HK1066807B - Indole and 2,3-dihydroindole derivatives, their preparation and use - Google Patents

Description

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

The present application is a pending divisional application filed on 20/07/1998 under the same name as the present application and having application number 98807554.0.

The present invention relates to novel indole and 2, 3-indoline derivatives which are potent 5-hydroxytryptamine reuptake inhibitors, pharmaceutical compositions containing these compounds and their use in the treatment of 5-hydroxytryptamine reuptake inhibition or 5-HT_1AUse of a disorder or disease susceptible to receptor antagonism. The compounds of the invention are also active against 5-HT_1AThe receptors have antagonistic activity and are believed to be particularly useful in the treatment of depression.

Background

Compared to the first generation of antidepressant drugs (tricyclic compounds and non-selective MAO inhibitors), selective 5-hydroxytryptamine (or 5-TH) reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram show a greater improvement in the treatment of depression, as they have fewer side effects and less severity. The side effects caused by the first generation antidepressant drugs were so severe that some patients were withdrawn from treatment.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. The lag in onset of drug action is a serious problem, especially for treating patients with major depression and patients with suicidal tendencies. In addition, one third of patients are not sensitive to SSRI.

Electrophysiological experiments in mice have shown that acute administration of SSRI reduces agonism of 5-HT neurons in the dorsal suture core in rodent brain, and that continued treatment with SSRI normalizes agonistic activity of 5-HT neurons (Arborrelius, L. et al, Naunen-Schmiedeberg's research. Pharmacol.1995, 352, 157; Gartside, S.E. et al, Br.J.Pharmacol.1995, 115, 1064; Chaput, Y. et al, Naunen-Schmiedeberg's Arch.Pharmacol.1986, 33, 342). Furthermore, restoration of 5-HT neuronal agonist activity and somatic dendritic (somatodendritic)5-HT have been shown_1ADesensitization of autoreceptors is implicated (Le Poul, E. et al, Nauyn-Schmiedeberg's Arch. Pharmacol.1995, 352, 141; Inveminzi, R. et al, Eur. J. Pharmacol.1994, 260, 243).

It has therefore been proposed that SSRI and a compound capable of causing 5-HT_1ASimultaneous administration of agents that rapidly desensitize or inhibit the functioning of the receptor under feedback mechanisms will lead to a rapid onset of antidepressant effects (Artigas, f. et al, Trends neurosci.1996, 19, 387; De Vry, j. drug news perspec.1996, 9, 270).

Compound for inhibiting reuptake of 5-hydroxytryptamine and 5-HT_1AThe effect of combined administration of receptor antagonists has been evaluated in several studies (Innis, R.B. et al, Eur.J.Pharmacol.1987, 143, p195-204 and Gartside, S.E., Br.J.Pharmacol.1995, 115, p 1064-1070; Blier, P.et al, Trends Pharmacol.Sci.1994, 15, 220) in which 5-HT was found_1AThe receptor antagonist can prevent the decrease in agonistic activity caused by acute administration of a 5-hydroxytryptamine reuptake inhibitor.

In addition, pindolol (a well-known 5-HT) is used in combination_1AReceptor and beta-adrenoceptor antagonists) and SSRIs have been evaluated in clinical trials, and significant improvement in the mood of patients has been reported within a week. In addition, the combination of pindolol and SSRI also showed good results in patients who were not susceptible to current antidepressant drug therapy (arthritis F. et al, Arch. Gen. Psychiary, 1994, 51, p248-251 and Blier, P. et al, J. Clin. Phychopharmacol.1995，15，p217-222)。

Several of the patents filed include the combined use of 5-HT_1AAntagonists and 5-hydroxytryptamine reuptake inhibitors for the treatment of depression (see EP-A2-687472 and EP-A2-714663).

EP-A1-529462 discloses certain 1, 4-benzodioxane derivatives of the general formula:

wherein B is optionally substituted indol-3-yl, Q is C_nH_2nWherein n is 1, 2, 3, 4, 5 or 6. These compounds are said to have 5-hydroxytryptamine agonistic and 5-hydroxytryptamine antagonistic activities as well as 5-hydroxytryptamine reuptake inhibitory activities and to be useful as anxiolytics, antidepressants, antihypertensive agents and cerebral protective agents.

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

wherein X is-CH-, -CH₂-, -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_1AA receptor ligand.

Object of the Invention

It is an object of the present invention to provide a compound having an effective 5-hydroxytryptamine reuptake inhibiting activity and an effective 5-HT inhibiting activity_1ACompounds whose receptors have antagonistic properties are useful as fast acting drugs for the treatment of affective disorders, such as depression.

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

Summary of The Invention

The invention comprises in particular the following, independently of one another or in combination with one another.

