UA59408C2 - indole and 2,3- dihydroindole derivatives, their preparation and application - Google Patents

Abstract

The present invention relates to indole and 2,3- dihydroindole derivatives having formula (I) any of its enantiometers 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-НT1A receptor antagonistic activity.

Description

Description of the invention

This invention relates to novel indole and 2,3-dihydroindole derivatives that are potent serotonin 2 reuptake inhibitors, pharmaceutical preparations containing these compounds, and their use in the treatment of disorders or diseases susceptible to serotonin reuptake inhibition. The compounds of the invention also have antagonistic activity to 5-HT.d-receptors and are considered particularly useful for the treatment of depression.

Selective serotonin (or 5-HT, i.e., 5-hydroxytryptamine) reuptake inhibitors (SSIs), such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram, are a major step forward in the treatment of depression because they have fewer and less serious side effects. compared to first-generation antidepressants (tricyclic compounds and non-selective monoamine oxidase (MAO) inhibitors). Side effects associated with first-generation antidepressants are such that they force some patients to abandon treatment.

ZK and all other antidepressants that are currently available have a serious drawback, which is that several weeks of treatment are required to achieve a therapeutic effect. Late onset of action is a significant problem, especially in the treatment of patients with major depression and suicidal potential. In addition, every third patient is not susceptible to ZZKI.

Electrophysiological experiments on rats showed that the urgent administration of Z5KI reduces the excitation of 5-HT neurons (serotonergic neurons) of the nucleus of the dorsal seam in the brain of rodents, while long-term treatment with Z5KI leads to the normalization of the excitatory activity of 5-HT neurons (Agrogeiyi5, | hey hey

Mashypup-Zsptiedereguz Agsp. Ripaptasoi. 1995, 352, 157; Sagivide, 5. E. ei aiYi, Vg. U. Rpagtasoi. 1995, 115, 1064; Sparyi, U. ei ai, Maopup-Zspitiedereguz Agsp. Riaptasoi 1986, 33, 342). In addition, it was found that the restoration of the excitatory activity of 5-HT neurons is associated with the desensitization of somatodendritic 5-HT/d autoreceptors (Ge Rotsi, E. ei aiYii, Mashypup-Zspitiedereguvz Agsy. RIaptasoi. 1995, 352, 141; p. 29 |pmetigli, V. ei ai, Yeshg. U. Rnagtasoi. 1944, 260, 243). at

It was suggested that the simultaneous introduction of Z5KI"5 and an agent that causes rapid desensitization or inhibition of the 5-HT 1d-receptor-mediated feedback mechanism leads to a rapid onset of antidepressant action (Apidavz, GR. ei and I. Ttepaz Meiygovzsi. 1966, 19, 378; Oe Mgu, 9., ek aiY, Ogyd Memuz Regzres. 1996, 9, 270). so 30 The effect of the combined administration of a compound that inhibits the reuptake of serotonin and an antagonist of the av 5-HT.d-receptor was evaluated in several studies (Ippi5, K.V. ei aiI., Eig. U. Rpagtasoi., 1987, 143, p 195-204 and Sagiside 5. E., Vg. U. Riiagtasoi. 1995, 115, p 1064- 1070, Wieg, R. ei aYi. Ttepav RVagptasso). in Si. 1994, 75, 220). In these studies, it was found that 5-HT 1d-receptor antagonists inhibit the decrease in Ge» excitation caused by emergency administration of reuptake inhibitors serotonin uptake. clinical trials. Significant improvement in patients' mood was reported within one week. In addition, it was shown that the combined administration of pindolol and Z5KI has a good effect on patients who were refractory to treatment with antidepressants available at that time. « du (Apidaz R. ei aYi., Agsy. Sep. Reuspiayu, 1994, 51, p 248-251 and Viieg, R. ei ai., 9. Siip. Rezusporpagtasoi). of 1995, 15, p 217-2220. c Several patent applications have been filed that include the use of a combination of a 5-HT/d-antagonist:c and a serotonin reuptake inhibitor for the treatment of depression (see European Patents EP-A2-687,472 | EP-A2-714,663).

European patent EP-A1-529 462 describes some derivatives of 1,4-benzodioxane, which have the general formula: -yl group and 0 is C Nord, where n is 1, 2, 3, 4, 5 or 6. o 20 It is noted that these compounds have serotonin-agonistic and serotonin-antagonistic activity, as well as reuptake inhibitory activity serotonin, which can be used as anxiolytics, antidepressants, antipsychotics, hypotensive and cerebroprotective agents.

US patent No. 5200943, Regtedaaga et al., describes related indoles, indazoles, 2-indolones and their 2,3-dihydro derivatives having the formula:

Uk (sno, MA-Ag in-- ri yu that i: 60 where X is -CH-, -CH»o-, -MH- or -CO- and Ag is ey b5 where ХУ is O or 5 , 7 are O, 5 or -CH»o- and n-1, 2 or 3.

These compounds are valuable 5-HT| ligands. d-receptor.

The task of the present invention is to provide compounds with strong serotonin reuptake inhibitory activity, as well as antagonistic properties to 5-HT 1d receptors. Such compounds can be used as fast-acting drugs for the treatment of affective disorders such as depression.

The next task of the present invention is to provide a pharmaceutical composition that includes the above-mentioned compounds as active ingredients.

The invention further includes, among others, the following compounds, alone or in combination.

An indole or 2,3-dihydroindole derivative having the formula: 70 cl

He

M / xu is any of its enantiomers or any mixture thereof, or its acid-addition salt, where X is -O-, -5- or -SV'K- and

In is-СВ5В7-, -СВ9в7-СВ8ве9- or -СВ5-СВ 7- or

X and X together form the group -"СВ7-СВ5- or -СВ7-СВ Свв, 7 is -О- or -5-;

MU is M, C or CH;

A is a group chosen from the group of formulas (I), (11) and (IM): (i (m) where the dashed line means an optional connection;

B", c, c c, B3 c, Bo, cv are each independently selected from hydrogen, halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, hydroxy, formyl, acyl, amino, alkylamino, dialkylamino, 09 acylamino, alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, (ab) nitro, cyano and aryl or arylalkyl, where aryl may be substituted with halogen, trifluoromethyl, alkoxy, hydroxy, amino, alkylamino, nitro and cyano;

B", b", 85, B", 8 and 29 are each independently selected from hydrogen and alkyl, and Ge)

B"! is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, acyl, and formyl.

According to one variant of the invention, 7 is -O- and other substituents are as defined above.

According to the second variant of the invention, 7 is -5- and other substituents are as defined above.

According to the third variant of the invention, A is a group of formula (II) and other substituents are as defined above.

According to the fourth variant of the invention, A is a group of formula (HER) and other substituents are as defined above. "

According to the fifth variant, A is a group of formula (IM) and other substituents are as defined above. with c Thus, according to a special variant of the invention. A is a group of formula (I) and 2 is -O-, A is a group of formula (PI) and 2 is -O-, and? A is a group of formula (IM) and 2 is -O-, A is a group of formula (II) and 2 is -5-,

A is a group of formula (PII) and 7 is -5- or A is a group of formula (IM) and 7 is -5-.

According to the following variant of the invention, B", B? 25, B", 8 and 29 are selected from hydrogen or methyl. c Examples of compounds according to the present invention are: 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|Iethyl|-5-chloro-1H-indole, and 3-(2- 14-(1,4-Benzodioxan-5-yl)piperazin-1-ylethyl|-5-bromo-1H-indole, "g" 3-(2-(4-(1,4-Benzodioxan-5-yl) Piperazin-1-yl|ethyl|-2-methyl-1H-indole, b-Chloro-3-(2-I4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1 -ylethylI|-1H-indole, o 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|Iethyl|-4-chloro-1H-indole, (Che b-Chlor -3-(2-(I4-(-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|iethylI|-1H-indole, b-Chlor-3-(2-I4 -(-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl|ethylI-1H-indole, 3-(2-(4-(1 ,4-Benzodioxan-5-yl)piperazin-1-yl|Hiethyl|-5-fluoro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-ylethyl) |-5-methoxy-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-methyl-1H-indole,

F, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-6-methyl-1H-indole, ko 3-(2-(4-(1, 4-Benzodioxan-5-yl)piperazin-1-ylethyl|-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-b-chloro -1H-indole, in 3-(2-I4-(5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-ylHyethylI|-1H-indole, b-Chlor-3 -(2-I4-(5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-ilyethylI|-1H-indole, b-Chlor-3-(2-I4-( 6-Chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl)piperazin-1-ilyethylI|-1H-indole, b-Chlor-3-(2-I4-(- 2,2-Dimethyl-2,3-dipdrobenzofuran-7-yl)piperazin-1-ylHyethylI|-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1- yl|ethyl|-4-methyl-1H-indole, 65 3-(2-I4-(7-Chloro-1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl)|-b-chloro- 1H-indole, 2-(2-(A-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole,

