (s, 1 H). 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] -1 H -indole fumarate, (compound 3e) 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, 1 H); 6.65 (d, IH); 6.70 (t, IH); 6.75 (d, IH); 7.00 (d, IH); 7.20 (s, IH); 7.35 (s, 1 H); 7.55 (d, IH). MS m / z (%): 410 (MH < ^{+ &gt};, 6%), 245 (67%), 209 (39%), 178 (8%), 127 (51%), 45 (100%).

1- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole oxalate (compound 3f), 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); 4.40 (t, 2 H); 6.45 to 6.55 (m, 3H); 6.70 (t, IH); 7.05 (d, IH); 7.45 (d, IH); 7.55 (d, IH); 7.70 (s, 1 H). 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, IH); 6.70 (t, IH); 7.15 (d, IH); 7.50 (s, 1 H);

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. 231 ° C.

¹ H NMR (DMSO-d 6): 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, IH); 6.75 (t, 1 H); 7.00 (t. 2H); 7.30 (d, IH);

7.50 (s, 1 H); 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] -1 H -indole oxalate, (compound 3i), mp 225-229 ° C.

¹ H NMR (DMSO-d 6): 2.95 (s, 4H); 3.05 to 3.20 (m, 6H); 4.10 to 4.30 (m, 4H); 4.45 (t, 2 H); 6.40 to 6.50 (m, 2H); 6.55 (d, IH); 6.75 (t, 1 H); 7.05 (t, 1 H); 7.40 (s, 1 H);

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] -1 H -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, IH); 6.65 (d, IH); 6.75 (t, 1 H); 6.85 (d, IH); 7.00 (t, 1H); 7.15 (t, 1 H); 7.40 (d, IH); 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 was obtained from the free base (1.4 g) as a crystalline material from ethanol by the addition of 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, IH); 4.20 (d, 4H); 6.50 (d, 2 H); 6.60 (d, 2 H); 6.75 (t, 1 H); 6.95 (t, IH);

-307.10 (d, 1 H). 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), at a temperature of 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, IH); 4.20 (d, 4H); 6.35 to 6.55 (m, 3H); 6.15 to 6.25 (m, 2H); 6.90 (d, IH). 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-1H-indole oxalate (compound 4c), m.p. 153 to 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, 1 H); 6.95 (dd, IH); 7.10 (d, IH). MS m / z (%): 400 (MH < ^{+ &gt};, 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), with temperature 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, IH); 4.15 to 4.30 (m, 4H); 6.45 (s, 1 H); 6.50 (d, IH); 6.55 (t, 2 H); 6.75 (t, 1 H); 7.05 (d, IH). 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)

-31 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, IH); 6.60 (d, IH); 6.75 (t, 1 H); 7.05 (t, 1 H); 7.15 (t, 1 H); 7.25 (s, 1 H); 7.45 (d, IH); 7.60 (d, IH). 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] -1H-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, IH); 5.15 (d, 1H); 5.90 to 6.05 (m, 1H); 6.50 (d, IH); 6.55 (d, IH); 6.75 (t, 1 H); 7.05 (t, 1 H); 7.15 (t, 1 H); 7.25 (s, 1 H); 7.40 (d, IH); 7.60 (d, IH). 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, IH); 4.25 (d, 4H); 5.05 (d, 2 H);

6.50 (d, 2 H); 6.55 (d, IH); 7.10 (t, 1 H); 7.20 (t, IH); 7.30 (s, 1 H); 7.50 (d, IH); 7.65 (d, IH). 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-1H-indole oxalate, (Compound 6a)

A solution of 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, IH); 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, 1 H); 7.10 (d, IH). 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), with temperature mp 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, IH); 4.15 to 4.25 (m, 5H); 4.35 (d, IH); 6.50 (d, IH); 6.55 (d, IH); 6.65 to 6.70 (m, 2H); 6.75 (t, 1 H); 7.00 (t, 1H); 7.10 (d, IH); 7.30 (t, IH); 7.35 (s, 4H). MS m / z (%): 456 (MH +, 19%), 236 (25%), 178 (100%), 130 (11%).

