JP2003521443A - 4,5,6 and 7-indole and indoline derivatives, their preparation and their use - Google Patents

Abstract

(57) The present invention relates to a substituted 4,5,6 and 7-indole or indoline derivative represented by the formula (I) wherein A represents a compound represented by the formula (IIA), (IIB) or (IIC) (Wherein X, U, Y, R ^{3 to} R ¹² , Z, W, n and m are as defined above). About｝. This compound is an effective serotonin reuptake inhibitor and has 5-HT _1A receptor antagonist activity.

Description

Detailed Description of the Invention

The present invention relates to novel 4,5,6 and 7-indole and indoline derivatives which are effective serotonin reuptake absorption inhibitors, pharmaceutical preparations containing these compounds and their inhibition of serotonin reuptake. A method for use in treating a responsive disorder or disease. The compound of the present invention further has antagonistic activity at the 5-HT _1A receptor,
It is considered to be particularly effective in treating depression.

BACKGROUND Selective serotonin (or 5-HT) reuptake inhibitors (SSRI's), such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram represent a major step in the treatment of depression. is doing. These are first generation antidepressants (tricyclics and non-selective MAO inhibitors)
It has a smaller number of side effects and a lighter side effect. Side effects associated with first-generation antidepressants have led some patients to discontinue treatment.

SSRI's and all other currently available antidepressants have the serious drawback of having to produce a therapeutic effect after a few weeks of treatment. The slow onset of action is an important issue especially for the treatment of patients with severe depression and suicide potential. Furthermore, one in three patients does not respond to SSRI's.

Electrophysiological studies in rats have shown that acute administration of SSRIs reduces the attack of dorsal raphe nucleus 5-HT neurons in the rodent brain. However, SSRI
Continuous treatment with s leads to normalization of the firing activity of 5-HT neurons (Arborelius, L. et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1995,35).
2,157; Gartside, SE et al., Br. J. Pharmacol. 1995, 115, 1064; Chaput, Y. et al.
Naunyn-Schmiedeberg's Arch. Pharmacol. 1986, 33, 342).

Furthermore, restoration of the aggressive activity of 5-HT neurons has been shown to be linked to desensitization of somatic 5-HT _1A autoreceptors (Le Poul, E. et al., Naunyn-Schmied.
eberg's Arch Pnarmacol. 1995, 352, 141; Invernizzi, R. et al., Eur. J. Pharma
col. 1994, 260, 243). Co-administration of SSRI's with agents that cause rapid desensitization or inhibition of 5-HT _1A receptors that mediate feedback mechanisms is thought to lead to a rapid onset of antidepressant action. Tekita (Artigas, F. et al., Trends Neurosci. 1996, 19, 378; De Vry, J.,
Et al., Drug News Perspec. 1996, 9, 270). The effects of combined administration of compounds that inhibit serotonin reuptake and 5-HT _1A receptor antagonists have been evaluated in several studies (Innis, RB et al., Eur.
J. Pharmacol., 1987, 143, pp. 195-204 and Gartside, SE, Br. J. Pharma.
col. 1995, 115, pp. 1064-1070, Blier, P. et al., Trends Pharmacol. Sci. 1994,
15,220). From these studies, 5-HT _1A receptor agonists were found to inhibit the reduction in attack caused by acute administration of serotonin reuptake inhibitors.

Moreover, treatment with a combination of pindolol (the well-known 5-HT _1A receptor and β-adrenoceptor antagonist) and SSRI's has been evaluated in clinical trials.
Significant improvement in patient mood was reported within a week. Also, pindolol and SS
The combined administration of RI was found to have a positive effect in patients who did not respond to treatment with currently available antidepressants (Artigas F. et al., Arch. Gen. Psychiatry,
1994, 51, p 248-251 and Blier, P. et al., J. Clin. Psychopharmacol. 1995,
15, pp. 217-222).

Several patent applications have been filed covering the use of a combination of 5-HT _1A antagonists and serotonin reuptake inhibitors for the treatment of depression (European Patent Publication (EP-A2) No. 687472). No. and 714663).