An indole or 2, 3-indoline derivative having the formula, its enantiomers or mixtures thereof, or acid addition salts thereof,

wherein:

x is-O-, -S-or-CR⁴R⁵-; and

y is-CR⁶R⁷-、-CR⁶R⁷-CR⁸R⁹-or-CR⁶＝CR⁷-; or

X and Y together form a group-CR⁴＝CR⁵-or-CR⁴＝CR⁵-CR⁶R⁷；

Z is-O-or-S-;

w is N, C or CH;

a is a group selected from the group represented by the formulae (II), (III) and (IV)

Wherein the dotted line refers to an optional bond;

R¹、R²、R³、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶and R¹⁷Each independently selected from the group consisting of 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 wherein the aryl group may be substituted with halogen, trifluoromethyl, alkoxy, hydroxy, amino, alkylamino, nitro and cyano;

R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Each independently selected from hydrogen and alkyl; and

R¹¹selected from the group consisting of 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 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.

In a particular embodiment of the invention, A is a radical of the formula (II) and Z is-O-, A is a radical of the formula (III) and Z is-O-, A is a radical of the 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 invention, R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Is selected fromHydrogen 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-pyridinyl ] 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) 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,

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-indoline,

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-pyridinyl ] 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,

3- [2- [4- (1, 3-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- (benzothien-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-pyridin-1-yl ] ethyl ] -5-chloro-1H-indole,

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

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

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

or an acid addition salt thereof.

The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, together with 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 preparation of a medicament suitable for the treatment of 5-hydroxytryptamine reuptake inhibition or 5-HT_1AA disorder or disease susceptible to receptor antagonism.

The invention particularly relates to the use of a compound of the invention or its use or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament suitable for the treatment of affective disorders such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive compulsive disorder.

In another embodiment, the invention relates to a method of treating a disorder or disease of a living animal body, including a human, which disorder or disease is an inhibition of 5-hydroxytryptamine reuptake or 5-HT_1ASusceptible to receptor antagonism, which method comprises administering to the living body of said animal, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

The present invention relates particularly to a method of treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive compulsive disorder, which comprises administering to a living animal, including a human, in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

Due to their combination with 5-HT_1AAntagonism of the receptor and inhibition of 5-hydroxytryptamine reuptake, the compounds of the present invention are believed to be particularly useful as fast acting drugs for the treatment of depression, as well as for the treatment of depression patients who are not susceptible to current antidepressant drug therapy.

The claimed compounds are particularly useful in the treatment of depression requiring rapid onset of antidepressant drugs, or depression resistant to other antidepressant drugs.

Halogen means fluorine, chlorine, bromine or iodine.

Alkyl means straight or branched chain alkyl of 1 to 4 carbon atoms and includes, for example, methyl, ethyl, propyl, isopropyl and butyl.

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

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

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

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

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

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

Amido means an-NH-acyl group, wherein acyl is as defined above.

Alkoxycarbonylamino means an alkyl-O-CO-NH-group in which alkyl is as defined above.

Alkylaminocarbonylamino is understood to mean alkyl-NH-CO-NH-, in which alkyl is as defined above.

Dialkylamino carbonylamino means (alkyl)₂-NH-CO-NH-, wherein alkyl is as defined above.

Aryl means an aromatic ring such as phenyl or naphthyl.

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

Typical organic acid addition salts according to the invention are the addition salts with the following acids: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylenesalicylic 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 (glycocolc), p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, theophylline acetic acid, and 8-halotheophyllines, such as 8-bromotheophylline. Typical inorganic acid addition salts are those with: hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acid addition salts. The acid addition salts of the present invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.

The compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. For the purposes of the present invention, the solvated forms are generally considered equivalent to unsolvated forms.

Some of the compounds of the present invention contain a chiral center, the central compound being present as an isomer (i.e., enantiomer), and the present invention includes all such isomers and mixtures thereof, such as racemic mixtures.

The racemic forms can be resolved into the optical enantiomers by known methods, for example, by separating the diastereomeric salts of them with optically active acids and treating with a base to liberate the optically active amine compounds. Another method for resolving racemic forms into optical enantiomers is based on chromatography on optically active matrices. The racemic compounds of the present invention can thus be resolved into their optical enantiomers, for example, by fractional crystallization of d-or l-salts, such as tartrate, mandelate or camphorsulfonate. The compounds of the present invention may also be resolved by forming diastereomeric derivatives.

Other methods known to those skilled in the art may also be used to resolve optical isomers. These methods include the methods discussed by j.jaques, ACollet and s.wilen in enantiomers, racemates and resolution (John Wiley and Sons, New York, (1981)).