-Alyl-3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -2,3-dihydro-1H-indole oxalate (compound 6c), m.p. 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, IH); 3.65 (dd, IH); 3.75 (dd, IH); 4.25 (d, 4H); 5.15 (d, IH); 5.30 (d, IH); 5.85 to 5.95 (m, 1H); 6.50 (d, IH); 6.55 (d, 2 H); 6.65 (t, 1 H); 6.75 (t, 1 H); 7.00 (t, 1 H); 7.10 (d, IH). MS m / z (%): 406 (MH +, 15%), 178 (178%), 158 (24%), 130 (31%), 117 (20%).

-33Example 7

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

¹ H NMR (DMSO-d 6): 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, IH); 6.55 (d, IH); 6.75 (t, 1 H); 7.30 to 7.40 (m, 2H); 7.70 (d, IH); 7.80 (s, 1 H); 8.35 (d, IH). MS m / z (%): 406 (MH < ^{+ &gt};, 28%), 233 (44%), 218 (39%), 144 (100%).

Pharmacological tests

The affinity of the compounds of the invention for 5-HT _1A receptors was determined by measuring inhibition of the binding of the radioactive ligand to 5-HT _1A receptors as described in the following assays:

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) was determined in vitro. The quantitative assay is performed as a modification of the method described by Harrington, MA et al., J. Pharmacol. Exp. Ther., 1994, 268, 1098. Human 5-HT _1A receptors (40 µg 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 μΜ of metergoline. The reaction was terminated by rapid filtration through Unifilter GF / B filters to

-34Tomtec Cell Harveste (cellular collector). Filters were calculated in a Packard Top Counter. The results are shown in Table 1.

Table 1

Compound No. Inhibition ^J H-5-CT binding IC ₅₀ (nM) 1 17 1b 7.2 1c 2.5 1d 55 1e 11 1f 6.1 ig 2.8 1h 4.6 1i 6.9 1J 14 1k 2.0 11 12 1 m 99 1n 8.2 2 2.9 2b 13 1V 0.81 3a 1.2 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) 1 5.0 1b 2.8 1c 45 1d 36 1e 0.25 1f 5.9 ig 3.8 1h 1.7 1i 6.8 1J 3.5 1k 18 11 7.7 1 m 57 1n 2.1 1V 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

The 5-HT 1A antagonist activity of some compounds of the invention was determined in vitro in cloned 5-HT _1A receptors stably expressed in transfected HeLa cells (HA7). 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 IC50 accumulation 1 2900 1b 5000 1e 2400 1f 1800 ig 1800 1h 280 1i 620 1J 980 1k 580 1n 1900 1o 3200 1 t 5900 1u 2000 1V 3300 1 3000

2 160 2b 250 3a 500 3c 2600 3d 2300 4c 890 6a 100 pindolol 270

Table 3: * compound shown

Some of the compounds of the invention have also been tested for their in vivo effect on

5-HT 1A receptors in the assay described by Sanchez C. 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 5MeO-DMT. The compounds of the invention have significant activity as serotonin feedback inhibitors and have 5-HT _1A receptor antagonistic activity. Thus, the compounds of the invention are believed to be useful in the treatment of diseases and disorders responsive to the inhibition of serotonin feedback and 5-HT 1A receptor antagonist activity. Diseases responding positively 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, etc.

As explained above, the antagonist 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 in the present invention are particularly useful as drugs 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 SSRIs.

-38Pharmaceutical preparations

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. For the preparation of such compounds, methods known in the art, and any pharmaceutically acceptable carriers, diluents, vehicles, or other supplements normally used in the art may be used.

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 from 0.05 to 500 mg and most preferably from 0.1 to 50 mg of the active compound of the invention.