1-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-ylylethyl|-5-chloro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5) -yl)piperazin-1-yl|Iethyl|-6-chloro-2,3-dihydroindole, b-Chloro-3-(2-I4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-ylIIethylI| -1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydro-1-pyridyl|ethyl|-b-chloro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperidin-1-yl|Hyethyl|-b-chloro-1H-indole, 3-(2-(4-(1,4-Benzodioxin) -5-yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole, 3-(2-(4--Benzofuran-7-yl)piperazin-1-yl|ethyl|-6-chloro- 1H-indole and 3-(2-(4-(1,3-Benzodioxolan-4-yl)piperazin-1-ylethyl|-b-chloro-1H-indole, 70 b-Chlor-3-(2-I4- (6-Chloro-1,4-benzodioxan-5-yl)piperazin-1-yl-1H-indole, 5-Chloro-3-(2-14-(2,3-dihydrobenzofuran-7-yl)piperazin- 1-IlyethylI|-1H-indole, 3-(2-I4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl|Iethyl|-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-I4-(Benzothiopyran-8-yl)piperazin-1-ylylethyl|- 5-bromo-1H-indole, 3-(2-(4-(Benzothiopyran-8-yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole, 3-(2-(4-(1 ,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl|ethyl|-5-chloro-1H-indole, 3-(2-(4-(1,4-Benzodioxane- 5-yl)-1,2,3,6-tetrahydropyridin-1-yl|ethyl|-5-fluoro-1H-yindole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperidine -1-yl|Hiethyl|-b-chloro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperidin-1-yl|Hiethyl|-5-chloro-1H- indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperidin-1-yl|IIethyl|-5-fluoro-1H-indole, b-Chlor-3-(2-I4-( 2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-ylylethyl-1H-indole, 3-(2-(4-Benzofuran-7-yl)-1,2, 3,6-tetrahydropyridin-1-ylethyl|-b-chloro-1H-indole, 3-(2-(4-«-Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-ylethyl) |-5-bromo-1H-indole, sc 3-(2-(4--Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl|Iethyl|-5-fluoro-1H- Indole, 3-(2-(4--Benzofuran-7-yl)piperidin-1-yl|Iethyl|-b-chloro-1H-indole, and) 3-(2-(4--Benzofuran-7-yl) )piperidin-1-yl|1-ethyl|-5-fluoro-1H-indole, 3-(2-(14-(Benzofuran-7-yl)piperidin-1-ylethyl|-5-bromo-1 H-indole, 1-Acetyl-3-(2-(4-(1,4-benzodioxan-4-yl)piperazin-1-ylylethyl-2,3-dihydro-1H-indole, so zo 1-(2- (4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-fluoro-1H-yiindole, 1-(2-(4-(1,4-Benzodioxan-5-yl) piperazin-1-ylethyl|-b-chloro-1H-indole, o 1-(2-(4-(1,4-Benzodioxan-5-yl)piperazine-1-ylylethyl|-1H-indole, "g 1- (2-I4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-ylHyethylI|-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1- yl|Iethyl|-2,3-dihydro-1H-indole, me) 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|IethylI|-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-I4-(1,4-Benzodioxan-5-yl)piperazin-1-ylHyethyl|-1-butyl-1H-indole, 1-Allyl-3-(2-I4-(1,4 -benzodioxan-5-yl)piperazin-1-ylethylI|-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|Iethyl|-1 -propargyl- 1H-indole, « 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-2,3-dihydro-1-methyl-1H-indole, with c 3 -(2-I4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-1-benzyl-2,3-dihydro-1 H-indole, . 1-Allyl-3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-ilyethylI-2,3-dihydro-1H-indole, i?» 1-Acetyl-3-(2- 14-(1,4-benzodioxan-5-yl)piperazin-1-ylethyl I|-1H-indole, 3-(2-(4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl) |iethyl|-5-chloro-1H-indole, 3-(2-(4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl|iethyl|-b-chloro-1H-indole, c 3-(2-(4-(Benzo-1,4-dithian-5-yl)piperazin-1-yl|ethyl|-5-fluoro-1H-yiindole, 3-(2-(4-(Benzo- 1-thia-4-oxan-5-yl)piperazin-1-yl|ethyl|-5-chloro-1H-indole, ik 3-(2-(4-(Benzo-1-thia-4-oxan-5 -yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole and their 3-(2-(4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl| Ethyl|-5-fluoro-1H-indole, or their acid addition salts. o The invention also relates to a pharmaceutical composition containing a compound of formula (I) or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent.

According to the following variant, the invention relates to the use of a compound of formula (I) or its pharmaceutically acceptable acid addition salt for the preparation of a medicinal product for the treatment of disorders or diseases susceptible to inhibition of serotonin reuptake and antagonism of 5-HTd receptors.

F) In particular, the invention relates to the use of a compound according to the present invention or its pharmaceutically acceptable acid-addition salt for the preparation of a medicinal product for the treatment of affective disorders, such as depression, psychosis, anxiety disorders, which include generalized anxiety disorder, panic disorder and panic disorder obsessive compulsive disorder.

According to yet another variant, the present invention relates to a method of treating a disorder or disease of a living animal organism, including a human, susceptible to serotonin reuptake inhibition and 5-HT.d receptor antagonism, which comprises administering to such an animal organism, including a human, a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable acid additive 65 salt.

In particular, the invention relates to a method of treating affective disorders, such as depression, psychosis,

anxiety disorders, including generalized anxiety disorder, panic disorder and obsessive compulsive disorder, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof to a living animal organism, including a human, in need thereof.

Due to their combined action, 5-HT /d-receptor antagonism and inhibition of serotonin reuptake, the compounds of the invention are considered particularly useful as drugs for the treatment of depression with a rapid onset of action. The compounds may also be useful in the treatment of depression in patients refractory to treatment with currently available antidepressants.

It is believed that the compounds disclosed herein may be used in the treatment of depression requiring a rapid 7/0 onset of antidepressant action, or depression refractory to other antidepressants.

Halogen means fluorine, chlorine, bromine or iodine.

Alkyl means a straight or branched chain containing from one to four carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl and butyl.

Alkenyl means a chain of two to four carbon atoms containing one double bond, /5 Including, for example, ethenyl, 1-,2-propenyl, 2-,3-propenyl, etc.

Alkynyl means a chain of two to four carbon atoms containing one triple bond, including, for example, ethynyl, 1-,2-propynyl, 2,3-propynyl, etc.

Cycloalkyl means a cyclic alkyl containing from three to seven carbon atoms, including cyclopropyl, cyclobutyl, etc.

Alkoxy is -O-alkyl where alkyl is as defined above.

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

Alkylamino is -MN-alkyl and dialkylamino is -M-(alkyl)", where alkyl is as defined above.

Acylamino is -MH-acyl, where acyl is as defined above.

Alkoxycarbonylamino is alkyl-O-CO-MH-, where alkyl is as defined above. high school

Alkylaminocarbonylamino is alkyl- MH-CO-MH-, where alkyl is as defined above.

Dialkylaminocarbonylamino is (alkyl)U-MN-CO-MNU-, where alkyl is as defined above. and)

An aryl is an aromatic ring such as phenyl or naphthyl.

Arylalkyl is aryl-alkyl, where aryl and alkyl are as defined above.

Examples of organic acid additive salts according to the invention are maleic, fumaric, isobenzoic, ascorbic, succinic, oxalic, bis-methylsalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, lemon, gluconic, milky, apple, almond salts. , cinnamic, citraconic, aspartic, stearic, palmitic, ithaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline-acetic acids, as well as 8-halogentheophylline, for example, 8-bromoteophylline. Examples of inorganic acid-addition salts are salts of hydrogen chloride, hydrogen bromide, sulfuric, sulfamic, phosphoric, and nitric acids. Acid addition salts according to the invention are preferably pharmaceutically acceptable salts formed by non-toxic acids.

In addition, the compounds of this invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In general, for purposes of this invention, solvated forms are considered equivalent to unsolvated forms. "

Some of the compounds of this invention contain chiral centers, and such compounds exist in the form of isomers (ie, with enantiomers). The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

Racemic forms can be split into optical antipodes by known methods, for example, by dividing their ;" of diastereoisomeric salts with an optically active acid and isolation of an optically active amine compound by treatment with a base. Another method of splitting racemates into optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of this invention can thus be resolved into their optical antipodes, for example, by fractional crystallization of, for example, 4- or 1-tartrate, mandelate or camphorsulfonate) salts. The compounds of this invention can also be cleaved by the formation of se) diastereoisomeric derivatives. It is possible to use additional methods of splitting optical isomers known to specialists in this field. Such methods include those discussed in .). dadtsev, A. SoiIe( apa 5. UMiep "Epapiotegv, Kasetaiyez apa o Kezoishiopvg", duopp UMieu apa Bopvz, Mem Hogk (1981). c Optically active compounds can also be obtained from optically active starting materials.

The compounds of the invention can be obtained by one of the following methods, which include: a) reduction of carbonyl groups of compounds of the formula: c: c! you in

Gee! / m i- M M v v Ou xy v Y v 60 (M de B! - 83, 812, 1 - V, X, U, 7, MU and the dashed line are as defined above;

B) alkylation of an amine of the formula: b5 vk v i MM xx zu mu dev'-v3X,x,7, Mi dashed line are as defined above, with the reagent of the formula С-СНоСН»-А, where A is as defined above, and C is a suitable leaving group such as halogen, mesylate or tosylate; c) reductive alkylation of an amine of the formula: c? in' , -t vk M Pl

M / 5 xy (m) dev'-v3,X,x,7, Mi dashed line are as defined above, by the reagent of the formula B-CH 5-A, where A is as defined above, and B is a group or aldehyde , or carboxylic acid; a) restoration of the double bond of indoles of the formula: c? in

Z, and U

В М М-(сн5р-А с хи о (MI) where В! - VU, X, M, 7, M and the dashed line are as defined above, and A" is the group of formula (I), (11) or (IM), as indicated above, in which the dashed line is a bond for obtaining the corresponding derivatives e) 2,33-dihydroindole; e) reduction of the double bond of tetrahydropyridines of the formula: o vk in "I

But not)

IS c) hu (MI) de V! - BZ, A, X, Y and 7 are as defined above to obtain the corresponding piperidine derivatives; "

In the treatment of compounds of the general formula (I), where M is -СВ5У-СВ'- or where X and M together form a group SHE with -Св7-Св5- or -СВ7-СвР-СВ5В, a reducing agent for the reduction of a double bond bond, obtaining "thereby, the corresponding reduced cyclic system; " 9) reductive removal of one or more substituents B - BEZ or 2/2 - VE! in the compound of the general formula (I), in which one or more of the specified substituents are selected from chlorine, bromine or iodine;

P) dialkylation of an amine of the formula: 1 v v! se)

VZ MN sh» av) 20 kh

IR e) (o dev! - VZ, X, Y and 7 are as defined above by the reagent of the formula: v - o rik ko s (x) 60 where A is as defined above, and C is a suitable leaving group, such as a halogen, mesylate or tosylate; i) dialkylation of an amine of the formula: "H sha (xi) 65 where A - as defined above, with a reagent of the formula:

there is; ,-y- v M, t, xy (XY) 70 where v'- v, X, M, 7 and M are as defined above and b is a suitable leaving group such as halogen, mesylate or tosylate; or

І) alkylation or acylation of the nitrogen atom of indole compounds of the formula: c? И) ki (ХП) where В! - VU, X, Y, 7, M/ and the dashed line are as defined above, and A" is a group selected from the group of formula (II) or (IM) as shown above, in which B 1! is hydrogen, by alkylating or acylating reagents of the formula !-c, where o is a suitable leaving group such as halogen, mesylate or tosylate, and K 1 is as defined above but not hydrogen, whereupon the compounds of formula (I) are isolated as free base or in the form of its acid additive salt.

