CN1293075C - Indole and 2,3-indoline derivative, their preparation and application - Google Patents

Abstract

The present invention relates to indole and 2,3-dihydroindole derivatives having formula any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein A, R1, R2, R3, W, X, Y and Z are as described in the description. The compounds are potent serotonin reuptake inhibitors and have 5-HT1A receptor antagonistic activity.

Description

Indole and 2,3-dihydroindole derivatives, their preparation and use

This trial application was submitted on July 20, 1998, the application number is 98807554.0, and the invention title is the same as the divisional application of this trial application.

The present invention relates to novel indole and 2,3-dihydroindole derivatives which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and their therapeutic effects on serotonin reuptake inhibition Use in disorders or diseases sensitive to 5-HT _1A receptor antagonism. The compounds of the present invention also have antagonistic activity at the 5-HT _1A receptor and are believed to be particularly useful in the treatment of depression.

Background technique

Selective serotonin (or 5-TH) reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, Sertraline, fluvoxamine, and citalopram have shown major advances in treating depression because they have fewer and less severe side effects. The side effects caused by first-generation antidepressants were so severe that some patients were withdrawn from treatment.

Current SSRIs, and all other antidepressants, have a serious drawback in that several weeks of treatment are necessary to produce a therapeutic effect. Lags in the onset of drug action are a serious problem, especially in the treatment of intensely depressed and suicidal patients. In addition, one-third of patients were SSRI-insensitive.

Electrophysiological experiments in mice have shown that acute administration of SSRI can reduce the excitation of 5-HT neurons in the dorsal raphe core of the rodent brain, and continuous treatment with SSRI will normalize the activation of 5-HT neurons (Arborelius, L. et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1995, 352, 157; Gartside, SE et al., Br. J. Pharmacol. 1995, 115, 1064; Chaput, Y. et al., Naunyn-Schmiedeberg's Arch . Pharmacol. 1986, 33, 342). It has also been shown that restoration of agonistic activity in 5-HT neurons is associated with desensitization of the somatodendritic 5-HT _1A autoreceptors (Le Poul, E. et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1995, 352, 141; Invemizzi, R. et al., Eur. J. Pharmacol. 1994, 260, 243).

It has therefore been proposed that simultaneous administration of an SSRI and an agent that causes a rapid desensitization or inhibition of the 5-HT _1A receptor by a feedback mechanism would lead to a rapid initiation of the antidepressant effect (Artigas, F. et al., Trends Neurosci. 1996, 19, 387; De Vry, J. Drug News Perspec. 1996, 9, 270).

The effect of a compound that inhibits serotonin reuptake in combination with a 5-HT _1A receptor antagonist has been evaluated in several studies (Innis, RB et al., Eur.J.Pharmacol.1987, 143, p195 -204 and Gartside, SE, Br.J.Pharmacol.1995, 115, p1064-1070; Blier, P. et al., Trends Pharmacol.Sci.1994, 15, 220), in these studies it was found that 5-HT _1A was regulated by Antibody antagonists can prevent the decrease in agonistic activity caused by acute administration of serotonin reuptake inhibitors.

In addition, combination therapy with pindolol (a well-known 5-HT _1A receptor and β-adrenergic receptor antagonist) and SSRI has been evaluated in clinical trials, and patients' mood was reported to be improved within one week. Significant improvement was obtained. In addition, for patients who are not sensitive to the current antidepressant drug treatment, the combined administration of pindolol and SSRI also shows good results (Artigas F. et al., Arch.Gen.Psychiary, 1994, 51, p248-251 and Blier, P. et al., J. Clin. Phychopharmacol. 1995, 15, p217-222).

Several patents have been filed covering the combined use of 5-HT _1A antagonists and serotonin reuptake inhibitors for the treatment of depression (see EP-A2-687472 and EP-A2-714663).

In EP-A1-529462 certain 1,4-benzodioxane derivatives are disclosed having the general formula:

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

In patent US 5002948, Perregaard et al. disclose related indoles, indazoles, 2-indolinones and their 2,3-dihydro derivatives having the formula:

Wherein X is -CH-, -CH ₂ -, -NH- or -CO-; Ar is

wherein Y is O or S, Z is O, S or -CH-, and n is 1, 2 or 3. These compounds are valuable 5-HT _1A receptor ligands.

purpose of invention

The object of the present invention is to provide compounds with potent serotonin reuptake inhibitory activity and antagonistic properties on 5-HT _1A receptors, which can be used as fast-acting drugs for the treatment of affective psychotic disorders such as depression .

Another object of the present invention is to provide a pharmaceutical composition containing the above compound as an active ingredient.

Summary of the invention

The invention particularly includes the following, independently of each other or in combination with each other.

Indole or 2,3-dihydroindole derivatives of the formula, their enantiomers or mixtures thereof, or their acid addition salts,

in:

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 the group -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 selected from the group represented by formula (II), (III) and (IV)

where the dashed line refers to 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 selected from hydrogen, halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, Cycloalkyl, Alkoxy, Hydroxy, Formyl, Acyl, Amino, Alkylamino, Dialkylamino, Amido, Alkoxycarbonylamino, Aminocarbonylamino, Alkylaminocarbonylamino, Dialkylaminocarbonylamino , nitro and cyano and aryl or aralkyl where aryl can be substituted by halogen, trifluoromethyl, alkoxy, hydroxyl, amino, alkylamino, nitro and cyano;

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

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

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

In another embodiment of this 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 present invention, A is a group of formula (III), and the other substituents are as defined above.

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

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-, A is a group of formula (IV) and Z is -S-;

In a further embodiment of the present invention ^R4 , ^R5 , ^R6 , ^R7 , ^R8 and ^R9 are selected from hydrogen or methyl.

Examples of compounds according to 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-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]-1H- 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-pyridine Base] ethyl] -1H-indole,

3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-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-benzodioxan-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]-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)piperazine-1- Base] 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,

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)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 (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,

3-[2-[4-(1,3-Benzodioxolan (Benzodioxolan)-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-1-pyridyl-1-yl]ethyl]-5- Chloro-1H-indole,

3-[2-[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydro-1-pyridyl-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)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,

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,

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-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-indole ,

1-allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-ind 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-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-oxa-cyclohexane(oxan)-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H- indole,

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

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

or their acid addition salts.

The present invention also relates to a pharmaceutical composition, comprising the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent.

In a further embodiment, the present 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 suitable for the treatment of serotonin reuptake inhibition or 5-HT Dysfunction or disease sensitive to HT _1A receptor antagonism.

The present invention particularly relates to the use of the compound of the present invention or its compound use or its pharmaceutically acceptable acid addition salt for the preparation of medicines, which are suitable for the treatment of affective mental disorders, such as depression, psychosis, anxiety diseases including general Sexual Anxiety Disorders, Panic Disorders and Obsessive-Compulsive Symptoms.

In another embodiment, the present invention relates to a method of treatment of a disorder or disease in a living animal, including man, which is sensitive to serotonin reuptake inhibition or 5-HT _1A receptor antagonism, the The method includes, administering a therapeutically effective dose of the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof to the living animal including human.