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

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

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

wherein R is¹-R³、R¹²、R¹⁴-R¹⁷X, Y, Z, W and the dotted line are as defined above;

b) reacting an amine of formula (VI)

Wherein R is¹-R³X, Y, Z, W and the dotted line are as defined above, with the formula G-CH₂CH₂Alkylating the reagent of A, wherein A is as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate;

c) an amine of the formula (VI)

Wherein R is¹-R³X, Y, Z, W and the dotted line are as defined above, with formula B-CH₂CH₂-reductive alkylation of a reagent of a, wherein a is as defined above and B is an aldehyde or carboxylic acid group;

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

Wherein R is¹-R³X, Y, Z, W and the dotted line are as defined above, A' is a group of formula (II), (III) or (IV) above and the dotted line represents a single bond;

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

Wherein R is¹-R³A, X, Y and Z are as previously defined;

f) treating a compound of formula (I) wherein Y is-CR with a reducing agent⁶＝CR⁷-, or in which X and Y together form a group-CR⁴＝CR⁵-or-CR⁴＝CR⁵-CR⁶R⁷To reduce the double bond, thereby reducing the ring system accordingly;

g) the substituent R of the compound of the general formula (I)¹-R³Or R¹²-R¹⁷One or more of these substituents are selected from chlorine, bromine or iodine;

h) reacting an amine of formula (IX)

Wherein R is¹-R³X, Y and Z are as defined above, dialkylating 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) reacting an amine of formula (XI)

Wherein A is as defined above, dialkylating with a reagent represented by the formula (XII),

wherein R is¹-R³X, Y, Z and W are as defined above, 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 the formula (XIII)

Wherein R is¹-R³X, Y, Z, W and the dotted line are as defined above, A' is selected from a group of formula (III) or (IV) as defined above, wherein R is¹¹As hydrogen, use is made of the formula R¹¹An alkylating or acylating agent represented by G, wherein G is a suitable leaving group such as halogen, mesylate or tosylate, R¹¹As defined above but not hydrogen.

The compounds of formula (I) are therefore isolated as the free base or as an acid addition salt thereof.

The reduction of process a) is preferably carried out in an organic inert solvent, such as diethyl ether or tetrahydrofuran, in the presence of lithium aluminium hydride and at reflux temperature, and the starting compound of formula (V), generally the reagent represented by formula (IV), the unsubstituted indole or oxalyl chloride in the 1, 3-position, is prepared as described in the examples below.

The alkylation according to process b) is conveniently carried out in an inert organic solvent, such as an alcohol or ketone having an appropriate boiling point, preferably in the presence of a base, such as potassium carbonate or triethylamine, at reflux temperature.

Arylpiperazine derivatives of formula (IV) are conveniently prepared from the corresponding aromatic amines according to the methods described in Martin et al, j.med.chem., 1989, 32, 1052, or the methods described in Kruse et al, Rec trav.chim.pays bas, 1988, 107, 303; the starting aromatic amines are commercially available or have been fully described in the literature.

Aryl tetrahydropyridine derivatives represented by the formula (IV) are known in the literature, see US patent No. US 2891066; McElvain et al, j.amer.chem.soc., 1959, 72, 3134. The corresponding arylamine is lithiated simply by butyl lithium, then 1-benzyl-4-piperidone is added, and then N-benzyl-aryl tetrahydropyridine is obtained by acid treatment; removal of the benzyl group can be by catalytic hydrogenation or by treatment with a reagent such as ethyl chloroformate to give the corresponding ethyl carbamate, followed by acid or base hydrolysis. The starting aryl bromides are either commercially available or have been fully described in the literature.

Formula G-CH₂CH₂The reagents of-A are commercially available or can be prepared according to literature procedures, for example, reduction from the corresponding acetic acid derivative to the 2-hydroxyethyl derivative, followed by conversion of the hydroxyl group to the group G according to conventional methods.

The reductive alkylation reaction of process c) is carried out according to conventional literature procedures and may be carried out in two steps, i.e. (VI) and a compound of formula B-CH₂The reagent represented by-A is coupled by an acid chloride or using a coupling reagent such as dicyclohexylcarbodiimide according to a conventional method, and then the resulting amide is reduced with lithium aluminum hydride. The reaction can also be carried out according to the conventional one-pot method, of the formula G-CH₂The carboxylic acids or aldehydes represented by-A are commercially available or have been described in the literature.

The double bond reduction of the indole according to process d) is easily carried out by first acid-catalyzed hydrolysis of the intermediate diborane derivative with diborane or diborane precursors such as triethylammonium or dimethylsulfide complexes in an inert solvent such as tetrahydrofuran or dioxane at temperatures from 0 ℃ to reflux temperature; the reduction may alternatively be carried out by treatment with sodium cyanoborohydride in trifluoroacetic acid.

The methods e) and f) are most convenient to implement in the double bond reduction reaction, in the presence of a noble metal catalyst: such as platinum or palladium, in the presence of an alcohol.