Recovery according to method a) is preferably carried out in an inert organic solvent, such as diethyl ether or tetrahydrofuran, in the presence of lithium aluminum hydride at the reflux temperature. (3

Starting compounds of formula (M) are usually prepared from reagents of formula (MI), 1,3-unsubstituted indoles and oxalyl chlorides, as described in the following examples.

Alkylation according to method B) is conveniently carried out in an inert organic solvent, such as alcohol or a ketone with a suitable boiling point, preferably in the presence of a base (potassium carbonate or triethylamine) at a reflux temperature of 30°C. (av)

Arylpiperazine derivatives of the formula (MI) are usually prepared from the corresponding arylamine by the method described

Mapyip ei ai., U. Mea. Spet., 1989, 32, 1052, or by the method described by Kgize et al., Kes. Tgam Sleep t

Rause-Vaz, 1988, 107, 303. Starting arylamines are either commercially available or well described in the literature. (at)

Derivatives of aryltetrahydropyridines of the formula (MI) are well known from the literature, compare US patent Mo2891066; yu

MesEimaip ei aiYi., 9. Ateg. Spent Zos. 1959, 72, 3134. It is convenient when the corresponding aryl bromide is lithiated by the subsequent addition of 1-benzyl-4-piperidone. Subsequent acid treatment will give

M-benzylaryltetrahydropyridine. The benzyl group can then be removed by catalytic hydrogenation or treatment with, for example, ethyl chloroformate to give the corresponding ethyl carbamate followed by acid or alkaline hydrolysis. The starting aryl bromides are either commercially available or well described in the literature. -at

Reagents of the formula 5-SNSNO-A are either commercially available or can be obtained by literature c methods, for example, from the corresponding acetic acid derivative by reduction to the 2-hydroxyethyl derivative and "c" conversion of the hydroxy group to the C group by conventional methods.

Reductive alkylation by method c) is carried out according to standard literature methods. The reaction can be carried out in two stages, that is, by combining (MI) and the reagent of the formula B-CH»-A according to standard methods of step 15 through the formation of carboxylic acid chloride or by using combined reagents, such as, for example, dicyclohexylcarbodiimide, followed by reduction of the resulting amide with lithium aluminum hydride. (se) The reaction can also be carried out according to the standard method in one vessel. Carboxylic acids or aldehydes 1" of the formula B-CH"-A are either commercially available or described in the literature.

Recovery of the double bond of indole according to method 4) is conveniently carried out by treatment with diborane or (c) 50 a precursor of diborane, such as a complex with trimethylamine or dimethyl sulfide, in an inert solvent, such as tetrahydrofuran or dioxane, at a temperature from 0"C to dephlegmation followed by hydrolysis of the intermediate borane derivative with an acid catalyst.Reduction can alternatively be carried out by treatment with sodium cyanoborohydride in trifluoroacetic acid.

Recovery of double bonds according to methods e) and U is very conveniently carried out by hydrogenation in alcohol in the presence of a catalyst of the noble metal type, such as, for example, platinum or palladium.

HF) Extraction of halogen substituents according to method 9) is conveniently carried out by catalytic hydrogenation in alcohol in the presence of a palladium catalyst or by treatment with ammonium formate in alcohol at elevated temperatures in the presence of a palladium catalyst.

Dialkylation of amines according to methods Пп) and Я) is very convenient to carry out at elevated temperatures in an inert 60 solvent, such as chlorobenzene, toluene, M-methylpyrrolidone, dimethylformamide or acetonitrile. The reaction can be carried out in the presence of a base such as, for example, potassium carbonate or triethylamine. The starting materials for methods j) and i) are commercially available or can be obtained from commercially available materials using conventional methods.

M-alkylation according to method |) is carried out in an inert solvent, such as, for example, alcohol or ketone, 65 at elevated temperatures in the presence of a base, for example, potassium carbonate or triethylamine, at reflux temperature. Alternatively, a phase transfer reagent can be used.

The following examples will further illustrate the invention. They should not, however, be construed as limiting the invention.

Examples

Halogen-, methyl- or methoxy-substituted indoles, which are used as described in example 1, are commercially available.

Substituted 2-(1-indolyl)acetic acids, which were used as described in example C, are prepared from the corresponding substituted indole and ethyl bromoacetate by conventional methods. 70 Substituted 3-(2-bromoethyl) indoles, which were used as described in example 2, are obtained from the corresponding ester of 2-(1-indolyl)acetic acid by reduction to alcohol with lithium aluminum hydride and subsequent treatment with the tetrabromomethane/triphenylphosphine system according to a standard literature method.

Arylpiperazines, which were used as described in examples 1, 2 and 3, are obtained from the corresponding arylamine according to the method described in Mapip et al., 9). Honey. Spent 32 (1989) 1052, or by the method described in Kgize ei ai., /5 Kebs. Tgah Sleep Rouse-Vaz 107 (1988) 303.

Starting arylamines are either commercially available or described in the literature as follows.

The synthesis of 5-amino-1,4-benzodioxane is described in ХОашиквзаз ей а, 7й. Oh Capt. Z (1967) 1121. Corresponding chlorinated derivatives are obtained in a similar way.

The synthesis of 7-amino-2,3-dihydrobenzofuran is described in US patent application Mo4302592.

The synthesis of 7-amino-benzofuran is described in Map M/i|pdaagaep ei a/i., U. Med. Spent 31 (1988) 1934.

The synthesis of 7-aminobenzo|b|giophene is described in Vozmea! ei a/!., U. Nei(egosusi. Spet. 5 (1968) 69. 7-amino-2,3-dimethylbenzofuran and the corresponding 5-chloro- and 5-methyl derivatives are obtained according to the description given in the German patent application Mo3526510. 4-aminobenzothiopyran is obtained according to the application for the European patent Mo79683. c 8-amino-6-chloro-2,2-dimethylbenzopyran was obtained by the usual nitration of b-chloro-2,2-dimethylbenzopyran (obtained according to the method of Voigopi et al., Apdemzh. Spet 90 (1978) 727) followed by reduction of the obtained i) 8-nitro derivative. In a similar way //7-amino-5-chloro-3,3-dimethylbenzofuran was obtained from 5-chloro-3,3-dimethylbenzofuran (obtained according to the European patent application Mo 7719 800206).

Corresponding dechloroderivatives were obtained by treatment with gaseous hydrogen in the presence of a catalyst of the noble metal type, according to standard methods.

Derivatives of aryltetrahydropyridines are known from the literature (compare, US patent Mo2891066 or MesE|/maip ei ai., o

U. Ateg. Spent boss. 72 (1959) 3134). More conveniently, the corresponding aryl bromide is lithiated with the subsequent addition of 1-benzyl-4-piperidone. Subsequent treatment with mineral acid or trifluoroacetic acid will give M-benzylaryltetrahydropyridine. The benzyl group can be removed by catalytic hydrogenation or treatment with, for example, ethyl chloroformate to form the corresponding ethyl carbamate followed by acid or alkaline hydrolysis. Corresponding piperidine derivatives can be obtained by reductive removal of the double bond of the tetrahydropyridine ring. All of these techniques are well known to specialists in this field. The starting aryl bromides are well described in the literature. 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, with c 4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridine, 4-(benzofuran-7-yl)-1,2,3 ,6-tetrahydropyridine, and the corresponding piperidines. ;" Melting points were determined on a Wyspi 5MP-20 instrument and were uncorrected. Mass spectra were obtained on the Otsatsgo M5-M5 system from Vioyesa MO, Rizopz Ipzigitepi. The M5-M5 system was connected to the modular system

HPLC HP 1050. A sample in a volume of 20-BOmcl (1Omkg/ml), dissolved in a mixture of 190 acetic acid in a mixture of 1:1 with acetonitrile/water, was introduced through an auto-injector for introducing samples at a leakage of ZOmcl/minute into the electrospray source. Spectra were obtained under two standard series of operating conditions. One series was performed to obtain information about the molecular mass (MH k) (21eV) and the second series was performed to obtain patterns of their fragmentation (7/OeV). The background was subtracted. The relative intensities of the ions were obtained from the fragmentation pattern. When 5p Intensity is not detected for a molecular ion (MN), this ion was present only in the first series of operating conditions. "H NMR spectra were recorded for all new compounds at 250 MHz on VgyKeg AC 250 or at 500 MHz on (Che Vgykeg OKX 500. Deuterated chloroform (99.895 0) or dimethyl sulfoxide (99.9956 0) were used as solvents. TMS (tetramethylsilane) was used as an internal reference standard Chemical shifts were expressed in parts per million For multiplicity of NMR signals

The following abbreviations are used: c-singlet, d-doublet, t-triplet, k-quartet, q-quintet, d-heptet, pd-double doublet, pt-double triplet, pk-double quartet, tt-triplet of triplets, m- multiplet iF) NMR signals corresponding to acidic protons are usually not included. The water content in crystalline compounds was determined by Karl Fischer titration. Standard working procedures refer to extraction with the specified organic solvent from suitable aqueous solutions, drying of the combined organic extracts (anhydrous Ma5OH bo or Ma»3O)), filtration and evaporation of the solvent in a vacuum. For column chromatography, silica gel of the Kiesei type was used! 60, 230-400 mesh according to AZTM.