In particular, the present invention relates to a method for the treatment of emotional disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive-compulsive symptoms. A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof is administered to a living body.

Because of their combined antagonism of the 5- _HT1A receptor and inhibition of serotonin reuptake, the compounds of the invention are considered to be particularly useful as fast-acting agents for the treatment of depression, which may also be useful due to the therapeutic effect on Depressed patients insensitive to antidepressant medication.

The claimed compounds are particularly useful in the treatment of depression requiring rapid action of antidepressants, or resistant to other antidepressants.

Halogen means fluorine, chlorine, bromine or iodine.

The alkyl group means a straight or branched chain alkyl group of 1 to 4 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl and butyl.

Alkenyl means a chain group of 2 to 4 carbon atoms containing a double bond, including, for example, vinyl, 1-, 2-propenyl, 2-, 3-propenyl and the like.

Alkynyl refers to a chain group with 2-4 carbon atoms containing a triple bond, including, for example, ethynyl, 1-, 2-propynyl, 2-, 3-propynyl and the like.

Cycloalkyl refers to a cyclic alkyl group of 3-7 carbon atoms, including cyclopropyl, cyclobutyl and the like.

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

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

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

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

Alkoxycarbonylamino refers to alkyl-O-CO-NH-, wherein alkyl is as defined above.

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

Dialkylaminocarbonylamino refers to (alkyl) ₂ -NH-CO-NH-, wherein alkyl is as defined above.

Aryl refers to an aromatic ring such as phenyl or naphthyl.

Aralkyl means an aryl-alkyl group wherein aryl and alkyl are as defined above.

Typical organic acid addition salts according to the invention are addition salts with the following acids: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylenesalicylic acid, methanesulfonic acid , ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid , itaconic acid, gluconic acid (glycolic), p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, and 8-halogenated theophylline, such as 8-bromotheophylline. Typical inorganic acid addition salts are those with: hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the present invention are preferably pharmaceutically acceptable salts with non-toxic acids.

The compounds of the present invention may exist in unsolvated form or in solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

Some of the compounds of the present invention contain chiral centers, and the central compounds exist as isomers (ie, enantiomers), and the present invention includes all such isomers and mixtures thereof, such as racemic mixtures.

The racemic forms can be resolved into the optical antipodes by known methods, eg, separation of their diastereomeric salts with optically active acids and treatment with base to liberate the optically active amine compound. Another method for the resolution of racemic forms into the optical antipodes is based on chromatography on optically active matrices. The racemic compounds of the invention can thus be resolved into their optical antipodes, for example, by fractional crystallization of d- or l-salts such as tartrates, mandelates or camphorsulfonates. The compounds of the invention can also be resolved by the formation of diastereomeric derivatives.

Optical isomers can also be resolved by other methods known to those skilled in the art. These methods include those described by J. Jaques, ACollet and S. Wilen in "Enantiomers, Racemates and Resolutions" (John Wiley and Sons, New York, (1981)).

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

The compounds of the present invention can be prepared according to one of the following methods, including:

a) reducing the carbonyl group in the compound of formula (V),

wherein R ¹ -R ³ , R ¹² , R ¹⁴ -R ¹⁷ , X, Y, Z, W and dashed lines are as defined above;

b) the amine of formula (VI)

wherein R ¹ -R ³ , X, Y, Z, W and dashed lines are as defined above, alkylation is carried out with a reagent of formula G-CH ₂ CH ₂ -A where A is as defined above and G is an appropriate leaving group Groups such as halogens, mesylate or tosylate;

c) Amines of formula (VI)

wherein R ¹ -R ³ , X, Y, Z, W and dashed lines are as defined above, reductive alkylation with a reagent of formula B-CH ₂ CH ₂ -A, wherein A is as defined above and B is an aldehyde or carboxylic acid group;

d) reduction of the indole double bond of formula (VII) to obtain the corresponding 2,3-dihydroindole derivative

wherein R ¹ -R ³ , X, Y, Z, W and the dotted line are as defined above, A' is a group of the above formula (II), (III) or (IV), and its dotted line part represents a single bond;

e) reduction of the tetrahydropyran double bond of formula (VIII) to obtain the corresponding piperidine derivative

wherein R ¹ -R ³ , A, X, Y and Z are as defined above;

f) Treating the compound of general formula (I) with a reducing agent, Y in the general formula is -CR ⁶ ═CR ⁷ -, or wherein X and Y together form a group -CR ⁴ ═CR ⁵ - or -CR ⁴ ═CR ⁵ -CR ⁶ R ⁷ -, to reduce the double bond, thereby reducing the corresponding ring system;

g) Reductive removal of one or more of the substituents R ¹ -R ³ or R ¹² -R ¹⁷ of the compound of general formula (I), in the general formula, one or more of these substituents are selected from chlorine , bromine or iodine;

h) the amine of formula (IX)

wherein R ¹ -R ³ , X, Y and Z are as defined above, and dialkylation is carried out with a reagent represented by formula (X),

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

i) the amine of formula (XI)

wherein A is as defined above, dialkylated with a reagent represented by formula (XII),

wherein R ¹ -R ³ , X, Y, Z and W are as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate; or

j) alkylation or acylation of the indole nitrogen atom of the compound of formula (XIII)

Wherein R ¹ -R ³ , X, Y, Z, W and dashed lines are as defined above, A" is selected from the group of formula (III) or (IV) above, and R ¹¹ in the formula is hydrogen, and the formula R ¹¹ used is - an alkylating or acylating agent represented by G, wherein G is a suitable leaving group such as halogen, mesylate or tosylate, and ^R11 is as defined above but is not hydrogen.

Accordingly, the compound of formula (I) is isolated as a free base or as an acid addition salt thereof.

The reduction reaction of method a) is preferably carried out in an organic inert solvent (such as ether or tetrahydrofuran), in the presence of lithium aluminum hydride and under reflux temperature conditions, the starting compound formula (V) is generally from the reagent represented by formula (IV), 1, The 3-position unsubstituted indole or oxalyl chloride was prepared as described in the following examples.

The alkylation reaction of method b) is conveniently carried out in an inert organic solvent (such as an alcohol or ketone with a suitable boiling point), preferably in the presence of a base (such as potassium carbonate or triethylamine) and at reflux temperature.

The arylpiperazine derivative represented by formula (IV) is according to the method described in Martin et al., J.Med.Chem., 1989,32,1052, or Kruse et al., Rec Trav.Chim.PaysBas, 1988,107 , 303, are conveniently prepared from the corresponding arylamines; starting arylamines are either commercially available or well described in the literature.