[0008]   German patent application (DE) 4414113 describes the general formula

[0009]

[Chemical 13] (In the formula, n is 2 to 6, and the other substituents are as defined in the above-mentioned patent application specification.) A specific 4- (indol-3-yl) -1- (Indol-3-yl-alkylene) -piperidine is disclosed. It is claimed that the compounds described herein have serotonergic and serotonin antagonistic activity and affect DOPA-accumulation in the striatum and 5-HTP accumulation in the raphe (N. Raphe). ing. However, no biological data is disclosed in this patent specification.

[0010]   International Patent Application Publication (WO) 94/21626 describes the general formula

[0011]

[Chemical 14] Wherein R ² is heteroaryl and the other substituents are as defined in the above-mentioned patent application specification. ) Are described. Compounds that are structurally similar to the compounds of the present invention (R ² is 5-indolyl) are specifically mentioned in this patent specification. However, no data is disclosed. It is only mentioned in this patent specification that this compound produces a K _j value of less than 1.5 μM in the test for displacement of ³ H spiperone from the human dopamine D ₄ receptor subtype in the clonal cell line. The inventions described in WO 94/21627 and 94/21630 relate to similar compounds having an affinity for the human dopamine D ₄ receptor.

The invention described in International Patent Application Publication (WO) 95/33721 is
General formula

[0013]

[Chemical 15] (Wherein one of X and Y is CH ₂ , the other is CH ₂ , O or S, Ar is aryl or heteroaryl, for example 1-, 2- or 3-indolyl, And other substituents are as defined in the above patent application specification.
) 1- (indanmethyl, dihydrobenzofuranylmethyl, dihydrobenzothiophenylmethyl) -piperidine, -tetrahydro-pyridine or -piperazine derivative. These compounds are central 5-HT receptors, especially 5-
It interacts with the HT _1A and 5-HT _2A receptors. Some of these compounds are said to have a 5-HT reuptake inhibitory effect. OBJECT OF THE INVENTION The object of the present invention is to provide a compound having an effective serotonin reuptake inhibitory activity and an antagonistic property at the 5-HT _1A receptor. Such compounds are effective as fast-acting agents for the treatment of affective disorders such as depression.

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

[0015]   Summary of the invention   The invention consists in particular of the following requirements, alone or in combination: Formula (I)

[0016]

[Chemical 16] {Wherein, W is N, C, CH or COH, the dotted line indicates an arbitrary bond, A is the formula (IIA)

[0017]

[Chemical 17] Wherein X is CR ^1A , CHR ^1A , N, NR ^1B , O or S, where R ^1A is as defined below for R ^{3 to} R ⁹ and R ^1B is R ¹⁰ . As defined below, Y is CR ^2A , CHR ^2A , N, NR ^2B , O or S, wherein R ^2A is as defined below for R ³ to R ⁹ , And R ^2B is as defined below for R ¹⁰ and the dotted line indicates any bond, provided that X and Y are not O or S at the same time. ] Is a residue represented by: or A is of the formula (IIB)

[0018]

[Chemical 18] Wherein X is CR ^1A , CHR ^1A , N, NR ^1B , O or S, where R ^1A is as defined below for R ^{3 to} R ⁹ and R ^1B is R ¹⁰ . As defined below, U is C, CH, or N, and the dotted line indicates any bond. ] Or A is of the formula (IIC)

[0019]