Example 1

Oxalate 3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-yl|Iethyl|-5-chloro-1H-indole, Ta

A solution of 5-chloroindole (5.0g) in diethyl ether (1300ml) is cooled to 0"C in a nitrogen atmosphere, then a solution of oxalyl chloride (4.bg) in diethyl ether (20.0ml) is added dropwise. After stirring for 16 hours the crystalline product, 2-(5-chloro-1H-indol-3-yl)-2-oxoacetyl chloride, was collected by filtration (7.2g). A solution of the obtained 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 (7bml) at room temperature. The mixture was stirred for 16 hours followed by filtration and removal of the solvent in vacuo , giving crude 3-(2-14-(1,4-benzodioxan-5-yl)piperazin-1-yl|-1,2-dioxoethyl|-5-chloro-1H-indole as a solid product.

The specified product is dissolved in tetrahydrofuran (2 mL) and added dropwise to a suspension of lithium aluminum hydride (2.1 g) in tetrahydrofuran at room temperature under a nitrogen atmosphere. After boiling in a reflux flask for 3.5 hours, the reaction mixture is quenched with aqueous sodium hydroxide, and 7/0 is then treated with ethyl acetate in the standard manner. The obtained oil is purified by flash chromatography (eluent: heptane/ethanol/ethyl acetate/triethylamine, 15:2:2:1). The oxalate salt is obtained from a solution in acetone with the addition of oxalic acid and recrystallized from a mixture of methanol/tetrahydrofuran (1:5), obtaining 0.8 g of 1a. T. pl. 224-28"S. "H NMR (DMSO-AiV): 3.05 (t, 2H); 3.10-3.50 (m, 10Н); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.10 (d, 71Н); 7.30 (c, 1H); 7.40 (d, 1H); 7.65 (c, 1H); 11.15 (c, 1H). MS t/: 75 (Cho): 398 (MNK, 995), 233 (100905), 221 (2990), 218 (1995), 178 (59905).

Similarly, the following compounds are obtained:

Oxalate 3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-bromo-1H-indole, 15, m.p. 236-40C. "NN NMR ( DMSO-jv): 3.10 (t, 2H); 3.15-3.45 (m, 10H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6 .60 (d, 1); 6.75 (t, 1H); 7.20 (d, 1); 7.30 (s, 1H); 7.35 (d, 1H); 7.80 (s, 1H); 11.20 (c, 13). MS t/2 (90): 444 (MN 595), 442 (595), 233 (8095), 224 (2195), 222 (2290), 221 (2590) , 218 (2390), 190 (1990), 70 (10096).

Oxalate 3-(2-(4-(1,4-benzodioxan-5-yl)piperazin-1-ylethyl|-2-methyl-1H-indole, Ts, m.p. 2005-80. "H NMR (DMSO -yv): 2.35 (s, ЗН); 2.95-3.15 (m, 4Н); 3.15-3.45 (m, 8Н); 4.15-4.30 (m, 4Н ); 6.50 (d, 71H); 6.60 (d, 1H); 6.75 (t, 1); 6.95 (t, 1H); 7.00 (t, 18); 7.25 (d, 1H); 7.50 (d, 1H); 10.85 (s, 1H). MS t/" (Uv): 378 (MH, 5965), 233 (990), 221 (790), 218 (5905), 158 (10096). p

b-Chloro-3-(2-I4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-ylethyl I|-1H-indole fumarate, La, m.p. 232 -37"S. "H NMR (DMSO-yv): 1.40 (s, 6H); 1.65-1.85 (m, 4H); 2.20 (s, ЗН); 2.30 (t , 2H); 2.60 (t, 2H); 2.70-2.85 (m, ЗН); 2.90 (s, ЗН); 3.10-3.30 (m, 2Н); 6, 60 (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 t/ (96): 423 (MNK, 1196), 258 (100965), 178 (1490), 70 (4196).

Oxalate 3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-4-chloro-1H-indole, Te, m.p. 210-180. "NN NMR so (DMSO-α): 3.10-3.50 (m, 12H); 4.10-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1n); 7.00 (d, 18); is 7.05 (t, 1H); 7.30-7.40 (m, 2H); 11.40 (s, 1H). MS t/2 (uv): 398 (MN, 1090), 233 (100965), 221 (47965), 218 (1895), 180 (2595), 178 (8496). h

Oxalate b-chloro-3-(2-(4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|iethylI-1H-indole, Her, m.p. F3 190 -932С, "NN NMR (DMSO-ydv): 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, ju 1H); 7.55 (d, 1H); 11.00 (s , 1H). MS t/ (Uv): 409 (MN.k, 69), 244 (100965), 232 (995), 178 (1696).

b-chloro-3-(2-(4-(-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl|ethyl|-1H) oxalate -indole, 19, vol. "407. 200-4С, "H NMR (DMSO-yv): 1.40 (s, 6H); 2.70-2.80 (m, 2H); 3.00 (s , 2H); 3.15 (t, 2H); 3.30 (t, 2H); - about 3.35-3.50 (m, 2H); 3.85-4.00 (m, 2H); 6.35 (s, 1H); 6.85 (t, 1); 7.00 (d, 71H); 7.05-7.15 (m, 2H); 7.30 (s, s 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.15 (s, 1H). MS t/ (96): 407 (MNK, 295), 207 (8905), 180 (3390) , 178 (10096). ;» Oxalate of 3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-fluoro-1H-indole, 1H, m.p. 224-26"p. "H NMR (DMSO-iv): 3.10 (t, 2H); 3.10-3.50 (m, 10H); 4.15-4.35 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1); 6.75 (t, 1H); 8.95 (t, 1H); 7.30 (s, 1H); 7.30-7 .50 (m, 2H); 11.10 (s, 1H). MS t/2 (90): 382 (MH, 990), 233 (7890), 221 s (3090), 218 (2290), 190 ( 2090), 162 (9790), 70 (10090).

3-(2-(4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-methoxy-1H-indole semioxalate, Ti, m.p. 189-962, /H -o NMR (DMSO-α): 3.00 (t, 2H); 3.05-3.30 (m, 10H); 3.80 (s, ZN); 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 t/2 (U): 394 (MH, 795), 233 (7990), 218 (21905), 190 (2190 ), 174 (6190), 70 (100905). o Semifumarate 3-(2-(4-(1,4-benzodioxan-5-yl)piperazine-1-ylylethyl|-5-methyl-1H-indole, 1) , t. pl. 147-542S, /N

IR e) NMR (DMSO-α): 2.40 (s, ZN); 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 (c, 1H); 6.70 (t, 1H); 6.90 (d, 1H); 7.10 (c, 1H); 7.20 (d, 1H); 7.30 (c, 1H); 10.65 (c, 1H).

3-(2-(4-(1,4-benzodioxan-5-yl)piperazin-1-yl)ethyl I|-b-methyl-1H-indole semifumarate, TC, m.p. 204-727, /H

NMR (DMSO-ydv): 2.35 (s, ZN); 2.60-2.80 (m, 6H); 2.90 (t, 2H); 2.95-3.15 (m, 4H); 4.10-4.30 (m, 4H); 6.45 o (d, 1H); 6.50 (d, 1H); 6.60 (c, 1H); 6.70 (t, 1H); 6.80 (d, 1H); 7.05 (c, 1H); 7.10 (c, 1H); 7.40 (d, 1H); 10.60 (c, 1H).

b-Chloro-3-(2-I4-(7-chloro-1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-1H-indole oxalate, LI, m.p. 237-382С. /H o NMR (DMSO-iv): 3.00-3.15 (m, 2H); 3.15-3.40 (m, TON); 4.20 (s, 4H); 6.50 (d , 1H); 6.65 (d, 1H); 7.00 (pd, 1H); 7.25 (d, 1); 7.40 (d, 1H); 7.60 (d, 1H); 10 .95 (p, 13). MS t/2 (9Ub): 432 (MN, 390), 267 (4290), 252 60 (1296), 224 (1096), 178 (2796), 70 (10096).

b-Chloro-3-(2-I4-(6-chloro-1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-1H-indole oxalate, it, m.p. 216-170. /N

NMR (DMSO-γ): 2.60 (t, 2H); 2.85 (t, 2H); 3.10 (6.4H); 3.30 (c, 4H); 4.15-4.30 (m, 4H); 6.15 (d, 1H); 6.35 (d, 1H); 7.00 (south, 1H); 7.20 (d, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.95 (c, 1H). MS t/: (90): 432 (MNkyu, 290), 267 (4790), 252 (16905), 224 (1695), 178 (30905), 70 (10096). bo Oxalate B-chloro-3-(2-I(4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl|ethylI|-1H-indole, Tp, m.p. 134-380. / N

NMR (DMSO-γ): 2.65-2.80 (m, 6H); 2.90 (t, 2H); 3.00-3.25 (m, 6H); 4.50 (t, 2H); 6.60 (c, 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 (c, 1H); 11.05 (c, 1). MO t/ (U): 382 (MN), 217 (39965), 205 (1790), 178 (3890), 143 (1190), 70 (10090).

b-Chloro-3-(2-(4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl|ethyl|-1H-indole oxalate, 10, m.p. 205-77C. "IN NMR (DMSO-yv): 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 t/: (Ov): 382 (MN), 217 (3390), 202 (1890), 70 (100905).