Aryltetrahydropyridine derivatives represented by formula (IV) are known in the literature, see US Patent No. 2,891,066; McElvain et al., J.Amer.Chem.Soc., 1959, 72, 3134. Lithiation of the corresponding arylamine with butyl lithium followed by addition of 1-benzyl-4-piperidone followed by acid treatment gave N-benzyl-aryltetrahydropyridines very simply; removal of the benzyl group The corresponding ethyl carbamate can be obtained by catalytic hydrogenation, or first treatment with a reagent such as ethyl chloroformate, followed by acid or base hydrolysis. Starting aryl bromides are either commercially available or well described in the literature.

Reagents of formula G- _CH2CH2 -A are commercially available or can be prepared according to literature methods, for example, from _the corresponding acetic acid derivatives by reduction to 2-hydroxyethyl into the group G.

The reductive alkylation reaction of method c) is carried out according to the conventional literature method, and the reaction can be divided into two steps, that is, (VI) and the reagent represented by the formula B-CH ₂ -A are carried out according to the conventional method, through the acid chloride or using a coupling reagent such as two Coupling with cyclohexylcarbodiimide followed by reduction of the resulting amide with lithium aluminum hydride. The reaction can also be carried out according to a conventional one-pot method, and the carboxylic acid or aldehyde represented by the formula G-CH ₂ -A is commercially available or has been described in the literature.

The indole double bond reduction reaction of method d) is easy to implement, first in an inert solvent, such as tetrahydrofuran or dioxane, at 0 ° C to reflux temperature with diborane or diborane precursors such as triethylammonium or dimethyl Sulfur complexes, followed by acid-catalyzed hydrolysis of the intermediate diborane derivatives; reductions can also be carried out optionally by treatment with sodium cyanoborohydride in trifluoroacetic acid.

Methods e) and f) are carried out most simply by double bond reduction reactions, hydrogenation in alcohols in the presence of noble metal catalysts such as platinum or palladium.

Process g) The removal of the halogen substituents can be conveniently carried out by catalytic hydrogenation in alcohol in the presence of a palladium catalyst or by treatment with ammonium formate in the presence of a palladium catalyst in alcohol at elevated temperature.

Method h) and i) the dialkylation reaction of amine is very easy to implement in the inert solvent (such as chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide or acetonitrile) at higher temperature, and the reaction can also In the presence of a base such as potassium carbonate or triethylamine. The starting materials for processes h) and i) are commercially available or can be prepared from commercially available substances by conventional methods.

The N-alkylation reaction of process j) is carried out in an inert solvent such as an alcohol or a ketone at elevated temperature and in the presence of a base such as potassium carbonate or triethylamine at reflux temperature. In addition, phase transfer reagents can also be used.

The following examples are further illustrations of the present invention, but they should not be construed as limiting the present invention.

Example

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

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

The substituted 3-(2-bromoethyl)indole used in said Example 2 was reduced by the corresponding 2-(1-indolyl)acetate in alcohol with lithium aluminum hydride followed by conventional literature procedures Prepared by treatment with tetrabromomethane/triphenylphosphine.

The arylpiperazines used in said Examples 1, 2 and 3 were prepared from the corresponding arylamines according to the method described in Martin et al., J.Med.Chem., 32(1989), 1052, or Kruse et al. , Rec Trav.Chim.PaysBas, 107 (1988), the method described in 303 is prepared.

Starting arylamines are commercially available or have been described in the following literature:

5-Amino-1,4-benzodioxane was synthesized as described by Dauksas et al., Zh. Org. Khim. 3 (1967) 1121 . The corresponding chloro derivatives were prepared in a similar manner.

The synthesis of 7-amino-2,3-dihydrobenzofuran is described in US patent application US 4302592.

The synthesis of 7-amino-benzofuran was described by Van Wijingaarden et al., J. Med. Chem. 31 (1988) 1934 .

7-Amino-benzo[b]thiophene was synthesized as 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 were prepared according to German patent DE 3526510.

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

8-Amino-6-chloro-2,2-dimethylbenzopyran was prepared by 6-chloro-2,2-dimethylbenzopyran (according to Bolzoni et al., Angew.Chem.90 (1978) 727-preparation) was nitrated according to the usual method, followed by reduction of the resulting 8-nitro derivative. In a similar manner, 7-amino-5-chloro-3,3-dimethylbenzofuran was prepared from 5-chloro-3,3-dimethylbenzofuran (prepared according to European patent application EP7719 800206). The corresponding dechlorinated derivatives are obtained conventionally by treatment with hydrogen in the presence of a noble metal catalyst.

Aryltetrahydropyridine derivatives are known in the literature (see US Pat. No. 2,891,066; or McElvain et al., J. Amer. Chem. Soc., 1959, 72, 3134). Quite simply, the corresponding arylamine is lithiated with butyllithium, followed by the addition of 1-benzyl-4-piperidone, followed by treatment with mineral acid or trifluoroacetic acid to give N-benzyl-aryltetrahydropyridine; The benzyl group can be removed by catalytic hydrogenation, or first treated with a reagent such as ethyl chloroformate to obtain the corresponding ethyl carbamate, followed by acid hydrolysis or base hydrolysis. The corresponding piperidine derivatives can be obtained by reductive removal of the double bond in the tetrahydropyridine ring. All of these methods are well known to those skilled in the art. Bromides of starting aryl groups are well described in the literature. According to this method, 4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridine, 4-(2,3-dihydro-2,2-dihydropyridine, Methylbenzofuran-7-yl)-1,2,3,6-tetrahydropyridine, 4-(2,3-dihydro-benzofuran-7-yl)-1,2,3,6- Tetrahydropyridine, 4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridine and the corresponding piperidine derivatives.

Melting points were measured on a Buchi SMP-20 instrument without correction. Mass spectra were acquired on a Quattro MS-MS system provided by VGBiotech, Fisons Instruments. The MS-MS system is connected to the HPLC system of HP 1050 standard components. A volume of 20-50 μL of sample (10 μg/mL) solvent in a 1:1 mixture of 1% acetic acid in acetonitrile/water was introduced into the electrospray source at a flow rate of 30 μL through an active sampler. Spectra were acquired under two sets of standard operating conditions. One group obtained molecular weight information (MH+) (21ev) and the other derived the fragmentation pattern (70ev). The background is subtracted, and the relative intensity of the ion is obtained according to the fragmentation mode. If the intensity of the molecular ion (MH+) is not shown, the ion exists only under the first set of operating conditions. 1H NMR spectra of all new compounds were recorded on a Brucker AC 250 spectrometer at 250 MHz or on a Brucker DRX 500 spectrometer at 500 MHz. Deuterochloroform (99.8%D) or deuterodimethylsulfoxide (99.9%D) was used as solvent and TMS was used as internal standard. Chemical shift values are expressed in ppm and the following abbreviations are used to denote the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = septet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet triplet, m = multiplet. NMR signals corresponding to acid protons are generally omitted. The water content of the crystalline compounds was determined by Karl Fischer titration. The general separation and purification procedure is to extract the specified aqueous solution with the specified organic solvent, dry the combined organic extracts (anhydrous magnesium sulfate or sodium sulfate), filter and evaporate the solvent in vacuo. The silica gel used for column chromatography is Kieselgel 60 type, 230-400 mesh ASTM (American Society for Testing and Materials).