[Chemical 19] Wherein U is C, CH, or N, Y is CR ^2A , CHR ^2A , N, NR ^2B , O or S, where R ^2A is defined below with respect to R ³ to R ^9. And R ^2B is as defined below for R ¹⁰ and the dotted line indicates an optional bond. ], N is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, 4, or 5, and Z is CH ₂ , O, S, CO, SO or SO ₂ , where n is 0, Z is CH ₂ , R ³ -R ⁹ and R ¹¹ -R ¹² are independently hydrogen, halogen, cyano, nitro, C _{1- 6} alk (/ en / yn) yl, C _1-6 alkoxy, C _1-6 alkylthio, human Dorokishi, hydroxy -C _1-6 alkyl, C _1-6 alkoxycarbonyl, C _3-8 cycloalk (g / Keny) yl, C _3-8 cycloal (ki / keni) yl-C _1-6 alk (ki / keni / quini) yl, C _1-6 alkylcarbonyl, phenylcarbonyl, halogen-substituted phenylcarbonyl, Trifluoromethyl, trifluoromethylsulfonyloxy, C _1-6 alkylsulfonyl, aryl and hetero Is selected from the group consisting of aryl and / or, two adjacent groups selected from R ^{3 to} R ⁹ may together form a methylenedioxy group, and / or 2 The adjacent groups R ^{7 to} R ⁹ may together form a cyclopentyl ring or a cyclohexyl ring group which may be substituted with one or more methyl groups, and / or R ³ -R ⁹ One of the groups is optionally a group --NR ¹³ R ¹⁴ (wherein R ¹³ is as defined below for R ¹⁰ and R ¹⁴ is hydrogen, C _1-6 ar (ki / keni / yn) yl, C _3-8 cycloalk (g / en) yl, C _3-8 cycloalk (g / en) yl -C _1-6 alk (/ en / yn) yl, aryl, heteroaryl, aryl -C _1-6 alkyl or heteroaryl -C _1-6 alkyl.), and, R ¹⁰ is hydrogen, C _1-6 alk (/ en / D) le, C _3-8 Shiruroaru (g / en) yl, C _3-8 Shiruroaru (g / en) yl -C _1-6 alk (/ en / yn) yl, aryl, heteroaryl, aryl -C _1-6 alkyl, heteroaryl-C _1-6 alkyl, acyl, thioacyl, C _1-6 alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl or heteroarylsulfonyl, R ¹⁵ VCO— (wherein V is a is O or S, R ¹⁵ is C _1-6 alk (/ en / yn) yl, C _3-8 cycloalk (g / en) yl, C _3-8 cycloalk (g / en) yl -C _{1 -6 is} ar (ki / keni / quini) yl, aryl or heteroaryl. ) Or where group R ¹⁶ R ¹⁷ NCO-- or R ¹⁶ R ¹⁷ NCS @ - (wherein, R ¹⁶ and R ¹⁷ are independently hydrogen, C _1-6 alk (/ en / yn) yl, C _3-8 cycloar (ki / keny) yl, C _3-8 cycloar (ki / keny) yl-C _1-6 ar (ki / keni / quini) yl, heteroaryl or aryl, or R ¹⁶ And R ¹⁷ together with the N-atom to which they are attached form pyrrolidinyl, piperidinyl, morpholinyl or perhydroazepine.). } The substituted 4,5,6 and 7-indole and indoline derivative represented by these or its acid addition salt.

[0020]   In a detailed embodiment, the compounds of the present invention have the formula where A is

[0021]

[Chemical 20] (Wherein R ³ -R ⁶ and the dotted line are as defined above), wherein A is a residue of formula (IIA).

[0022]   In a detailed embodiment, A is of formula

[0023]

[Chemical 21] (In the formula, R ³ -R ⁶ and the dotted line are as defined above.).

[0024] In another detailed embodiment, the invention provides compounds of formula (II)

[0025]

[Chemical formula 22] (In the formula, R ^{7 to} R ¹² , W, A, Z, n, m and the dotted line are as defined above.).

[0026] In a detailed embodiment Z is CH ₂ and n + m is 0, 1, 2, 3, 4,
5 or 6.

In another embodiment, the present invention provides compounds of formula (II) above, wherein A is of formula IIA above
Is the residue of. ) Concerning.

[0028]   In another detailed embodiment, the present invention provides a compound of formula (II) above, wherein A is of formula

[0029]

[Chemical formula 23] (Wherein R ³ -R ⁶ and the dotted line are as defined above). ] Regarding

[0030]   In a more detailed embodiment, the present invention provides compounds of the above formula (II)

[0031]

[Chemical formula 24] (Wherein R ³ -R ⁶ and the dotted line are as defined above). ] Regarding

[0032]   In a detailed embodiment, the compound of the invention is a compound wherein R³-R⁹And R ¹¹ -R¹²Is hydrogen, halogen, cyano, nitro, C_1-6Alkyl, C_1-6Arcoki
Ci, hydroxy, hydroxy-C_1-6Alkyl, C_1-6Alkoxycarbonyl and
And trifluoromethyl, R^TenIs hydrogen. ).

[0033]   In another detailed embodiment of the invention W is N.