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

The dialkylation of the process h) and i) amines is easily carried out at relatively high temperatures in inert solvents such as chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide or acetonitrile, it also being possible for the reaction to be carried out in the presence of bases such as potassium carbonate or triethylamine. The starting materials for processes h) and i) are commercially available or can be prepared in a conventional manner from commercially available materials.

The N-alkylation of process j) is carried out in an inert solvent, such as an alcohol or 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 may also be used.

The following examples are further illustrative of the present invention but should not be construed as limiting thereof.

Examples

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

The substituted 2- (1-indolyl) acetic acid used in said example 3 was prepared from the corresponding substituted indole and ethyl bromoacetate according to a common method.

The substituted 3- (2-bromoethyl) indole used in said example 2 was prepared by reduction of the corresponding 2- (1-indolyl) acetate in alcohol with lithium aluminum hydride followed by treatment with tetrabromomethane/triphenylphosphine according to the conventional literature methods.

The arylpiperazines used in the examples 1, 2 and 3 were prepared from the corresponding aromatic amines according to the methods described in Martin et al, j.med.chem., 32(1989), 1052, or Kruse et al, Rec trav.chim.paysbas, 107(1988), 303.

The starting aromatic amines are commercially available or have been described in the following documents:

the synthesis of 5-amino-1, 4-benzodioxane is 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.

Synthesis of 7-amino-benzofuran is described by Van Wijingaarden et al, J.Med.chem.31(1988) 1934.

The synthesis of 7-amino-benzo [ b ] thiophenes is described by Boswell et al, j.heterocyclic. chem.5(1968) 69.

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

4-amino-thiochromanes were prepared according to European patent application EP 79683.

8-amino-6-chloro-2, 2-dimethylbenzopyran was prepared by nitration of 6-chloro-2, 2-dimethylbenzopyran (prepared according to Bolzoni et al, Angew. chem.90(1978) 727-) 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 EP 7719800206). The corresponding dechlorinated derivatives are obtained according to conventional methods by treatment with hydrogen in the presence of noble metal catalysts.

Aryl tetrahydropyridine derivatives are known in the literature (see US patent 2891066; or McElvain et al, j. amer. chem. soc., 1959, 72, 3134). The method is simple, the corresponding arylamine is lithiated by butyl lithium, then 1-benzyl-4-piperidone is added, and then the N-benzyl-aryl tetrahydropyridine is obtained by treatment with inorganic acid or trifluoroacetic acid; removal of the benzyl group can be by catalytic hydrogenation or by treatment with a reagent such as ethyl chloroformate to give the corresponding ethyl carbamate, followed by acid or base hydrolysis. The corresponding piperidine derivative may be obtained by reductive removal of the double bond in the tetrahydropyridine ring. All these methods are well known to the person skilled in the art. The bromides of the starting aryl groups are well described in the literature. This procedure gives 4- (1, 4-benzodioxan-5-yl) -1, 2, 3, 6-tetrahydropyridine, 4- (2, 3-dihydro-2, 2-dimethylbenzofuran-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 and uncorrected. Mass spectra were obtained on a Quattro MS-MS system supplied by VGBiotech, Fisons Instruments. The MS-MS system was connected to the HPLC system of the HP 1050 standard block. A volume of 20-50. mu.L of sample (10. mu.g/mL) solvent in a 1: 1 mixture of 1% acetic acid in acetonitrile/water was introduced into the electrospray source through an active sampler at a flow rate of 30. mu.L. Spectra were acquired under two sets of standard operating conditions. One group obtained molecular weight information (MH +) (21ev) and the other group derived cleavage patterns (70 ev). The relative intensity of the ion is obtained from the fragmentation pattern, with background subtraction, and is only present under the first set of operating conditions if the intensity of the molecular ion (MH +) is not shown. 1H NMR spectra of all new compounds were recorded on a Brucker AC 250 spectrometer at 250MHz or on a Brucker DRX 500 spectrometer at 500 MHz. Deuterated chloroform (99.8% D) or deuterated dimethylsulfoxide (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 indicate the multiplicity of NMR signals: s is singlet, d is doublet, t is triplet, q is quartet, qui is quintet, h is heptat, dd is doublet, dt is doublet, dq is doublet, tt is triplet, and m is multiplet. The NMR signal corresponding to the acid proton is generally omitted. The water content of the crystalline compound was determined by Karl Fischer titration. The general separation and purification procedure is to extract the particular aqueous solution with the indicated 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 was Kieselgel type 60, 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.