Example 1

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

Under a nitrogen atmosphere, a solution of 5-chloro-indole (5.0g) in ether (130mL) was cooled to 0°C, then a solution of oxalyl chloride (4.6g) in ether (20mL) was added dropwise, stirred for 16h, and the crystals were collected by filtration Product, 2-(5-Chloro-1H-indol-3-yl)-2-oxoacetyl chloride (7.2g).

A solution of this product (2.0 g) in dry tetrahydrofuran (25 mL) was added dropwise to 1-(1,4-benzodioxan-5-yl)piperazine (1.2 g) and triethylamine (7.5 mL) at room temperature. ) in tetrahydrofuran (75 mL), the mixture was stirred for 16 h, then filtered, and the solvent was removed in vacuo to give 3-[2-[4-(1,4-benzodioxan-5-yl)piperazine-1- Base]-1,2-dioxoethyl]-5-chloro-1H-indole solid crude product. At room temperature and under a nitrogen atmosphere, the product was dissolved in tetrahydrofuran (25 mL), added dropwise to a suspension of lithium aluminum hydride (2.1 g) in tetrahydrofuran, and after reflux for 3.5 h, aqueous sodium hydroxide solution was added to terminate the reaction, and carried out with ethyl acetate. General separation and purification. The resulting oil was purified by flash chromatography (eluent: heptane/ethanol/ethyl acetate/triethylamine 15:2:2:1), the oxalate salt was prepared by adding oxalic acid in acetone and dissolved in methanol/THF (1:5) to give 0.8g 1a, mp 224-28°C, ¹ HNMR (DMSO-d ₆ ): 3.05(t, 2H); 3.10-3.50(m, 10H); 4.15-4.30(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+, 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, 1b, mp236- 40°C. ¹ H NMR (DMSO-d ₆ ): 3.10(t, 2H); 3.15-3.45(m, 10H); 4.15-4.30(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+, 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, 1c, mp205 -8°C. ¹ H NMR (DMSO-d ₆ ): 2.35 (s, 3H); 2.95-3.15 (m, 4H); 3.15-3.45 (m, 8H); 4.15-4.30 (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+, 5%), 233 (9%), 221 (7%), 218 (5%), 158 (100%).

6-Chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H- Indole fumarate, 1d, m.p.232-37°C,

¹ H NMR (DMSO-d ₆ ): 1.40(s, 6H); 1.65-1.85(m, 4H); 2.20(s, 3H); 2.30(t, 2H); 2.60(t, 2H); (m, 3H); 2.90(s, 3H); 3.10-3.30(m, 2H); 660(s, 2H); 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+, 11%), 258(100%), 178 (14%), 70 (41%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-chloro-1H-indole oxalate, 1e, m.p.

210-18°C. ¹ H NMR (DMSO-d ₆ ): 3.10-3.50(m, 12H); 4.10-4.30(m, 4H); 6.50(d, 1H); 6.60(d, 1H); 6.75(t , 1H); 7.00(d, 1H); 7.05(t, 1H); 7.30-7.4D(m, 2H); 11.40(s, 1H).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, 1f, m.p.190-93°C,

¹ H NMR (DMSO-d ₆ ): 1.40(s, 6H); 1.75-.1.95(m, 4H), 2.50-2.70(m, 2H); 2.70-2.80(m, 1H); 2.85-3.05(m , 6H); 3.25-3.40(m, 2H); 6.75(t, 1H); 6.95(d, 1H); 6.95-7.10(m, 2H); 7.25(s, 1H); 7.40(s, 1H); 7.55 (d, 1H); 11.00 (s, 1H).). MSm/z (%): 409 (MH+, 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-pyridine Base]ethyl]-1H-indole oxalate, 1g, mp200-4℃ ¹ H NMR (DMSO-d ₆ ): 1.40(s, 6H); 2.70-2.80(m, 2H); 3.00(s, 2H); 3.15(t, 2H); 3.30(t, 2H); 3.35-3.50(m, 2H); 3.85-4.00(m, 2H); 6.35(s, 1H); 6.85(t, 1H); 7.00 (d, 1H); 7.05-7.15(m, 2H); 7.30(s, 1H); 7.40(s, 1H); 7.60(d, 1H); 11.15(s, 1H).MS m/z(%) : 407 (MH+, 2%), 207 (8%), 180 (33%), 178 (100%).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole oxalate, 1c, mp224- 26°C. ¹ H NMR (DMSO-d ₆ ): 3.10(t, 2H); 3.10-3.50(m, 10H); 4.15-4.35(m, 4H); 6.50(d, 1H); 6.60(d, 1H ); 6.75(t, 1H); 6.95(t, 1H); 7.30(s, 1H); 7.30-7.50(m, 2H); 11.10(s, 1H).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-1H-indole hemioxalate, 1i , mp 189-96°C. ¹ H NMR (DMSO-d ₆ ): 3.00 (t, 2H); 3.05-3.30 (m, 10H); 3.80 (s, 3H); 4.15-4.35 (m, 4H); 6.50 (d, 1H); 6.55(d, 1H); 6.70-6.80(m, 2H); 7.10(s, 1H); 7.15(s, 1H); 7.25(d, 1H); 10.70(s, 1H). MS m/z (%): 394 (MH+, 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, 1j , mp 147-54°C. ¹ H NMR (DMSO-d ₆ ): 2.40 (s, 3H); 2.60-2.80 (m, 6H); 2.85 (t, 2H); 2.95-3.15 (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-1H-indole hemifumarate, 1k , mp 204-7°C. ¹ H NMR (DMSO-d ₆ ): 2.35 (s, 3H); 2.60-2.80 (m, 6H); 2.90 (t, 2H); 2.95-3.15 (m, 4H); 4.10 -4.30(m, 4H); 6.45(d, 1H); 6.50(d, 1H); 6.60(s, 1H); 6.70(t, 1H); 6.80(c, 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]-1H-indole oxalate, 1l, mp 237-38°C. ¹ H NMR (DMSO-d ₆ ): 3.00-3.15 (m, 2H); 3.15-3.40 (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+, 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, 1m, mp 216-17°C. ¹ H NMR (DMSO-d ₆ ): 2.60(t,?H); 2.85(t, 2H); 3.10(b, 4H); 3.30(s, 4H); 4.15-4.30 (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+, 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, 1n, mp 134 -38°C. ¹ H NMR (DMSO-d ₆ ): 2.65-2.80 (m, 6H); 2.90 (t, 2H); 3.00-3.25 (m, 6H); 4.50 (t, 2H); 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/(%): 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, 1o, mp 205 -7°C. ¹ H NMR (DMSO-d ₆ ): 2.60-2.75 (m, 6H); 2.90 (t, 2H); 3.00-3.20 (m, 6H); 4.50 (t, 2H); 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, 1p, mp 145 -49°C. ¹ H NMR (DMSO-d ⁶ ): 2.65-2.85 (m, 6H); 2.90 (t, 2H); 3.00-3.20 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65(d, 1H); 6.75(t, 1H); 6.85(d, 1H); 6.90(t, 1H); 7.25(s, 1H); 7.25-7.35(m, 2H); 10.95(s , 1H). MS m/z (%): 366 (MH+, 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, 1q, mp175.2-176.6℃. ¹ H NMR (DMSO-d ₆ ): 3.10 (m, 2H), 3.26 (m, 2H), 3.38-3.36 (m, 6H), 7.05 (d, 1H), 7.09 (d, 1H), 7.33 (s, 1H), 7.40-7.37(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, 1r, m.p.152-153°C,