Examples of the compound of the present invention include 1- (2- (3-benzofuranyl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (3-benzofuranylmethyl) -4- (1H-Indol-4-yl) piperazine, 1- (2- (5-fluoro-3-benzofuranyl) ethyl) -4- (1H-indole-4-yl)
Piperazine, 1- (4- (5-fluoro-3-benzofuranyl) -1-butyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (1H-indole-3-yl) ethyl ) -4- (1H-Indol-4-yl) piperazine, 1- (3- (1H-Indol-3-yl) -1-propyl) -4- (1H-Indol-4-yl) piperazine, 1- (4- (1H-indole-3-yl) -1-butyl) -4- (1H-indole-4-yl) piperazine, 1- (3- (5-fluoro-3-benzofuranyl) -1-propyl) -4- (1H- indole-4-
Yl) piperazine, 1- (2- (2-methyl-4,5,6,7-tetrafluoro-3-benzofuranyl) ethyl) -4- (1H
-Indole-4-yl) piperazine, 1- (2- (3-indazolyl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (6-chloro-3-indazolyl) ethyl ) -4- (1H-Indol-4-yl) piperazine, 1- (2- (7-cyano-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl)
) Piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl
) Piperazine, 1- (2- (4-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl
) Piperazine, 1- (2- (5-fluoro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (6-chloro-1H-indole -3-yl) ethyl) -4- (1H-indole-4-yl
) -1,2,3,6-Tetrahydropyridine 1- (2- (5-fluoro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl) -1,2,3 , 6-Tetrahydropyridin 1- (2- (7-bromo-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl
) Piperazine, 1- (1-allyl-1H-indol-4-yl) -4- (2- (6-chloro-1H-indol-3-yl)
) Ethyl) piperazine, 1- (1-allyl-1H-indol-4-yl) -4- (2- (5-fluoro-1H-indol-3-yl) ethyl) piperazine, 1- (1-benzyl- 1H-Indol-4-yl) -4- (2- (6-chloro-1H-indol-3-yl) ethyl) piperazine, 1- (1-benzyl-1H-indol-4-yl) -4- ( 2- (5-fluoro-1H-indole-3-
1- (1-benzyl-1H-indol-4-yl) -4- (2- (5-bromo-1H-indol-3-yl) ethyl) piperazine, 1- (2- ( 6-chloro-1H-indol-3-yl) ethyl) -4- (1-propargyl-1H-indol-4-yl) piperazine, 1- (2- (1H-indole-3-yl) ethyl) -4 -(1-Propargil-1H-Indole-4
-Yl) piperazine, 1- (2- (5-fluoro-1H-indol-3-yl) ethyl) -4- (1-propargyl-1H-indol-4-yl) piperazine, 1- (2- (5 -Bromo-1H-indol-3-yl) ethyl) -4- (1-propargyl-1H-indol-4-yl) piperazine, 1- (1-benzyl-1H-indol-4-yl) -4- ( 2- (1H-Indol-3-yl) piperazine, 1- (2- (5-Bromo-1H-indol-3-yl) ethyl) -4- (1H-Indol-5-yl) piperazine, 1- ( 2- (5-Chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-5-yl) piperazine, 1- (2- (5-Fluoro-1H-indol-3-yl) ethyl ) -4- (6-Hydroxymethyl
-1H-Indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (6-hydroxymethyl-1
H-indol-4-yl) piperazine, 1- (2- (5-bromo-1H-indol-3-yl) ethyl) -4- (6-hydroxymethyl-1
H-indol-4-yl) piperazine, 1- (3- (6-fluoro-1,2-benzisoxazol-3-yl) -1-propyl) -4- (1H
-(Indole-4-yl) piperazine, 1- (2- (1H-indole-3-yl) ethyl) -4- (6-methoxycarbonyl-1H-indol-4-yl) piperazine, 1- (2- ( 6-Chloro-1H-indol-3-yl) ethyl) -4- (6-methoxycarbonyl)