Claims (19)

PATENT CLAIMS An indole or 2,3-dihydroindole derivative of the general formula I, its 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 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, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, hydroxy, formyl, acyl , amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, nitro, cyano; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen or alkyl; and -40R ¹¹ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, acyl and formyl. Indole or 2,3-dihydroindole derivatives according to claim 1, wherein Z is -O-. r 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. T 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. The indole or 2,3-dihydroindole derivatives of claims 1 to 12, wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is selected from hydrogen or methyl. Indole or 2,3-dihydroindole derivatives according to claim 1, selected from the group consisting of: 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-1H-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] -1 / - / indole, 3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -4-chloro-1H-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-1H-indole; 4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-methoxy-1H-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-1-yl] ethyl] -1H-indole; 3- [2- [4- (1,4-benzodioxan-5-yl) piperazine- 1-yl] ethyl] -6-chloro-1H-indole, 3- [2- [4- (5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazine-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] -1H-indole, 6-chloro-3- [2- [4- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-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-1H-indole, -421- [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-1-yl] ethyl] -1H-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-1H-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-1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1H-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-1H-indole, 3- [2- [4- (benzothiophen-7-yl) piperazin-1-yl] ethyl] -5-chloro -1H-indole, 3- [2- [4- (benzothiopyran-8-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole, 3- [2- [4- (benzothiopyran-8)] -yl) piperazin-1-yl] ethyl] -5-bromo-1H-indole, 3- [2- [4- (benzothiopyran-8-yl) piperazin-1-yl] ethyl] -6-chloro-1H- indole, 3- [2- [4- (1,4-Benzodioxan-5-yl) -1,2,3,6-tetrahydro-indin-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-1-yl] ethyl] -6-chloro-1H-indole, 3- [2- [4- (1,4-benzodioxan-5- yl) piperidin-1-yl] ethyl] -5-chloro-1H-indole, 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-yl) -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -6-chloro-1H-indole, 3- [2- [4- (benzofuran-7-yl)] -1,2,3,6-tetrahydropyridin-1-yl] ethyl] -5-bromo-1H-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-1-yl] ethyl] -6-chloro-1H-indole 3- [2- [4- (Benzofuran-7-yl) piperidin-1-yl] ethyl] -5-fluoro-1H-indole, 3- [2- [4- (benzofuran-7-yl) piperidine] -1-yl] ethyl] -5-bromo-1H-indole, 1-acetyl-3- [2- [4- (1,4-benzodioxan-4-yl) piperazin-1-yl] ethyl] -2, 3-Dihydro-1H-indole, 1- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-fluoro-1H-indole, 1- [2 - [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -6-chloro-1H-indole, 1- [2- [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -1H-indole, -431- [2- [4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl] ethyl] -1H-indole, 3- [2- [4- (1,4-benzodioxan-5) -yl) piperazin-1-yl] ethyl] -2,3-dihydro-1H-indole, 3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -2,3-dihydro-5-fluoro-1H-indole, 3- [2- [4- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -5-chloro 1R-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- (1,4-benzodioxan-5-yl) piperazin-1-yl] ethyl] -1H-indole; 3- [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-indole, 3- [2 - [4- (1,4-Benzodioxan-5-yl) piperazin-1-yl] ethyl] -1-benzyl-2,3-dihydro-1H-indol, 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] -1H-indole, 3- [2- [4- (benzo-1,4-dithian-5-yl) piperazin-1 -] - ylethyl] -5-chloro-1H-indole, 3- [2- [4- (benzo-1,4-dithian-5-yl) piperazin-1-yl] ethyl] -6-chloro-1 Hiindole, 3- [2- [4- (benzo-1,4-dithian-5-yl) piperazin-1-yl] ethyl] -5-fluoro-1H-indole, 3- [2- [4- (Benzo-1-thia-4-oxan-5-yl) piperazin-1-yl] ethyl] -5-chloro-1H-indole, 3- [2- [4- (benzo-1-thia-4)] -oxan-5-yl) piperazin-1-ylmethyl-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. 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. and The indole or 2,3-dihydroindole derivatives according to claims 1 to 14, or a pharmaceutically acceptable acid addition salt 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 antagonism. receptors. 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.