Oxalate of 3-(2-I4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl|ethyl|-5-fluoro-1H-indole, Tr, m.p. 145-4920. /H 70 NMR (DMSO-α): 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, 1); 6.85 (d, 1H); 6.90 (t, 1H); 7.25 (s , 1H); 7.25-7.35 (m, 2H); 10.95 (s, 18). MS t/" (Ob): 366 (MNK, 4965), 217 (3195), 205 (1895) , 174 (1690), 162 (8190), 70 (10096).

Oxalate 3-(2-I4-(benzothiophen-7-yl)piperazin-1-yl)ethyl|-5-chloro-1H-indole, 14, m.p. 175.2-176.68С. "NN NMR (DMSO-4v): 310 (m, 2Н); 3.26 (m, 2Н); 3.38-3.36 (m, 6Н); 7.05 (d, 71Н); 7.09 (d, 71H); 7.33 (c, 1H); 75 7.40-7.37 (m, ЗН); 7.47 (d, 1H); 7.62 (d, 1H); 7.69 (s, 1H); 7.76 (d, 1H). MS t/: 398.1 (MH, 1.195 (97CI)), 396.1 (MH, 2.895 (25CI)), 230.9 (1005), 177.8 (5896), 69.8 (50.89). 3-(2-(4-(Benzothiopyran-8-yl)piperazin-1-yl|ethyl|-5-chloro-1H-indole, 1g, t. pl. 152-15320. "H NMR (SOCI3): 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 (c, 1H); 7.14 (d, 2H); 7.26 (d, 1H); 7.59 (s, 1H); 8.00 (s, 1H). MS t/» 412.3 (МН.к, 10095 (39СИ)), 414.5 (МН .yu, 6396 (ZSU), 247.1 (23.790). 3-(2-(4-(Benzothiopyran-8-yl)piperazin-1-yl)ethyl|-5-bromo-1H-indole, 15, t . pl. 166-167. "H NMR (SOCI3): 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 ... SU (79Vg), 232.0 (58.795), 1 43.1 (10096). Ge) 3-(2-(4-(Benzothiopyran-8-yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole, 1i, m.p. 178-17920. "H NMR (SOCIv8) : 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 . (63.690), 143.1 (100965). со 3о 3-(2-(4-(Benzofuran-7-yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole, i, m.pl . 202-42b. "H NMR (DMSO-iv): (α) 2.65-2.85 (m, 6Н); 2.90 (t, 2Н); 3.20-3.40 (m, 4Н ); 6.60 (s, 1H); 6.80 (d, 1H); 6.90 (d, 1H); 7.00 (d, tn); 7.05-7.30 (m, ЗН) ; 7.40 (d, 1); 7.55 (d, 1H); 7.95 (d, 1H); 11.00 (s, 18). MS t/2 (95): 380 (MH, 495 ), 215 h (10095), 200 (1290), 178 (3690), 172 (2090). Ge)

Oxalate of 3-(2-I4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-ylethyl|-b-chloro-1H-indole, i.e., m.p. 240-47"s. "H NMR (DMSO-iv): 2.70 (s, 2H); 310 (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, 71H); 7, 30 (s, 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.10 (s, 1H). MO t/z (96): 395 (MNK, 196), 178 (10096).

Oxalate b-chloro-3-(2-(4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-ylethyl|-1H-indole, 1x, « 4007. pl 211-1476. TN NMR (DMSO-iv): 2.75 (s, 2H); 3.05-3.15 (m, 2H); 3.20 (t, 2H); 3.25-3, 50 (m, 4H); 3.85 in s (s, 2H); 4.55 (t, 2H); 6.30 (s, 1); 6.85 |, 71); 7.00 (d, 1); 7.10 (d, 1); 7.15 (d, 1H); 7.30 (c, 1H);

Y 7.40 (c, 1H); 7.60 (d, 1H); 11.10 (c, 1H). MS p/z (965): 379 (MN Kk, 395), 178 (100905). a Semifumarate 3-(2-(4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-ilyethyl|-b-chloro-1H-indole, Lu, m.p. 214-200 . "H NMR (DMSO-aiv): 2.65 (s, 2H); 2.75-2.85 (m, 4H); 2.90-3.00 (m, 2H); 3.10-3 .50 (m, ЗН); 6.55 (s, 2Н); 6.90-7.00 (m, 2Н); 7.15-7.30 (m, ЗН); 7.35 (s, 1Н ); 7.50-7.60 (m, 2H); 8.00 (s, 1H); 10.90 (s, 1H). s MS ti/z (90): 377 (MN.k, 2596) , 178 (7390), 143 (2296). so Oxalate 3-(2-(4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl|ethyl|-5-bromo- 1H-indole, 17, m.p. 185-940. "NN NMR (DMSO-yv): 2.90 (s, 2H); 3.10-3.20 (m, 2H); 3.25-3 .55 (m, 4H); 3.95 (s, 2H); 6.60 (s, t. 1H); 7.00 (s, 1); 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). o 50. MS those / (95): 423 (МН. (ВГ), 2296), 421 (МН. (79ВГ), 2096), 224 (7095), 222 (7296), 143 (3396).

3-(2-(4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl|ethyl|-5-fluoro-1H-indole semioxalate, aa, m.p. so 176 -790. "NN NMR (DMSO-yv): 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, 1); 7.20-7.40 (m, 5H); 7.60 (d, 1H); 8.00 ( s, 1H); 11.00 (s, 18). MS t/: (9Uv):; 361 (MN, 12965), 162 (10096), 115 (13905).

3-(2-I(4-(benzofuran-7-yl)piperidin-1-yl|ethyl|-b-chloro-1H-indole semifumarate, 165, m.p. 245-500. "H NMR

HF) (DMSO-iv): 1.85-2.00 (m, 4H); 2.75 (t, 2H); 2.90 (t, 2H); 3.05 (tt, 1H); 3.25 (d, 2H); 6.55 (c, 2H); 6.95 (p. 18); 7.00 (d, 1); 7.15-7.25 (m, ZN); 7.40 (c, 1H); 7.50 (d, 1H); 7.55 (d, 1H); 8.00 (c, 1H); 10.95 (c, per 1H). MO t/z (90): 379 (MNK, 595), 214 (1096), 178 (2090), 143 (10096).

Oxalate of 3-(2-I4-(benzofuran-7-yl)piperidin-1-yl)ethyl|-5-fluoro-1H-indole, cc, m.pl. 191-940. 7"H NMR bo (DMSO-yv): 2.05-2.25 (m, 4H); 3.05-3.20 (m, 4H); 3.20-4.440 (m, ЗН); 3, 60-3.70 (m, 2H); 6.90-7.00 (m, 2H); 7.15-7.25 (m, 2H); 7.35-7.45 (m, ZN); 7.55 (d, 1H); 8.00 (s, 1H); 11.05 (s, 1H). MS t/2 (9Ub): 363 (MNK, 595), 214 (995), 161 (1095 ), 143 (24905).

Oxalate 3-(2-I4-(benzofuran-7-yl)piperidin-1-yl)ethyl|-5-bromo-1H-indole, yes, m.pl. 153-570. "H NMR be (DMSO-yv): 2.05-2.20 (m, 4H); 3.05-3.20 (m, 4H); 3.20-3.40 (m, ЗН); 3 .70 (d, 2H); 6.95 (s, 1H); 7.15-7.25 (m, ЗН); 7.30-7.40 (m, 2H); 7.55 (d, 1H ); 7.80 (s, 1H); 8.00 (s, 1H); 11.20 (s, 18). MS t/» (9): 423 (MNk,

Zbov), 224 (2790), 202 (45905), 143 (27905), 117 (18965).

Example 2

3-(2-I(4-(1,4-benzodioxan-5-yl)piperazin-1-yl)ethyl|-1H-indole semifumarate, 2a.

A mixture of 3-(2-bromoethyl)-1H-indole (1.5g), 1-(1,4-benzodioxan-5-yl)upiperazine (1.2g), potassium carbonate (1.9g) and potassium iodide (0 ,1 g) in methyl isobutyl ketone (10 Oml) was refluxed for 16 hours. Standard treatment with ethyl acetate gives an oil which is purified by flash chromatography (eluent: heptane/ethanol/ethyl acetate/triethylamine, 15:2:2:1). The fumarate salt is obtained from a solution in ethanol by adding fumaric acid. Recrystallization from ethanol gave semifumarate 2a (0.9g). T. pl. 204-7C, "H NMR 70 (DMSO-a): 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, 1); 7.10 (t, 1H); 7.20 (s, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.75 (s, 1H). MS t/z (Uv): 364 (MN, 596), 233 (5790), 218 (2195), 190 (1990), 144 (5490), 70 (100905). 1-Acetyl-3-( 2-(4-(1,4-benzodioxan-4-yl)piperazin-1-yl|ethyl|-2,3-dihydro-1H-indole, 265, m.p. 119-200. "H NMR (DMSO -4c): 1.90 (d, 1H); 2.20 (s, 4H); 2.95-3.30 (m, 11H); 3.40-3.50 (m, 4H); 3, 75-3.85 (m, 1H); 4.20-4.30 (m, 4H); 645 (pd, 1H); 6.55 (pd, 1H); 6.75 (t, 1H); 7 .00 (t, 1H); 7.20 (t, 1H); 7.30 (d, 1H); 8.0 (d, 1H).

MS ti/z (Uv): 408 (MNK, 5490), 233 (1790), 178 (100905), 119 (20905).

Example C

Semifumarate 3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-yl|Iethyl|-b-chloro-1H-indole, Za.