-1H-indol-4-yl) piperazine, 1- (2- (5-fluoro-3-benzofuranyl) ethyl) -4- (6-methoxycarbonyl-1
H-indol-4-yl) piperazine, 1- (5-fluoro-3-benzofuranylmethyl) -4- (1H-indole-4-yl) piperazine, 1- (3-cyano-1H-indole-4 -Yl) -4- (2- (1H-indole-3-yl) ethyl) piperazine, 1- (3-cyano-1H-indol-4-yl) -4- (2- (5-fluoro-3- Benzofuranyl
) Ethyl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (3-cyano-1H-indol-4-yl) piperazine, 1- (2- (3 -Benzofuranyl) ethyl) -4- (3-cyano-1H-indol-4-yl) piperazine, 1- (1H-indol-4-yl) -4- (2- (5-methyl-3-benzofuranyl) ethyl ) Piperazine, 1- (1H-indol-4-yl) -4- (2- (4-methyl-3-benzofuranyl) ethyl) piperazine, 1- (3- (5-fluoro-3-benzofuranyl) -1- Propyl) -4- (1H-indole-4-
Yl) -1,2,3,6-tetrahydropyridine, 1- (2- (5-chloro-3-benzofuranyl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (1H-indole -4-yl) -4- (2- (6-methyl-3-benzofuranyl) ethyl) piperazine, 1- (2- (7-chloro-3-benzofuranyl) ethyl) -4- (1H-indole-4- Yl) piperazine, 1- (2- (4-chloro-1H-indol-3-yl) ethyl) -4- (3-cyano-1H-indol-4-yl) piperazine, 1- (2- (6- Chloro-1H-indol-3-yl) -4- (1H-indole-4-yl) piperidine, 1- (2- (5-chloro-1H-indol-3-yl) ethyl) -4- (1H- Indole-4-yl) piperazine, 1- (2- (7-bromo-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (4- Chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (6-trifluoromethyl-1H-yne Dole-3-yl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (1H-indole-4-yl) -4- (2- (5-methyl-1H-indole-3- 1- (1H-Indol-4-yl) -4- (2- (6-methyl-1H-indole-3-yl) ethyl) piperazine, 1- (1H-indole-4-yl) ) -4- (2- (7-Methyl-1H-indol-3-yl) ethyl) piperazine, 1- (2- (4,5-dichloro-3-benzofuranyl) ethyl) -4- (1H-indole- 4-Il
) Piperazine, 1- (2- (5-bromo-3-benzofuranyl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (4-chloro-1H-indol-3-yl ) Ethyl) -4- (1H-indole-4-yl) piperidine, 4- (1H-indol-4-yl) -1- (2- (5-methyl-1H-indol-3-yl) ethyl) piperidine , 4- (1H-indol-4-yl) -1- (2- (1H-indol-3-yl) ethyl) piperidine, 1- (1H-indol-4-yl) -4- (3- (4 -Methyl-3-benzofuranyl) -1-propyl) piperazine, 4- (1H-indol-4-yl) -1- (3- (4-methyl-3-benzofuranyl) -1-propyl) piperidine, 1- ( 3- (4-chloro-3-benzofuranyl) -1-propyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (6-Chloro-1H-indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) eth ) -4- (6-Fluoro-1H-indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (6-cyano-1H-indole -4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (7-chloro-1H-indol-4-yl) piperazine, 1- (2- (6-Chloro-1H-indol-3-yl) ethyl) -4- (7-cyano-1H-indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ) Ethyl) -4- (2-cyano-1H-indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1H-indoline-4 -Yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-6-yl) piperazine, 1- (2- (6-chloro-1H -Indol-3-yl) ethyl) -4- (1H-indole-7-yl) piperazine or a pharmaceutically acceptable acid addition salt thereof.