¹ H NMR (CDCl ₃ ): 2.08 (m, 2H), 2.75 (m, 6H), 2.83 (m, 2H), 2.98 (m, 4H), 3.05 (m, 2H), 6.80 (d, 1H), 6.99-6.94(m, 2H), 7.08(s, 1H), 7.14(d, 2H), 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-(Benzthiopyran-8-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole, 1s, m.p.166-167℃,

¹ H NMR (CDCl ₃ ): 2.04 (m, 2H), 2.75 (m, 6H), 2.82 (m, 2H), 2.98 (m, 4H), 3.05 (m, 4H), 6.81 (d, 1H), 6.98-6.93(m, 2H), 7.05(s, 1H), 7.21(d, 1H), 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, 1t, m.p.178-179℃,

¹ H NMR (CDCl ₃ ): 2.07 (m, 2H), 2.75 (m, 6H), 2.83 (m, 2H), 2.98 (m, 4H), 3.04 (m, 4H), 6.80 (d, 1H), 6.98-6.92(m, 2H), 7.04(s, 1H), 7.08(d, 1H), 7.33(s, 1H), 7.52(d, 1H), 7.95(s, 1H). 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, 1u, mp202-4℃, ¹ HNMR (DMSO-d ₆ ): 2.65-2.85(m, 6H); 2.90(t, 2H); 3.20-3.40(m, 4H); 6.60(s, 1H); 6.80(d, 1H); 6.90(d, 1H); 7.00 (d, 1H); 7.05-7.30(m, 3H); 7.40(d, 1H); 7.55(d, 1H); 7.95(d, 1H); 11.00(s, 1H).MS m/z(%) : 380 (MH+, 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, 1v, m.p.240-47°C,

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

6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-1H- Indole oxalate, 1x, m.p.211-14°C,

¹ H NMR (DMSO-d ₆ ): 2.75(s, 2H); 3.05-3.15(m, 2H); 3.20(t, 2H), 3.25-3.50(m, 4H); 3.85(s, 2H); 4.55 (t, 2H); 6.30(s, 1H); 6.85(t, 1H); 7.00(d, 1H); 7.10(d, 1H); 7.15(d, 1H); 7.30(s, 1H); 7.40( s, 1H); 7.60 (d, 1H); 11.10 (s, 1H). MS m/z (%): 379 (MH+, 3%), 178 (100%).

3-[2-[4-(Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-6-chloro-1H-indole hemifumaric acid Salt, 1y, m.p.214-20°C,

¹ H NMR (DMSO-d ₆ ): 2.65(s, 2H); 2.75-2.85(m, 4H): 2.90-3.00(m, 2H); 3.10-3.50(m, 3H); 6.55(s, 2H) ;6.90-7.00(m,2H);7.15-7.30(m,3H);7.35(s,1H);7.50-7.60(m,2H);8.00(s,1H);10.90(s,1H).MS m/z (%): 377 (MH+, 25%), 178 (73%), 143 (22%).

3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-bromo-1H-indole oxalate, 1z, mp 185-94°C. ¹ H NMR (DMSO-d ₆ ): 2.90 (s, 2H); 3.10-3.20 (m, 2H); 3.25-3.55 (m, 4H); 3.95 (s, 2H); 6.60(s, 1H); 7.00(s, 1H); 7.20(d, 1H); 7.20-7.45(m, 4H); 7.60(d, 1H); 7.80(s, 1H); 8.05(s, 1H) ; 11.20(s, 1H).MS m/z(%): 423(MH+( ^81Br ), 22%), 421(MH+( ^79Br ), 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 , 1aa, m.p.176-79°C,

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

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole hemifumarate, 1bb, mp245-50℃. ¹ H NMR (DMSO-d ₆ ): 1.85-2.00 (m, 4H); 2.75 (t, 2H); 2.90 (t, 2H); 3.05 (tt, 1H); 3.25 (d, 2H); 2H); 6.95(s, 1H); 7.00(d, 1H); 7.15-7.25(m, 3H); 7.40(s, 1H); 7.50(d, 1H); 7.55(d, 1H); 8.00(s , 1H); 10.95 (s, 1H). MS m/z (%): 379 (MH+, 5%), 214 (10%), 178 (20%), 143 (100%).

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole oxalate, 1cc, mp191-94℃. ¹ H NMR (DMSO-d ₆ ): 2.05-2.25(m, 4H); 3.05-3.20(m, 4H); 3.20-4.40(m, 3H); 3.60-3.70(m, 2H); 6.90-7.00(m, 2H ); 7.15-7.25(m, 2H); 7.35-7.45(m, 3H); 7.55(d, 1H); 8.00(s, 1H); 11.05(s, 1H).MS m/z(%): 363 (MH+, 5%), 214 (9%), 161 (10%), 143 (24%).

3-[2-[4-(Benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1H-indole oxalate, 1dd, mp153-57℃. ¹ H NMR (DMSO-d ₆ ): 2.05-2.20(m, 4H); 3.05-3.20(m, 4H); 3.20-3.40(m, 3H); 3.70(d, 2H); 6.95(s, 1H); 7.15- 7.25(m, 3H); 7.30-7.40(m, 2H); 7.55(d, 1H); 7.80(s, 1H); 8.00(s, 1H); 11.20(s, 1H).MS m/z(% ): 423 (MH+, 36%), 224 (27%), 202 (45%), 143 (27%), 117 (18%).

Example 2

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

3-(2-bromoethyl)-1H-indole (1.5g), 1-(1,4-benzodioxan-5-yl)piperazine (1.2g), potassium carbonate (1.9g) and potassium iodide (0.1 g) were placed in methyl isobutyl ketone (100 mL), refluxed for 16 hours, and generally purified with ethyl acetate to obtain an oil, which was purified by flash chromatography (elution Agent: heptane/ethanol/ethyl acetate/triethylamine 15:2:2:1), fumarate is obtained by adding fumaric acid to ethanol solution, recrystallized in ethanol to obtain hemifumarate 2a (0.9g). mp204-7°C, ¹ HNMR (DMSO-d ₆ ): 2.60-2.80 (m, 6H); 2.90 (t, 2H); 2.95-3.10 (m, 4H); 4.15-4.30 (m, 4H); 6.50 ( d, 1H); 6.55(d, 1H); 6.60(s, 1H); 6.75(t, 1H); 7.00(t, 1H); 7.10(t, 1H); 7.20(s, 1H); , 1H); 7.55 (d, 1H); 10.75 (s, 1H). MS m/z (%): 364 (MH+, 5%), 233 (57%), 218 (21%), 190 (19%) ), 144 (54%), 70 (100%).