A mixture of 2-(6-chloro-1H-indol-3-yl)acetic acid (2.0g), 1-(1,4-benzodioxan-5-yl)piperazine (3.bg)

M,M-dicyclohexylcarbodiimide (2.4 g) and 4-dimethylaminopyridine (0.2 g) in dry tetrahydrofuran (10 Oml) were stirred for 16 hours at room temperature under a nitrogen atmosphere. Filtration and standard methylene chloride work-up gave an oil which was purified by flash chromatography (eluent: ethyl acetate/heptane/methanol, 16:3:1) to give 3-(2-14-(1,4-benzodioxan-5-yl)piperazin- 1-yl|-2-oxoethyl|-b-chloro-1H-indole in the form of oil (2.00 g).

The oil is dissolved in tetrahydrofuran (25 ml) and added dropwise to a suspension of lithium aluminum hydride (0.9 g) in dry tetrahydrofuran (5 ml) at room temperature, followed by refluxing for 3 hours. Quenching with 2M aqueous sodium hydroxide and standard work-up gave the free base Za as an oil (1.9g). The semi-fumarate salt, Za (1.0 g), is obtained from a solution in ethanol by adding fumaric acid. T. pl. 215-1676. IR nMR (DMSO-α): 2.60-2.85 (m, 6H); 2.85-2.95 (m, 2H); 2.95-3.10 (m, so

Academy of Sciences); 4.10-4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (c, 1H); 6.70 (t, 1H); 7.00 (south, 1H); 7.25 (d, 1H); at 7.40 (d, 1H); 7.55 (d, 1H); 10.95 (c, 1H). MS p/z (Uv): 398 (MNK, 1096), 234 (1395), 233 (100965), 178 (12960).

Similarly, the following compounds were obtained: -

Semifumarate / 3-(2-I4-(5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl|)ethylI-1H-indole, Zb, du) t.pl . 210-12"S. "H NMR (DMSO-iv): 1.40 (s, 6H); 2.55-2.75 (m, 6H); 2.80-3.00 (m, 4H); 3.05-3.20 (m, 4H); in (p. 13); 6.65 (d, 1); 6.80 (d, 1H); 6.95 (t, 1H); 7.05 (t, 1H); 7.15 (d, 71Н); 7.35 (d, tn); 7.55 (d, yuyu 1H); 10.70 (c, 1H). MS t/z (96): 410 (MNK, 18965), 281 (3290), 279 (10965), 144 (3996).

b-Chloro-3-(2-I(4-(5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl|Iethyl|-1H-indole semifumarate, Zs, mp. "130-320." NN NMR (DMSO-yv): 1.25 (s, 6H); 2.55-2.70 (m, 6H); 2.85 (t, 2H); 3 .00-3.20 (m, 4H); 4.25 (s, -o to 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 (s, 1H). MS t/ with (c): 446 (896), 444 (MN, 1190), 281 (3495), 280 (1696), 279 (10095), 178 (1596). :z» fumarate b-chloro-3-(2- I4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl)piperazin-1-ylethyl|-1H-indole, by, vol. 1L. 224-250. "H NMR (DMSO-yv): 1.30 (s, 6H); 1.70 (t, 2H); 2.60-2.75 (m, 8H); 2.90 (t, 2H); 2 .95-3.10 (m, sl 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.70 (d, 1H); 7.00 (d, 1H); 7 .20 (s, 1); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (s, 1H). MS t/z (Uv): 458 (MNK, 1190), 295 (3295), 293 (10096), 259 (1195), 178 (14905). is) b-chloro-3-(2-I4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) fumarate )piperazin-1-yl|ethyl|-1H-indole, Ze, m.p. O-jv): 1.40 (c, 6H); 2.65-2.80 (m, 6H); 2.90 (t, 2H); 2.95 (c, 2H); 3.00-3.20 (m,

NU 6.60 (c, 1H); 6.65 (d, 1H); 6.70 (t, 1H); 6.75 (d, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (c, 1H); 7.55 o (dD, 1H). MS ti/z (90): 410 (MN, 690), 245 (67905), 209 (39960), 178 (890), 127 (5190), 45 (100965). (Che Oxalate of 1-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole, ZE, m.p. 234-35"C. TN NMR (DMSO-iv): 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, ЗН); 6.70 (t, 1H); 7.05 (d, 1H); 7.45 (d, 1H); 7.55 (d, 1H) 7.70 (s, 1H). MS t/ (9c): 398 (MNK, 4590), 218 (100965), 178 (5096).

Oxalate 1-(2-(4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-chloro-1H-indole, 39, m.p. 234-35"C. " H NMR (DMSO-yv): 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, o 1H); 6.70 (t, 1H); 7.15 (d, 1H); 7.50 (s, 1H ); 7.55-7.65 (m, 2H). MO ti/z (Uv): 398 (MN kyu, 4490), 218 (10096), 178 (6295). where Oxalate 1-(2-I4- (1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-fluoro-1H-indole, ZY, m.p. 230-31 "S. "H NMR (DMSO-4v): 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, 60 1n); 6.75 (t, 1H); 7.00 (t, 2H); 7.30 (d, 1); 7.50 (s, 1H ); 7.50-7.55 (m, 1H). MS t/ (90): 382 (MNkyu, 7), 218 (6390), 162 (10096).

Oxalate 1-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl|-IN-indole, Z, m.p. 225-290. /7H NMR (DMSO-a, ): 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 t/ (in): 364 (MNK, 100965), 218 (8596), 146 (80905). bo Oxalate 1-(2-I4-(2,3-dihydrobenzofuran-7-yl)piperazin- 1-yl|ethyl|-1H-indole, 3), m.p. 223-260. "NN NMR

(DMSO-iv): 2.85 (c, 4H); 3.00 (t, 2H); 3.05-3.20 (m, 6H); 4.40 (t, 2H); 4.50 (t, 2H); 645 (d, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 7.00 (t, 1H); 7.15 (t, 1); 7.40 (d, 1H); 7.55 (pd, 2H). MS t/ (9Uv): 348 (MN, 3890), 231 (5090), 201 (10090), 174 (2590), 162 (4190), 146 (9895).

Example 4

3-(2-I(4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl)-2,3-dihydro-1H-indole sesquioxalate, 4a.

A solution of 2a (16g) in trifluoroacetic acid (200ml) is treated in portions with sodium borohydride (2 x 2.9g, interval 1.5 hours) at room temperature with subsequent stirring for 2.5 hours at room temperature. The reaction mixture was poured onto ice and made alkaline with aqueous sodium hydroxide, followed by 7/0 standard treatment. The resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/ethanol/triethylamine, 15:2:2:1), obtaining the title base as a yellow oil (13.8 g). The oxalate specified in the title, in the form of a crystalline material, is obtained from the free base (1.4 g) from ethanol by adding oxalic acid (0.9 g). T. pl. 145-500. "H NMR (DMSO-ydv): 1.75-1.85 (m, 1H); 2.05-2.15 (m, 1H); 2.95-3.30 (m, 12H); 3, 60 (t, 1); 4.20 (d, 4H); 6.50 (d, 2H); 6.60 (d, 2H); 6.75 (t, 1H); 75 8.95 (t, 1H); 7.10 (d, 1H). MS t/ (dv): 366 (MNK, 1095), 221 (1095), 178 (1490), 150 (2090), 118 (100905).

The following compounds were similarly obtained:

3-(2-I4-(1,4-benzodioxan-5-yl)piperazine-1-ylethyl I|-2,3-dihydro-b-fluoro-1H-indole semioxalate, 46, m. pl. 201-5" S. "NN NMR (DMSO-yv): 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, ЗН); 6.15-6.25 (m, 2H); 6.90 (d, 1H). MS t/2 (90): 384 (MN, 3296), 178 (28905), 150 20. (12905), 136 (10096).

Oxalate of 3-(2-14-(1,4-benzodioxan-5-yl)piperazin-1-ylethyl|-5-chloro-2,3-dihydro-1H-indole, 4c, m.p. 153-570. "H NMR (DMSO-iv): 1.70-1.85 (m, 1); 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, ЗН); 6.75 ( t.

Oxalate 3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-ylethyl|-b-chloro-2,3-dihydro-1H-indole, 44, m.p. ("U 185 -880. "NN NMR (DMSO-yv): 1.75-1.85 (m, MH); 2.00-2.10 (m, 71Н); 2.90-3.30 (m, 12Н) 3.60 (t, MH); 4.15-4.30 (m, 4H); 6.45 (s, 1); 6.50 (d, 1H); 6.55 (t, 2H); 6.75 (t, 1H); 7.05 (d, 1H). MS t/2 (Uv): 400 (MH, 1496), 221 (5290), 180 (2290), 152 (10095).