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

A solution of this product (2.0g) in dry tetrahydrofuran (25mL) was added dropwise to a mixture of 1- (1, 4-benzodioxan-5-yl) piperazine (1.2g) and triethylamine (7.5mL) in tetrahydrofuran (75mL) at room temperature, the mixture was stirred for 16h, then filtered and the solvent removed in vacuo to give 3- [2- [4- (1, 4-benzodioxan-5-yl) piperazin-1-yl]-1, 2-dioxoethyl group]-5-chloro-1H-indole as a crude solid product. This product was dissolved in tetrahydrofuran (25mL) at room temperature under a nitrogen atmosphere, and added dropwise to a tetrahydrofuran suspension of lithium aluminum hydride (2.1g), and after refluxing for 3.5 hours, the reaction was terminated by adding an aqueous sodium hydroxide solution, followed by general separation and purification with ethyl acetate. The resulting oil was purified by flash chromatography (eluent: heptane/ethanol/ethyl acetate/triethylamine 15: 2: 1), the oxalate salt was prepared from acetone solution with oxalic acid and recrystallized in methanol/tetrahydrofuran (1: 5) to give 0.8g of 1a, m.p.224-28 deg.C,¹HNMR(DMSO-d₆)：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 radical]-5-bromo-1H-indole oxalate, 1b, m.p.236-40 ℃.¹H NMR(DMSO-d₆)：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 radical]-2-methyl-1H-indole oxalate, 1c, m.p.205-8 ℃.¹H NMR(DMSO-d₆)：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 ℃,

¹H NMR(DMSO-d₆)：1.40(s，6H)；1.65-1.85(m，4H)；2.20(s，3H)；2.30(t，2H)；2.60(t，2H)；2.70-2.85(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℃.¹H NMR(DMSO-d₆)：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 ℃,

¹H NMR(DMSO-d₆)：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-pyridinyl]Ethyl radical]-1H-indole oxalate, 1g, m.p.200-4 deg.C¹H NMR(DMSO-d₆)：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 radical]-5-fluoro-1H-indole oxalate, 1c, m.p.224-26 ℃.¹H NMR(DMSO-d₆)：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 radical]-5-methoxy-1H-indole hemioxalate, 1i, mp 189-96 ℃.¹H NMR(DMSO-d₆)：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 radical]-5-methyl-1H-indole hemifumarate, 1j, mp 147-54 ℃.¹H NMR(DMSO-d₆)：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 radical]-6-methyl-1H-indole hemifumarate, 1k, mp 204-7 ℃.¹H NMR(DMSO-d₆)：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 radical]-1H-indole oxalate, 1l, mp 237-38 ℃.¹H NMR(DMSO-d₆)：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 radical]-1H-indole oxalate, 1m, mp 216-17 ℃.¹H NMR(DMSO-d₆)：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 radical]-1H-indole oxalate, 1n, mp 134-38 ℃.¹H NMR(DMSO-d₆): 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/of (%)：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 radical]-1H-indole oxalate, 1o, mp 205-7 ℃.¹H NMR(DMSO-d₆)：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 radical]-5-fluoro-1H-indole oxalate, 1p, mp 145-49 ℃.¹H NMR(DMSO-d⁶)：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- (benzothien-7-yl) piperazin-1-yl]Ethyl radical]-5-chloro-1H-indole oxalate, 1q, m.p.175.2-176.6 ℃.¹H NMR(DMSO-d₆)：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％(³⁷Cl))，396.1(MH+，2.8％(³⁵Cl))，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 ℃,

¹H NMR(CDCl₃)：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％(³⁵Cl))，414.5(MH+，63.％(³⁷Cl))，247.1(23.7％).

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

¹H NMR(CDCl₃)：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％(⁸¹Br)，456.3(MH+，23.9％(⁷⁹Br)，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 ℃,

¹H NMR(CDCl₃)：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％(³⁵Cl))，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 radical]-6-chloro-1H-indole, 1u, m.p.202-4 ℃,¹HNMR(DMSO-d₆)：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 ℃,

¹H NMR(DMSO-d₆)：2.70(s，2H)；3.10(t，2H)；3.20-3.70(m，4H)；3.80(s，2H)；4.25(s，4H)；5.85(s，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 ℃,

¹H NMR(DMSO-d₆)：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 hemifumarate, 1y, m.p.214-20 ℃,

¹H NMR(DMSO-d₆)：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 radical]-5-bromo-1H-indole oxalate, 1z, mp 185-94 ℃.¹H NMR(DMSO-d₆)：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 ℃,

¹H NMR(DMSO-d₆)：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 radical]-6-chloro-1H-indole hemifumarate, 1bb, m.p.245-50 ℃.¹H NMR(DMSO-d₆)：1.85-2.00(m，4H)；2.75(t，2H)；2.90(t，2H)；3.05(tt，1H)；3.25(d，2H)；6.55(s，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 radical]-5-fluoro-1H-indole oxalate, 1cc, m.p.191-94 ℃.¹H NMR(DMSO-d₆)：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 radical]-5-bromo-1H-indole oxalate, 1dd, m.p.153-57 ℃.¹H NMR(DMSO-d₆)：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.