1-Acetyl-3-[2-[4-(1,4-benzodioxan-4-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole , 2b, mp119-20°C. ¹ H NMR (DMSO-d ₆ ) 1.90 (d, 1H); 2.20 (s, 4H); 2.95-3.30 (m, 11H); 3.40-3.50 (m, 1H); 3.75 -3.85(m, 1H); 4.20-4.30(m, 4H); 6.45(dd, 1H); 6.55(dd, 1H); 6.75(t, 1H); 7.00(t, 1H); 7.20(t, 1H ); 7.30 (d, 1H); 8.05 (d, 1H). MS m/z (%): 408 (MH+, 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, 3a.

2-(6-chloro-1H-indol-3-yl)acetic acid (2.0g), 1-(1,4-benzodioxan-5-yl)piperazine (3.6g), N,N -A mixture of dicyclohexylcarbodiimide (2.4g) and 4-dimethylaminopyridine (0.2g) was placed in dry tetrahydrofuran (100mL), stirred at room temperature under nitrogen atmosphere for 16h, filtered and treated with dichloromethane General isolation and purification gives 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 (2.0 g).

This oil was dissolved in tetrahydrofuran (25mL), and added dropwise to a suspension of lithium aluminum hydride (0.9g) in dry tetrahydrofuran (50mL) at room temperature, and then refluxed for 3h, the reaction was terminated with 2M aqueous sodium hydroxide solution, and General isolation and purification afforded the free base form of 3a (1.9 g) as an oil, and the hemifumarate salt of 3a (1.0 g) was obtained by adding fumaric acid from ethanol solution. mp215-16°C, ¹ H NMR (DMSO-d ₆ ): 2.60-2.85 (m, 6H); 2.85-2.95 (m, 2H); 2.95-3.10 (m, 4H); 4.10-4.30 (m, 4H) ;6.45(d,1H);6.50(d,1H);6.60(s,1H);6.70(t,1H);7.0(dd,1H);7.25(d,1H);7.40(d,1H); 7.55(d, 1H); 10.95(s, 1H), MS m/z(%): 398(MH+, 10%), 234(13%), 233(100%), 178(12%).

The following compounds were prepared analogously:

3-[2-[4-(5-Chloro-2,2-dimethyl-2,3-benzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole semi-rich Maleate, 3b, m.p.210-12°C,

¹ H NMR (DMSO-d ₆ ): 1.40(s, 6H); 2.55-2.75(m, 6H); 2.80-3.00(m, 4H); 3.05-3.20(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+, 18%), 281 (32%), 279 (100%), 144 (39%).

6-chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2,3-benzofuran-7-yl)piperazin-1-yl]ethyl]-1H- Indole hemifumarate, 3c, m.p.130-32°C,

¹ H NMR (DMSO-d ₆ ): 1.25 (s, 6H); 2.55-2.70 (m, 6H); 2.85 (t, 2H); 3.00-3.20 (m, 4H); 4.25 (s, 2H); 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)piperazine-1 -yl]ethyl]-1H-indole fumarate, 3d, mp224-25°C, ¹ H NMR (DMSO-d ₆ ): 1.30(s, 6H); 1.70(t, 2H); 2.60-2.75 (m, 8H); 2.90(t, 2H); 2.95-3.10(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+, 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, 3e, m.p.167-65°C,

¹ H NMR (DMSO-d ₆ ): 1.40 (s, 6H); 2.65-2.80 (m, 6H); 2.90 (t, 2H); 2.95 (s, 2H); 3.00-3.20 (m, 4H); (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+, 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, 3f, mp234- 35°C. ¹ H NMR (DMSO-d ₆ ): 2.85(s, 4H); 2.95-3.15(m, 6H); 4.15-4.30(m, 4H); 4.40(t, 2H); 6.45-6.55(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+ , 45%), 218 (100%), 178 (50%).

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole oxalate, 3g, mp234- 35°C. ¹ H NMR (DMSO-d ₆ ): 2.85(s, 4H); 2.95-3.15(m, 6H); 4.15-4.30(m, 4H); 4.45(t, 2H); 6.40-6.50(m , 2H); 6.55(d, 1H); 6.70(t, 1H); 7.15(d, 1H); 7.50(s, 1H); 7.55-7.65(m, 2H).MS m/z(%): 398 (MH+; 44%), 218 (100%), 178 (62%).

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole oxalate, 3h, mp230- 31°C. ¹ H NMR (DMSO-d ₆ ): 2.90(s, 4H); 2.95-3.20(m, 6H); 4.15-4.30(m, 4H); 4.45(t, 2H); 6.40-6.50(m , 2H); 6.55(d, 1H); 6.75(t, 1H); 7.00(t, 2H); 7.30(d, 1H); 7.50(s, 1H); 7.50-7.55(m, 1H).MS m /z (%): 382 (MH+,?), 218 (63%), 162 (100%).

1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole oxalate, 3i, mp225-29, ¹ HNMR (DMSO-d ₆ ): 2.95(s, 4H); 3.05-3.20(m, 6H); 4.10-4.30(m, 4H); 4.45(t, 2H); 6.40-6.50(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+, 100%), 218 (85%), 146 (80%).

1-[2-[4-(2,3-Benzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole oxalate, 3j, mp223-26℃. ¹ H NMR (DMSO-d ₆ ): 2.85(s, 4H); 3.00(t, 2H); 3.05-3.20(m, 6H); 4.40(t, 2H); 4.50(t, 2H); 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,2H). MS m/z (%): 348 (MH+, 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 , 4a.

At room temperature, sodium borohydride (2×2.9g, interval 1.5h) was reacted with 2a (16g) trifluoroacetic acid (200mL) solution in batches, then stirred at room temperature for 2.5h, and the reaction mixture was poured into ice, After basification with aqueous sodium hydroxide solution and general separation and purification, the resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/ethanol/triethylamine 15:2:2:1) to give The base of the title compound in the form of yellow oil, the oxalate of the title compound was obtained by adding oxalic acid to the free base (1.4g) in ethanol to obtain its crystal (0.9g), mp145-50℃. ¹ H NMR (DMSO-d ₆ ): 1.75- 1.85(m, 1H); 2.05-2.15(m, 1H); 2.95-3.30(m, 12H); 3.60(t, 1H); 4.20(d, 4H); 6.50(d, 2H); 6.60(d, 2H); 6.75(t, 1H); 6.95(t, 1H); 7.10(d, 1H). MSm/z(%): 366(MH+, 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 semi Oxalate, 4b, m.p.201-5°C