Example 5 so

Oxalate of 3-(2-(4-(1,4-benzodioxan-5-yl)piperazin-1-ylethyl|-1-butyl-1H-indole, ba o

A solution of 2a (1.0 g) in dry tetrahydrofuran (5 ml) was added dropwise to a suspension of sodium hydride (6090 in mineral oil, 0.14 g) in tetrahydrofuran (25 ml) at room temperature. After stirring for "

A solution of 1-bromobutane (0.85 g) in dry tetrahydrofuran (1 Oml) is added dropwise over 30 minutes. Shuffling Gee! for 1 hour followed by standard work-up to give an oil which is purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine, 15:3:2). The resulting oil is converted into an oxalate salt (0.7 g) with acetone by adding oxalic acid. T. pl. 168-747S. "H NMR (DMSO-yv): 0.90 (t, ZN); 1.25 (quin, 2H); 1.70 (quin, 2H); 3.05 (t, 2H); 3.15-340 (m, 8H); 4.10 (t, 2H); 4.15-4.30 (m, 4H); 6.55 (d, 71H); 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 t/" (96): 420 "ХК (МН, 3390), 233 (39905), 200 (10095), 158 (3695). З7З 70 The following compounds were similarly obtained: c Oxalate 1-allyl-3-(2- I(4-(1,4-benzodioxan-5-yl)piperazin-1-yl)ethyl|i!H-indole, 55, m.p. 187-900. "NN NMR:z" (DMSO-4v) : 3.05 (t, 2H); 3.10-3.40 (m, 70H); 420 (d, 4H); 4.75 (d, 2H); 505 (d, 1H); 5.15 ( d, 1); 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 pt/z (965): 404 ( MNK, 3896), 233 (3890), 184 (43905), 120 (2996). p 75 Oxalate 3-(2-I(4-(1,4-benzodioxan-5-yl)piperazin-1-yl)ethyl |-1-propargyl-1H-indole, 5c, mp 168-720. "YAN NMR (DMSO-4v): 3.00-3.30 (m, 12H); 3.40 (t, 1) ; 4.25 (d, 4H); 505 (d, 2H); 6.50 (d, 2H); 6.55 (d, 1H); 7.10 re) ( t, 18); 7.20 (t, 1H); 7.30 (c, 1H); 7.50 (d, 1H); 7.65 (d, 1H). MS t/ (9c): 402 (MN, 5295), 233 (50905), 182 iz (5790), 167 (10096).

Example 6 (in 3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-yl|ethyl)-2,3-dihydro-1-methyl-1H-indole oxalate, ba A solution of 4a (1.5g) in dry tetrahydrofuran (50ml) was added dropwise to a suspension of sodium hydride (6090 in mineral oil, 0.21g) in tetrahydrofuran (25ml) at room temperature. After stirring for

A solution of iodomethane (0.75 g) in dry tetrahydrofuran (25 ml) is added dropwise over 30 minutes. Stirring the mixture for 1 hour followed by standard ethyl acetate treatment gave an oil which was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine, 15:3:2). The obtained oil is converted into

F) the oxalate salt (0.3g) indicated in the title from acetone with the addition of oxalic acid. T. pl. 155-650. "NN NMR ka (DMSO-yv): 1.75-1.85 (m, 1H); 2.05-2.15 (m, 1); 2.70 (s, ZN); 2.90-3 .25 (m, 12H); 3.40 (t, 1H); 4.15-4.30 (m, 4H); 6.45-6.55 (m, ЗН); 6.65 (t, 1H ); 6.75 (t, 1); 7.05 (t, 1H); 7.10 (d, 18). MS t/l (9Uv): z80 (МНк, bo 470), 178 (496), 132 (5390).

The following compounds were similarly obtained:

Oxalate /3-(2-I(4-(1,4-benzodioxan-5-yl)piperazin-1-ylethyl|-1-benzyl-2,3-dihydro-1H-indole, bB, m.p. 158 -652. "H NMR (DMSO-ydv): 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); 65 70 (d, 1H); 7.30 (t, 1H); 7, 35 (p, 4H). MS t/ (90): 456 (MN kyu, 1995), 236 (2590), 178 (100905), 130 (1190).

Oxalate of 1-allyl-3-(2-I(4-(1,4-benzodioxan-5-yl)piperazine-1-ylethyl-2,3-dihydro-1H-indole), bs, m.p.

133-36S. "H NMR (DMSO-iv): 1.75-1.85 (m, 1H); 2.10-2.20 (m, 1H); 2.95-3.35 (m, 12H); 3, 50 (t, 1H); 3.65 (pd, 1H); 3.75 (pd, 1H); 4.25 (d, 4H); 5.15 (d, 71H); 5.30 (d, 1H ); 5.85-5.95 (m, 1H); 6.50 (d, 1H); 6.55 (d, 2H); 6.65 (t, 1); 6.75 (t, 1H) ; 7.00 (t, 1H); 7.10 (d, 1). MS t/2 (95): 406 (MN 1590), 178 (17895), 158 (2490), 130 (3190), 117 ( 2090).

Example 7

Oxalate of 1-acetyl-3-42-I(4-(1,4-benzodioxan-5-yl)/piperazine-1-ilyethyl|-1H-indole, 7a.

A mixture of 2a (2.0g), tetrabutylammonium hydrosulfate (0.2g), sodium hydroxide (1.0g) and methylene chloride (4Oml) was stirred for 10 minutes, then a solution of acetyl chloride (0.97g) in methylene chloride 70 was added dropwise at room temperature. After stirring for 1 hour, water is added with the following standard treatment. The resulting oil is purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine, 17:1:1). A yellow oil is obtained, which is converted into the oxalate salt indicated in the title (0.75 g) from acetone by adding oxalic acid. T. pl. 199-20276. IN nMR (DMSO-nMR): 2.65 (s, ZN); 3.05 (t, 2H); 3.15 (c, 10N); 4.20 (d, 2H); 425 (d, 2H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.30-7.40 (m, 2H); 7.70 (d, 1H); 75...7.80 (c, 1H); 8.35 (d, 1H). MS ti/z (U): 406 (MNyayu, 2890), 233 (44965); 218 (39905), 144 (100905).

Pharmacological test

The affinity of the compounds of the invention to 5-HT receptors is determined by measuring the inhibition of the binding of the radioactive ligand to 5-HT receptors, as described in the following test:

Inhibition of ZN-5-stypticin binding to human 5-HTd receptors.

This method is used to determine the inhibition by drugs of the binding of the 9-HT.d-agonist, ZH-5-carboxamidotryptamine (ZH-5-stypticin), to cloned human 5-HT/d receptors, stably expressed in Nea cells ( NA7) that underwent transfection (Ragoip, A. ei ai., U. Vioi. Spet., 1989, 264, 14848). The analysis is carried out as a modification of the method described in Nagtipdiop, M. A. ei ai., ..

RIagtasoi. Ex. TNeg., 1994, 268, 1098. Human 5-HTd receptors (4 µg of cell homogenate) are incubated for 15 minutes at 37"С in 5 µM Tris buffer at pH 7.7 in the presence of ZN-5-stypticin. Nonspecific binding o is determined by the inclusion of 10 µM metergoline.The reaction is completed by rapid filtration through filters

Opiineg SB/V on Topties cell harvester. The radioactivity of the filters is calculated in a counting device

Raskaga Thor. The obtained results are presented in Table 1

IJ

Ф зву " 79 Continuation of table 1 From p:" I ate sl

F g i 87 so ov o u 60

The compounds of the invention were also tested for their effects on serotonin reuptake in the following test:

Inhibition of entry of ZN-5-HT into synaptosomes of rat brain

The ability of drugs to inhibit the accumulation of ZN-5-HT in whole synaptosomes of the rat brain was determined using the specified method. The analysis is carried out as described in Nuieya, .).

Rezusporpagtasoiiodu, 1978, 60, 13. The obtained results are presented in table 2.

then in 1881 1,000,000 iv 2 cm o 5-HT.d-antagonistic activity of some compounds of the invention was evaluated in cloned (2,0) 5-HTide receptors, stably expressed in Naa (HA7) cells that were transfected. In the aforementioned test, 5-HT.d-antagonistic activity is assessed by measuring the ability of these compounds to counteract 5-HT-induced inhibition of forskolin-induced accumulation of CAMP. This analysis is carried out as a modification of the method described in Rashmzhmeev, R. u. ей айЙ.,, Viospet. RNagtasoi. 1993, 45, 375. The obtained Fo results are presented in Table 3.

Is) « 2 no; c g 2

F

F what is the current zone

Some of the compounds of the invention were also tested for their action on 5-HT chd-receptors in the analysis described in Zapspe, S. ei aiYi., Eig. U. Ripaptasoi!., 1996, 315, p 245. In this test, the antagonistic effect of the tested compounds was determined by measuring the ability of the tested compounds to inhibit

5-MeO-OTM-induced 5-HT syndrome.

The compounds of this invention have valuable activity as serotonin reuptake inhibitors and have an antagonistic effect on 5-HT.d-receptors. Therefore, the compounds of the invention are considered useful for the treatment of diseases and disorders susceptible to inhibition of serotonin reuptake and antagonistic activity to 5-HT.d-receptors. Diseases susceptible to serotonin reuptake inhibition are well known in the art and include affective disorders such as depression, psychosis, anxiety disorders including generalized anxiety disorder, panic disorder and obsessive compulsive disorder, etc.

As explained above, the 5-HT receptor antagonist activity of the compounds of the invention will counteract the negative feedback mechanism induced by inhibition of serotonin reuptake and, as a result, is expected to increase the effect of the compounds of the invention on the inhibitory activity of serotonin reuptake.

The compounds disclosed herein are therefore considered particularly useful in the treatment of depression as fast-acting drugs. These compounds may also be useful in the treatment of depressions refractory to currently available 5518 .

The ready-made pharmaceutical preparations of the invention can be prepared by conventional methods in this field. For example: tablets can be obtained by mixing the active ingredient with conventional adjuvants and/or diluents and then pressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, 20 lactose, gum and the like. Any other adjuvants or additives commonly used for this purpose, such as dyes, flavorings, preservatives, etc., may be used, provided they are compatible with the active ingredients.

Solutions for injections can be prepared by dissolving the active ingredient and, possibly, additives in the part of the solvent for injection, preferably in sterile water, adjusting the solution to the required volume, then sterilizing the solution and filling them into suitable ampoules or bottles. Any suitable additive commonly used in the art, such as tonicity agents, preservatives, antioxidants, etc., may be added.