Mixing 3- (2-bromoethyl) -1H-indole (1.5g) and 1- (1, 4-benzeneA mixture of oxadix-5-yl) piperazine (1.2g), potassium carbonate (1.9g) and potassium iodide (0.1g) was placed in methyl isobutyl ketone (100mL), refluxed for 16 hours, and purified by general separation with ethyl acetate to give an oil which was purified by flash chromatography (eluent: heptane/ethanol/ethyl acetate/triethylamine 15: 2: 1), fumarate salt was prepared from ethanol solution by addition of fumaric acid, and recrystallization from ethanol gave hemifumarate salt 2a (0.9 g). m.p.204-7 ℃,¹HNMR(DMSO-d₆)：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)；7.35(d，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 radical]-2, 3-dihydro-1H-indole, 2b, m.p.119-20 ℃.¹H NMR(DMSO-d₆)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.

A mixture of 2- (6-chloro-1H-indol-3-yl) acetic acid (2.0g), 1- (1, 4-benzodioxan-5-yl) piperazine (3.6g), N-dicyclohexylcarbodiimide (2.4g) and 4-dimethylaminopyridine (0.2g) was placed in dry tetrahydrofuran (100mL), stirring at room temperature under nitrogen atmosphere for 16h, filtering and general separation and purification with dichloromethane to obtain oil, this oil was 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 (2.0g) as an oil.

This oil was dissolved in tetrahydrofuran (25mL) and added dropwise to a suspension of lithium aluminium hydride (0.9g) in dry tetrahydrofuran (50mL) at room temperature, then after refluxing for 3h, the reaction was quenched with 2M aqueous sodium hydroxide and purified by general isolation to give the free base form of 3a as an oil (1.9g), and fumaric acid was added from the ethanol solution to give the hemifumarate salt of 3a (1.0 g). m.p.215-16 ℃,¹H NMR(DMSO-d₆)：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 hemifumarate, 3b, m.p.210-12 ℃,

¹H NMR(DMSO-d₆)：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 ℃,

¹H NMR(DMSO-d₆)：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) piperazin-1-yl]Ethyl radical]-1H-indole fumarate, 3d, m.p.224-25 ℃,¹H NMR(DMSO-d₆)：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 ℃,

¹H NMR(DMSO-d₆)：1.40(s，6H)；2.65-2.80(m，6H)；2.90(t，2H)；2.95(s，2H)；3.00-3.20(m，4H)；6.60(s，1H)；6.65(d，1H)；6.70(t，1H)；6.75(d，1H)；7.00(d，1H)；7.20(s，1H)；7.35(s，1H)；7.55(d，1H).MS m/z(％)：410(MH+，6％)，245(67％)，209(39％)，178(8％)，127(51％)，45(100％).

1- [2- [4- (1, 4-benzodioxan-5-yl) piperazin-1-yl]Ethyl radical]-6-chloro-1H-indole oxalate, 3f, m.p.234-35 ℃.¹H NMR(DMSO-d₆)：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 radical]-5-chloro-1H-indole oxalate, 3g, m.p.234-35 ℃.¹H NMR(DMSO-d₆)：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 radical]-5-fluoro-1H-indole oxalate, 3H, m.p.230-31 ℃.¹H NMR(DMSO-d₆)：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 radical]-1H-indole oxalate, 3i, m.p.225-29,¹HNMR(DMSO-d₆)：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 radical]-1H-indole oxalate, 3j, m.p.223-26 ℃.¹H NMR(DMSO-d₆)：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 salt, 4a.

Sodium borohydride (2X 2.9g, 1.5h apart) was reacted in portions with a solution of 2a (16g) trifluoroacetic acid (200mL) at room temperature, followed by stirring at room temperature for 2.5h, the reaction mixture was poured into ice, basified with aqueous sodium hydroxide solution and purified by general separation to give an oil which was purified by flash chromatography (eluent: heptane/ethyl acetate/ethanol/triethylamine 15: 2: 1) to give the title compound as a yellow oilBase, oxalate salt of the title compound crystals (0.9g) were obtained from the free base (1.4g) by adding oxalic acid to ethanol at m.p.145-50 ℃.¹H NMR(DMSO-d₆)：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-Benzodioxane-5-yl) piperazin-1-yl ] ethyl ] -2, 3-dihydro-5-fluoro-1H-indole hemioxalate, 4b, m.p.201-5 deg.C

¹H NMR(DMSO-d₆)：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 radical]-5-chloro-2, 3-dihydro-1H-indole oxalate, 4c, mp 153-57 ℃.¹H NMR(DMSO-d₆)：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 radical]-6-chloro-2, 3-dihydro-1H-indole oxalate, 4d, mp 185-88 ℃.¹H NMR(DMSO-d₆)：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.