¹ H NMR (DMSO-d ₆ ): 1.60-1.80 (m, 1H); 1.95-2.10 (m, 1H); 2.60-3.30 (m, 12H); 3.35 (t, 1H); 4.20 (d, 4H) 6.35-6.55 (m, 3H); 6.15-6.25 (m, 2H); 6.90 (d, 1H).MS m/z (%): 384 (MH+, 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 Salt, 4c, mp 153-57°C. ¹ H NMR (DMSO-d ₆ ): 1.70-1.85 (m, 1H); 2.05-2.20 (m, 1H); 2.85-3.05 (m, 2H); 3.05- 3.35(m, 10H); 3.60(t, 2H); 4.15-4.30(m, 4H); 6.45-6.60(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 Salt, 4d, mp 185-88°C. ¹ H NMR (DMSO-d ₆ ): 1.75-1.85 (m, 1H); 2.00-2.10 (m, 1H); 2.90-3.30 (m, 12H); 3.60 ( t, 1H); 4.15-4.30(m, 4H); 6.45(s, 1H); 6.50(d, 1H); 6.55(t, 2H); 6.75(t, 1H); 7.05(d, 1H).MS m/z (%): 400 (MH+, 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, 5a.

A solution of 2a (1.0 g) in dry tetrahydrofuran (50 mL) was added dropwise to a solution of sodium hydride (60% in mineral oil, 0.14 g) in tetrahydrofuran (25 mL) at room temperature, and after stirring for 30 min, 1-bromo A solution of butane (0.85 g) in dry tetrahydrofuran (10 mL) was stirred for 1 h and then purified by general isolation with ethyl acetate. The resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine 15:3:2), the obtained oil was converted into the title oxalate (0.7g) by adding oxalic acid in acetone, mp168-74°C, ¹ H NMR (DMSO-d ₆ ): 0.90 (t, 3H); 1.25(qv, 2H); 1.70(qv, 2H); 3.05(t, 2H); 3.15-3.40(m, 8H); 4.10(t, 2H); 4.15-4.30(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+, 33%), 233 (39%), 200 (100%), 158 (36%).

The following compounds were prepared analogously:

1-allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole oxalate, 5b, m.p.187-90℃

¹ H NMR (DMSO-d ₆ ): 3.05(t, 2H); 3.10-3.40(m, 10H); 4.20(d, 4H); 4.75(d, 2H); 5.05(d, 1H); , 1H); 5.90-6.05(m, 1H); 6.50(d, 1H); 6.55(d, 1H); 6.75(t, 1H); 7.05(t, 1H); 7.15(t, 1H); s, 1H); 7.40 (d, 1H); 7.60 (d, 1H). MS m/z (%): 404 (MH+, 38%), 233 (38%), 184 (43%), 120 (29 %).

3-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-propargyl-1H-indole oxalate, 5c, mp168-72°C. ¹ H NMR (DMSO-d ₆ ): 3.00-3.30 (m, 12H); 3.40 (t, 1H); 4.25 (d, 4H); 5.05 (d, 2H); 6.50 (d, 2H) ); 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+, 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, 6a.

At room temperature, a solution of 4a (1.5 g) in dry tetrahydrofuran (50 mL) was added dropwise to a solution of sodium hydride (60% in mineral oil, 0.21 g) in tetrahydrofuran (25 mL), and after stirring for 30 min, methyl iodide ( 0.75 g) in dry tetrahydrofuran (25 mL), stirred for 1 h, followed by general separation and purification with ethyl acetate, the resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine 15:3 : 2), the obtained oil was converted into the title oxalate (0.3g) by adding oxalic acid in acetone, mp 155-65°C, ¹ H NMR (DMSO-d ₆ ) 1.75-1.85 (m, 1H); 2.05- 2.15(m, 1H); 2.70(s, 3H); 2.90-3.25(m, 12H); 3.40(t, 1H); 4.15-4.30(m, 4H); 6.45-6.55(m, 3H); 6.65( t, 1H); 6.75(t, 1H); 7.05(t, 1H); 7.10(d, 1H).MS m/z(%); 380(MH+, 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, 6b, m.p.158-65°C

¹ H NMR (DMSO-d ₆ ): 1.75-1.85 (m, 1H); 2.10-2.20 (m, 1H); 2.90-3.30 (m, 12H); 3.45 (t, 1H); 4.15-4.25 (m, 5H); 4.35(d, 1H); 6.50(d, 1H); 6.55(d, 1H); 6.65-6.70(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+, 19%), 236(25%), 178(100%), 130(11% ).

1-allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-ind Oxalate, 6c, mp 133-36°C. ¹ H NMR (DMSO-d ₆ ): 1.75-1.85 (m, 1H); 2.10-2.20 (m, 1H); 2.95-3.35 (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);5.85-5.95(m,1H) ;6.50(d,1H);6.55(d,2H);6.65(t,1H);6.75(t,1H);7.00(t,1H);7.10(d,1H).MS m/z(%) : 406 (MH+, 15%), 178 (178%), 158 (24%), 130 (31%), 117 (20%).

Example 7

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

A mixture of 2a (2.0 g), tetrabutylammonium bisulfate (0.21 g), sodium hydroxide (1.0 g) and dichloromethane (40 mL) was stirred for 10 min, followed by the dropwise addition of diacetyl chloride (0.97 g) at room temperature. Chloromethane solution, stirred for 1 h, added water, and carried out general separation and purification, the obtained oil was purified by flash chromatography (eluent: heptane/ethyl acetate/ethanol/triethylamine 17:1:1), to obtain The yellow oil was converted into the title oxalate (0.75g) by adding oxalic acid in acetone, mp199-202°C, ¹ H NMR (DMSO-d ₆ ): 2.65 (s, 3H); 3.05 (t, 2H); 3.15(s, 10H); 4.20(d, 2H); 4.25(d, 2H); 6.50(d, 1H); 6.55(d, 1H); 6.75(t, 1H); 7.30-7.40(m, 2H) 7.70(d, 1H); 7.80(s, 1H); 8.35(d, 1H).MS m/z(%): 406(MH+, 28%), 233(44%), 218(39%), 144 (100%).

pharmacological test

The affinity of the compounds of the invention for the 5-HT _1A receptor was determined by measuring the inhibition of radioligand binding to the 5-HT _1A receptor, as described in the following assay: Binding of ³ H-5-CT to human 5 -Inhibition of HT _1A receptors

According to this method, the effect of drugs on the 5-HT _1A agonist ³ H-5-carboxamidotryptamine ( ³ H-5-CT) and cloned human 5 stably expressed in transfected Hela cells (HA7) was determined in vitro. - Inhibition of HT _1A receptor binding (Fargin, A. et al., J. Biol. Chem., 1989, 264, 14848). The assay was performed according to a modification of the method described by Harrington, MA et al., J. Pharmacol. Exp. Ther., 1994, 268, 1089 . In the presence of ³ H-5-CT, human 5-HT _1A receptors (40 μg cell tissue homogenate) were incubated at 37° C. for 15 minutes in 50 mM Tris buffer at pH 7.7, Non-specific binding was determined by taking 10 μM metergoline into account. Filter rapidly with the Unifilter GF/B filter on the Tomtec Cell Harvester (Tomtec Cell Harvester) to terminate the reaction, and the filter is counted on the Pakard Top Counter (Pakard Top Counter), and the results are shown in Table 1:

Compound No. Inhibitory IC ₅₀ of ³ H-5-CT binding (nM) 1a 17 1b 7.2 1c 2.5 1d 55 1e 11 1f 6.1 1g 2.8 1h 4.6 1i 6.9 1j 14 1k 2.0 1l 12 1m 99 1n 8.2 2a 2.9 2b 13 1v 0.81 3a 1.2 3b 3.6 3d twenty one 4d 14 Pindolol ^* 100

Table 1 ^* Reference compounds

The effect of the compounds of the invention on the reuptake of serotonin was also determined in the following test: Inhibition of uptake of ³ H-5-HT by rat brain synaptosomes

Using this method, the ability of the drug to inhibit the accumulation of ³ H-5-HT in the synaptosomes of the whole rat brain was determined in vitro. Measure by the method described in Hyttel, J., Psychopharmcology., 1978,60,13, the obtained results are shown in Table 2:

Compound No. Serotonin reuptake inhibition IC ₅₀ (nM) 1a 5.0 1b 2.8 1c 45 1d 36 1e 0.25 1f 5.9 1g 3.8 1h 1.7 1i 6.8 1j 3.5 1k 18 1l 7.7 1m 57 1n 2.1 1v 0.85 2a 3.5 2b 12 3a 5.3 3b 8.3 3d 15 4d 4.3 Pindolol ^* 0.29

Table 2 ^* Reference compounds

For the cloned 5-HT _1A receptor stably expressed in transfected HeLa cells (HA7), the 5-HT _1A antagonistic activity of some compounds of the present invention has been determined in vitro. -HT-induced inhibition of forskolin's ability to cause cyclic AMP (cAMP) accumulation, determination of its 5-HT _1A antagonistic activity, according to the method described by Pauwels, PJ et al., Biochem.Pharmacol., 1993, 45, 375 The modification is measured. The results obtained are shown in Table 3: Compound number Inhibitory IC ₅₀ of ³ H-5-CT binding (nM) 1a 2900 1b 5000 1e 2400 1f 1800 1g 1800 1h 280 1i 620 1j 980 1k 580 1n 1900 1o 3200 1t 5900 1u 2000 1v 3300 1x 3000 2a 160 2b 250 3a 500 3c 2600 3d 2300 4d 890 6a 100 Pindolol ^* 270

Table 3 ^* Reference compounds

The effect of some compounds of the invention on the 5-HT _1A receptor was also determined in vivo according to the assay method described by Sanchez, C. et al., Eur. J. Pharmacol., 1996, 315, pp245. In this method, antagonism of test compounds is determined by measuring the ability to inhibit 5-MeO-DMT-induced 5-HT syndrome.

The compounds of the invention possess valuable serotonin reuptake inhibitor activity as well as antagonistic activity at the 5-HT _1A receptor. The compounds of the invention are therefore useful in the treatment of diseases or disorders sensitive to serotonin reuptake inhibition or 5-HT _1A receptor antagonism. Diseases susceptible to serotonin reuptake inhibition are well known in the art and include affective psychiatric disorders such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive-compulsive symptoms, among others.

As stated above, the 5-HT _1A receptor antagonistic activity of the compound of the present invention can counteract the negative feedback mechanism through the 5-HT reuptake inhibitory effect, and the result of the 5-HT reuptake inhibitory effect of the compound of the present invention is expected to be obtained thereby improve.

Thus, the claimed compounds are particularly useful as fast-acting drugs for the treatment of depression, and these compounds may also be used in the treatment of depression insensitive to current SSRIs.

pharmaceutical preparations

The pharmaceutical preparation of the present invention can be prepared according to conventional methods in the art, for example, the preparation of tablets can mix active ingredients with common adjuvants and/or diluents, and then compress the mixture into tablets on a general tablet machine. Adjuvants or diluents include, for example, corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Other adjuvants or additives commonly used for coloring, flavouring, preserving etc. purposes may also be used provided they are compatible with the active ingredients.

Injection solutions are prepared by dissolving the active ingredient and permissible additives in one part of the injection solvent (preferably sterile water), adjusting the solution to the required volume, sterilizing the solution and filling it into appropriate ampoules or vials. Any suitable additive commonly used in the art may be added. Such as enhancers, preservatives, antioxidants, etc.

The pharmaceutical compositions of the present invention or those prepared according to the present invention can be administered by any suitable route, such as oral administration in the form of tablets, capsules, powders, syrups, etc., or parenteral administration in the form of solvent injection. To prepare these compositions, methods well known to those skilled in the art, and pharmaceutically acceptable carriers, diluents, excipients or other additives commonly used in the art can be used.

The compounds of the present invention are simply administered in unit dosage forms containing said compound in an amount of about 0.01-1000 mg, the daily dose of the active compound of the present invention being usually 0.05-500 mg, and most preferably 0.1-50 mg.

Claims (14)

1. An indole or 2,3-dihydroindole derivative of formula (I) or an acid addition salt thereof,

in: X is -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 the group -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 formulas (II) and (IV)

where the dashed line refers to 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 selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are each independently selected from hydrogen and C _1-4 alkyl; and R ¹¹ is selected from hydrogen, _{C 1-4} alkyl, C 2-4 alkenyl, C _2-4 alkynyl, phenyl, naphthyl, phenyl-C _1-4 alkyl, naphthyl-C _{1- 4} alkyl, and -CO-C _1-4 alkyl. 2. A compound according to claim 1, wherein Z is -O-. 3. The compound according to claim 1, wherein Z is -S-. 4. The compound according to claim 1, wherein A is a group of formula (II). 5. The compound according to claim 1, wherein A is a group of formula (IV). 6. The compound according to claim 2, wherein A is a group of formula (II). 7. The compound according to claim 2, wherein A is a group of formula (IV). 8. The compound according to claim 3, wherein A is a group of formula (II). 9. The compound according to claim 3, wherein A is a group of formula (IV). 10. The compound according to any one of claims 1-9, wherein ^R4 , ^R5 , ^R6 , ^R7 , ^R8 and ^R9 are selected from hydrogen or methyl. 11. A compound according to claim 1 which is 6-Chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-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-pyridine Base] ethyl] -1H-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)piperazine-1- Base] ethyl] -1H-indole, 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-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, 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)piperidin-1-yl]ethyl]-5-bromo-1H-indole, 1-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole, or their acid addition salts. 12. A pharmaceutical composition comprising the compound of claims 1-11 or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent. 13. Use of the compound of claims 1-11 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament suitable for the treatment of serotonin reuptake inhibition or 5-HT _1A receptor antagonism Sensitive to dysfunction or disease. 14. The use of the compound according to claim 13, said medicament is suitable for the treatment of affective mental disorders, including depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive-compulsive symptoms.