The pharmaceutical compositions of this invention or the compositions produced according to this invention can be administered by any suitable route, for example, orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injections. Such compositions can be prepared by any method well known in the art, and any pharmaceutically acceptable carriers, diluents, excipients or other additives commonly used in the art can be used. at

It is convenient to introduce the compounds of the invention in the form of a unified dosage form containing the specified compounds in the amount of about 0.01 to 1000 mg. The total daily dose is usually in the range of about 0.05-500Omg and, more preferably, about 1 to 5Omg of the active compound of the invention. (22)

IC c)

Claims (19)

The formula of the invention 1. Derivatives of indole or 2,3-dihydroindole of the general formula (I) , (0) - - | Huh? i y Y vi M M-A--(SNgdotTA M / t ho 2 Ku, (Se) U ve any of their enantiomers or any of their mixtures, or their acid-addition salts, where o X --0 ., -8- or -СВ'В. and so in --свбВ"-, -свбв"-св8в8. or -"СВб-СВ - or Х and X together form the group -"СВ7-СВ5- or -СВ7- SV Svv, 7 --O- or -5-, MU - M, C or SN, A - a group selected from the group of formulas (II), (1) and (M) (F. viz de I) dz you (1 schu (M o dz dz I d'? her Y . y vo v: ; « v /Я , M v" Y / to / v"? / v! v" d !! в"! di! 65 where the dashed line means an optional bond, в", в, ВЗ в, ВЗ в в", в!b в!i each independently selected from hydrogen, halogen, trifluoromethyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, hydroxy, formyl, acyl, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, nitro and cyano, B", in", 85, B", 8 and 29 each independently selected from hydrogen and alkyl, and B" selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, acyl and formyl. 2. Compound according to claim 1, where 2 - -О-. Z. The compound according to claim 1, where 7 - -5-. 4. Compound according to claim 1, where A is a group of formula (I). 70 5. Compound according to claim 1, where A is a group of formula (I). 6. Compound according to claim 1, where A is a group of the formula (IM). 7. Compound according to claim 2, where A is a group of formula (II). 8. Compound according to claim 2, where A is a group of formula (I). 9. Compound according to claim 2, where A is a group of the formula (IM). 10. The compound according to item C, where A is the group of formula (I). 11. The compound according to item C, where A is the group of formula (1). 12. The compound according to paragraph Z, where A is the group of the formula (IM). 13. The compound according to claims 1-12, where 27, 85, 9, c", B8 and 29 are selected from hydrogen or methyl. 14. The compound according to claim 1, which is 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-chloro-1H-indole, 3-(2 -I4-(1,4-Benzodioxan-5-yl)piperazin-1-ylethyl|-5-bromo-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin- 1-yl|ethyl|-2-methyl-1H-indole, b-Chloro-3-(2-I4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-ylethylI |-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|Iethyl|-4-chloro-1H-indole, c b-Chlor-3-( 2-(I4-(-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl|iethylI|-1H-indole, o b-Chlor-3-(2-I4-(- 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl|ethylI-1H-indole, 3-(2-(4-(1,4- Benzodioxan-5-yl)piperazin-1-yl|Hyethyl|-5-fluoro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-ylhyethyl|-5 -methoxy-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-ylethyl|-1H-indole, (2,0) 3-(2-(4- (1,4-Benzodioxan-5-yl)piperazin-1-yl|Iethyl|-b-chloro-1H-indole, o 3-(2-I4-(5-Chloro-2,2-dimethyl-2,3 -dihydrobenzofuran-7-yl)piperazin-1-yl-1-ethyl-1-1H-indole, b-Chlor-3-(2-14-(5-chloro) p-3,3-dimethyp-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl-1H-indole, b-Chloro-3-(2-14-(6-chloro-2,2- Dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl)piperazin-1-ilyethylI|-1H-indole, Pho b-Chlor-3-(2-I4-(-2,2-dimethyl-2 ,3-dihydrobenzofuran-7-yl)piperazin-1-ylylethyl|-1H-indole, 3-(2-I4-(1,4-Benzodioxan-5-yl)piperazin-1-ylethyl|-5-methyl-1H -indole or iv) 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-6-methyl-1H-indole, b-Chloro-3-(2- 14-(6-Chloro-1,4-benzodioxan-5-yl)piperazin-1-yl-1H-indole, 5-Chloro-3-(2-14-(2,3-dihydrobenzofuran-7-yl) Piperazine-1-ylethyl1-1H-indole, 3-(2-14-(2,3-dihydrobenzofuran-7-yl)piperazine-1-ylethyl-5-fluoro-1H-indole, 3-(2- (4-(Benzothiophen-7-yl)piperazin-1-yl|Hiethyl|-5-chloro-1H-indole, ts 3-(2-(4-(Benzothiopyran-8-yl)piperazin-1-yl| iethyl|-5-chloro-1H-indole, h 3-(2-I4-(Benzothiopyran-8-yl)piperazin-1-ylethyl|-5-bromo-1H-indole, » 3-(2-(4- (Benzothiopyran-8-yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)-1,2,3, 6-tetrahydropyridin-1-yl|ethyl|-5-chloro-1H-i ndol, 3-(2-(4-(1,4-Benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl|ethyl|-5-fluoro-1H-yiindole, 1 3- (2-(4-(1,4-Benzodioxan-5-yl)piperidin-1-yl|Hyethyl|-b-chloro-1H-indole, o 3-(2-(4-(1,4-Benzodioxan- 5-yl)piperidin-1-yl|1-ethyl|-5-chloro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperidin-1-yl|1-ethyl|-5 -fluoro-1H-indole, 1-b-Chloro-3-(2-I4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-ylethyl1|-1H-indole , o 20 3-(2-(4--Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-ylethyl|-b-chloro-1H-indole, 3-(2-(4- "-Benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-ylethyl)|-5-bromo-1H-indole, so 3-(2-(4--Benzofuran-7-yl)- 1,2,3,6-tetrahydropyridin-1-yl|Iethyl|-5-fluoro-1H-indole, 3-(2-(4--Benzofuran-7-yl)piperidin-1-yl|Iethyl|-b -chloro-1H-indole, 3-(2-(4--Benzofuran-7-yl)piperidin-1-yl|Iethyl|-5-fluoro-1H-indole, 22 3-(2-(I4-(Benzofuran -7-yl)piperidin-1-ylethyl|-5-bromo-1H-indole, Ge! 1-Acetyl-3-(2-(4-(1,4-benzodioxan-4-yl)piperazin-1-ilyethylI-2,3-dihydro-1H-indole, 1-(2-(4-(1, 4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-5-fluoro-1H-yindole, where 1-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-ylethyl) |-b-chloro-1H-indole, 1-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-ilyethyl|-1H-indole, 60 1-(2-I4-(2 ,3-dihydrobenzofuran-7-yl)piperazin-1-ylethyll|-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|lethyl|-2, 3-dihydro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|IethylI|-2,3-dihydro-5-fluoro-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|Iethyl|-5-chloro-2,3-dihydro-1H-indole, 3-(2-I4-( 1,4-Benzodioxan-5-yl)piperazin-1-ylHyethyl|-1-butyl-1H-indole, 65 1-Allyl-3-(2-I4-(1,4-benzodioxan-5-yl)piperazin- 1-ylethyl|-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|Iethyl|-1-propargyl-1H-indole, 3-(2-(4-(1,4-Benzodioxan-5-yl)piperazin-1-yl|Iethyl|-2,3-dihydro-1-methyl-1H-indole, 3-(2-I4-( 1,4-Benzodioxan-5-yl)piperazin-1-yl|ethyl|-1-benzyl-2,3-dihydro-1H-indole, 1-Allyl-3-(2-I4-(1,4-benzodioxane) -5-yl)piperazin-1-ylethyl-2,3-dihydro-1H-indole, 1-Acetyl-3-(2-I4-(1,4-benzodioxan-5-yl)piperazin-1-ylethyl- 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|-b-chloro-1H-indole, 3-(2-(4-(Benzo-1,4-dithian-5-yl) )piperazin-1-yl|ethyl|-5-fluoro-1H-yiindole, 3-(2-(4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl|iethyl|- 5-chloro-1H-indole, 70 3-(2-(4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl|ethyl|-b-chloro-1H-indole and 3 -(2-(4-(Benzo-1-thia-4-oxan-5-yl)piperazin-1-yl|ethyl|-5-fluoro-1H-indole or their acid addition salts. 15. A pharmaceutical composition for the treatment of a disorder or disease susceptible to serotonin reuptake inhibition and 5-HT/d receptor antagonism, which contains an active ingredient and 7/5 at least one pharmaceutically acceptable carrier or diluent, which is characterized in that as an active ingredient it contains an indole derivative or 2,3-dihydroindole according to any of claims 1-14, or any of its enantiomers or any mixture thereof, or its pharmaceutically acceptable acid addition salt in a therapeutically effective amount. 16. Derivatives of indole or 2,3-dihydroindole according to any of claims 1-14, or any of their enantiomers or any mixture thereof, or their pharmaceutically acceptable acid addition salts for the preparation of a medicinal product for the treatment of a disorder or a disease susceptible to serotonin reuptake inhibition and 5-HT.d-receptor antagonism. 17. The compound of claim 16, wherein the drug is a drug for the treatment of affective disorders that include depression, psychosis, anxiety disorders, including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. 18. A method of treating a disorder or disease of a living animal organism, including a human, i) susceptible to inhibition of serotonin reuptake and antagonism of 5-HT 4d receptors, in which such a living animal organism, including a human, is administered a therapeutically effective amount of an indole derivative or 2, 3-dihydroindole according to any one of claims 1-14, or any of its enantiomers or any of their so-so buffers, or its pharmaceutically acceptable acid addition salt. 19. The method of treatment according to claim 18, characterized in that the disorder or disease is an affective disorder, including depression, psychosis, anxiety disorders, including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder. (22) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 9, 15.09.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. - with . and? 1 se) sh» o 50 IR e) F) ime) 60 b5