At room temperature, a solution of 2a (1.0g) in dry tetrahydrofuran (50mL) was added dropwise to a solution of sodium hydride (60% in mineral oil, 0.14g) in tetrahydrofuran (25mL), stirred for 30min, then a solution of 1-bromobutane (0.85g) in dry tetrahydrofuran (10mL) was added dropwise, stirred for 1h and then purified by general separation with ethyl acetate, the resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine 15: 3: 2), oxalic acid was added to acetone to convert it to the title oxalate (0.7g), m.p.168-74 deg.C,¹H NMR(DMSO-d₆)：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 deg.C

¹H NMR(DMSO-d₆)：3.05(t，2H)；3.10-3.40(m，10H)；4.20(d，4H)；4.75(d，2H)；5.05(d，1H)；5.15(d，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)；7.25(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 radical]-1-propargyl-1H-indole oxalate, 5c, m.p.168-72 ℃.¹H NMR(DMSO-d₆)：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, 4a (1.5g) in dry tetrahydrofuran (50mL) was added dropwise to a solution of sodium hydride (60% in mineral oil, 0.21g) in tetrahydrofuran (25mL), stirred for 30min, then added dropwise with a solution of methyl iodide (0.75g) in dry tetrahydrofuran (25mL), stirred for 1h and then purified by general separation with ethyl acetate, the resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine 15: 3: 2), oxalic acid was added to acetone to convert it to the title oxalate (0.3g), m.p.155-65 deg.C,¹H NMR(DMSO-d₆)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-Benzodioxane-5-yl) piperazin-1-yl ] ethyl ] -1-benzyl-2, 3-dihydro-1H-indole oxalate, 6b, m.p.158-65 deg.C

¹H NMR(DMSO-d₆)：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 radical]-2, 3-dihydro-1H-indole oxalate, 6c, mp 133-36 ℃.¹H NMR(DMSO-d₆)：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 (2.0g), tetrabutylammonium hydrogen sulfate (0.21g), sodium hydroxide (1.0g) and dichloromethane (40mL) was stirred for 10min, then a solution of acetyl chloride (0.97g) in dichloromethane was added dropwise at room temperature, after stirring for 1h, water was added and general separation and purification was carried out, the resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/ethanol/triethylamine 17: 1), the resulting yellow oil was added with oxalic acid in acetone to convert to the title oxalate (0.75g), m.p.199-202 deg.C,¹H NMR(DMSO-d₆)：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 testing

Compounds of the invention para 5-HT_1AAffinity of the receptor is measured by binding to 5-HT of the radioligand_1AInhibition of the receptor was determined as described in the following assay: to pair³H-5-CT binds to human 5-HT_1AInhibition of receptors

According to this method, the 5-HT of a drug pair is determined in vitro_1AAgonists³H-5-carboxamido tryptamine(s) ((³H-5-CT) with cloned human 5-HT stably expressed in transfected HeLa cells (HA7)_1AInhibition of receptor binding (Fargin, a. et al, j. biol. chem., 1989, 264, 14848)). The assay was performed according to a modification of the method described in Harrington, m.a. et al, j.pharmacol.exp.ther., 1994, 268, 1089. In that³Human 5-HT in the presence of H-5-CT_1AThe receptors (40. mu.g of cell homogenate) were incubated at 37 ℃ for 15 minutes in 50mM Tris buffer, pH 7.7, and 10. mu.M metergoline was included to determine non-specific binding. The reaction was stopped by rapid filtration using a Unifilter GF/B filter on a Tomtec Cell Harvester (Tomtec Cell Harvester), the filters were counted on a Pakard Top Counter (Pakard Top Counter), and the results are shown in Table 1:

compound numbering	3Inhibition of H-5-CT binding IC50(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	21
		4d	14
Indolol*	100

TABLE 1^*Reference compound

The effect of the compounds of the invention on 5-hydroxytryptamine reuptake was also determined in the following assay: for the uptake of mouse brain synaptosomes³Inhibition of H-5-HT

Using this method, drug pairs are measured in vitro³Inhibitory ability of H-5-HT to accumulate in whole murine brain synaptosomes. The results were obtained according to the method described in Hyttel, j., psychopharma, 1978, 60, 13 and are shown in table 2:

compound numbering	5-hydroxytryptamine reuptake inhibition IC50(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
		Indolol*	0.29

TABLE 2^*Reference compound

5-HT for clones stably expressed in transfected HeLa cells (HA7)_1A5-HT of receptors, some of the compounds of the invention_1AAntagonistic Activity in vitro assays have been performed in which 5-HT is determined by measuring the inhibition of a compound's ability to antagonize 5-HT induction, to cause cyclic adenosine monophosphate (cAMP) accumulation by forskolin_1AAntagonistic activity was determined according to a modification of the method described by Pauwels, p.j. et al, biochem. pharmacol, 1993, 45, 375. The results obtained are shown in table 3:

compound numbering	3Inhibition of H-5-CT binding IC50(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
Indolol*	270

TABLE 3^*Reference compound

5-HT also for some compounds of the invention according to the assay described by Sanchez, C.et al, Eur.J.Pharmacol, 1996, 315, pp245_1AThe effect of the receptor was measured in vivo. In this method, antagonism of the test compound is determined by measuring the ability to inhibit 5-MeO-DMT-induced 5-HT syndrome.

The compounds of the present invention possess valuable 5-hydroxytryptamine reuptake inhibitor activity and are useful against 5-HT_1AAntagonistic activity of the receptor. The compounds of the invention are therefore useful in the treatment of 5-hydroxytryptamine reuptakeTaking inhibitory action or 5-HT_1ADiseases or disorders susceptible to receptor antagonism. Disorders susceptible to 5-hydroxytryptamine reuptake inhibition are well known in the art and include affective disorders such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, and obsessive compulsive disorder, among others.

As illustrated above, 5-HT of the Compounds of the invention_1AThe receptor antagonistic activity can counteract the negative feedback mechanism by the 5-hydroxytryptamine reuptake inhibition, and the modification of the 5-hydroxytryptamine reuptake inhibition of the compounds of the present invention is expected to be improved thereby.

The claimed compounds are therefore particularly useful as fast acting drugs for the treatment of depression, and these compounds may also be used for the treatment of depression which is not responsive to currently available SSRIs.

Pharmaceutical preparation

The pharmaceutical preparation of the present invention can be prepared according to a conventional method in the art, for example, tablets can be prepared by mixing the active ingredient with a commonly used adjuvant and/or diluent and then compressing the mixture into tablets on a general tableting machine. Examples of adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums, and the like. Other adjuvants or additives commonly used for coloring, flavoring, preserving, etc., may also be used, provided that they are compatible with the active ingredient.

Injectable solutions can be prepared by dissolving the active ingredient and the permissible additive solvents in a portion of injectable solvent, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling into suitable ampoules or vials. Any suitable additive commonly used in the art may be added. Such as enhancers, preservatives, antioxidants, and the like.

The pharmaceutical compositions of the invention or those prepared according to the invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups and the like, or parenterally by injection in the form of a solvent. To prepare these compositions, methods well known to those skilled in the art, and pharmaceutically acceptable carriers, diluents, excipients or other additives commonly employed in the art may be employed.

The compounds of the present invention are simply administered in a unit dosage form containing from about 0.01 to 1000mg of the compound, with the total daily dose of the active compound of the present invention generally ranging from 0.05 to 500mg, and most preferably ranging from 0.1 to 50 mg.

Claims (14)

1. Indole or 2, 3-indoline derivatives having formula (I) or acid addition salts thereof,

wherein:

x is-CR⁴R⁵-; and

y is-CR⁶R⁷-、-CR⁶R⁷-CR⁸R⁹-or-CR⁶＝CR⁷-; or

X and Y together form a group-CR⁴＝CR⁵-or-CR⁴＝CR⁵-CR⁶R⁷-；

Z is-O-or-S-;

w is N, C or CH;

a is a group selected from the group represented by the formulae (II) and (IV)

Wherein the dotted line refers to an optional bond;

R¹、R²、R³、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶and R¹⁷Each independently selected from hydrogen, halogen, C_1-4Alkyl radical, C_1-4An alkoxy group;

R⁴、R⁵、R⁶、R⁷、R⁸and R⁹Each independently selected from hydrogen and C_1-4An alkyl group; and

R¹¹selected from hydrogen, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, phenyl, naphthyl, phenyl-C_1-4Alkyl, naphthyl-C_1-4Alkyl, and-CO-C_1-4An alkyl group.

2. The compound according to claim 1, wherein Z is-O-.

3. The compound according to claim 1, wherein Z is-S-.

4. A compound according to claim 1, wherein a is a group of formula (II).

5. A compound according to claim 1, wherein a is a group of formula (IV).

6. A compound according to claim 2, wherein a is a group of formula (II).

7. A compound according to claim 2, wherein a is a group of formula (IV).

8. A compound according to claim 3, wherein a is a group of formula (II).

9. A compound according to claim 3, wherein a is a group of formula (IV).

10. A compound according to any one of claims 1-9, wherein R⁴、R⁵、R⁶、R⁷、R⁸And R⁹Selected 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-pyridinyl ] 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) 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,

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- (benzothien-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 an acid addition salt thereof.

12. A pharmaceutical composition comprising a 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 a compound according to claims 1 to 11 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament suitable for the treatment of 5-hydroxytryptamine reuptake inhibition or 5-HT_1AA disorder or disease susceptible to receptor antagonism.

14. The use of a compound according to claim 13, which is suitable for the treatment of affective disorders including depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive compulsive disorder.