The present invention also relates to pharmaceutical preparations containing a compound of the invention or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.

According to another aspect of the present invention, a compound of the present invention or a pharmaceutically acceptable compound thereof is used for the manufacture of a medicament for the treatment of a disorder or disease that responds to the inhibition of serotonin reuptake and the antagonism of 5-HT _1A receptors. The present invention relates to a method of using the acid addition salt.

As a final object, the present invention provides a serotonin reuptake characterized in that a therapeutically effective amount of the above compound or a pharmaceutically acceptable acid addition salt thereof is administered to an animal body including human. And a method for treating disorders or diseases of the living body of animals, including humans, which respond to inhibition of 5-HT _1A and disorders of 5-HT _1A receptor antagonism.

Diseases or disorders responsive to inhibition of serotonin reuptake and inhibition of antagonistic activity at the 5-HT _1A receptor include affective disorders such as depression, psychosis, anxiety disorders including general anxiety symptoms, panic disorders and Includes obsessive-compulsive disorder.

Because of this combination of 5-HT _1A receptor antagonism and serotonin reuptake inhibitory effect, the compounds of the present invention are effective as agents that initiate rapid action in the treatment of depression. These compounds are also effective in treating depression in patients who resist treatment with currently available antidepressants.

In the residues of formulas (IIA), (IIB) and (IIC), the presence and position of the double bond in the ring containing X, U and Y depends on the meaning of X, U and Y.

Thus, for the residue of formula (IIA), if the dotted line starting from X is a bond, then X is N or CR ^1A , and if the dotted line is not a bond, then X is CHR ^1A , N
If R ^1B , O or S and the dotted line starting from Y is a bond, then Y is N or CR ^1B , and if the dotted line is not a bond then Y is CHR ^2A , NR ^2B , O or S This is quite obvious to a person skilled in the art. Further, for the residue of formula (IIB), if the dotted line starting from X is a bond, then X
Is N or CR ^1A and if the dotted lines are not bonds, then X is CHR ^1A , NR ^1B ,
If O or S and the dotted line starting from U is a bond, then U is C,
And if the dotted line is not a bond, it is quite obvious to a person skilled in the art that Y is CH or N.

[0042] Finally, for the residue of formula (IIC), if the dotted line starting from U is a bond, then U is C, and if the dotted line is not a bond, then U is CH or N and starting from Y. It will be readily apparent to one skilled in the art that if the dotted line is a bond, Y is N or CR ^1A , and if the dotted line is not a bond, Y is CHCR ^2A , NR ^2B , O or S.

The same holds for W, if the dotted line starting from W is not a bond, then W is N, CH or COH.
And W is C if the dotted line is a bond.

[0044] C _1-6 alk (/ en / yn) yl term refers to C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl group. C _3-8 cycloalk (g / en) yl The term, C _3-8 - means or cycloalkenyl group - cycloalkyl.

The term “C _1-6 alkyl” refers to a straight or branched chain having 1 to 6 carbon atoms, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, Two
-Methyl-2-propyl and 2-methyl-1-propyl.

Similarly, C _2-6 alkenyl and C _2-6 alkynyl represent groups having 2 to 6 carbon atoms, each having one double bond and one triple bond, such as ethenyl, propenyl, butenyl, Includes, but is not limited to, ethynyl, propynyl and butynyl.

The terms “C _1-6 alkoxy”, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkylamino, C _1-6 alkylcarbonyl, hydroxy-C _1-6 alkyl, etc. C _1-6 alkyl represents a group as defined above.

The term “C _3-8 cycloalkyl” refers to a monocyclic or bicyclic carbocycle having 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl and the like. Not done.

The term “C _3-8 cycloalkenyl” refers to a monocyclic or bicyclic carbocycle having 3 to 8 carbon atoms and one double bond.

[0050]   The term "C_3-8Cycloal (ki / keni) ru-C_1-6Al (ki / keni / kini) ru ” ₆ At C_3-8Cycloal (ki / keni) and C_1-6Al (ki / keni / kini
) Le is as defined above.

The term “aryl” refers to a carbocyclic aromatic ring such as phenyl or naphthyl, especially phenyl. As used herein, aryl is halogen, cyano,
It may be substituted one or more times with nitro, trifluoromethyl, C _1-6 alkyl, hydroxy and C _1-6 alkoxy.

The term “heteroaryl” is a monocyclic or bicyclic heterocyclic residue such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl,
It means isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl, especially pyrimidyl, indolyl and thienyl.

As used herein, heteroaryl is halogen, cyano, nitro,
It may be substituted one or more times with trifluoromethyl, C _1-6 alkyl, hydroxy and C _1-6 alkoxy.

In aryl-C _1-6 alkyl and heteroaryl-C _1-6 alkyl, aryl, heteroaryl and C _1-6 alkyl are as defined above.

[0055]   Halogen means fluorine, chlorine, bromine or iodine.

As used herein, the term “acyl” refers to formyl-, C _1-6 ar (ki / keni / quinyl) carbonyl-, arylcarbonyl-, aryl-C _1-6 ar (ki / Keni / quini) rucarbonyl-, C _3-8 cycloar (ki / keni) rucarbonyl- or C _3-8 cycloar (ki / keni) ru-C _1-6 ar (ki / keni / quini) rucarbonyl- And the term "thioacyl" is the corresponding acyl group in which a carbonyl group is replaced with a thiocarbonyl group.

The acid addition salts of the present invention are preferably pharmaceutically acceptable salts of the compounds of the present invention with non-toxic acids. Examples of such organic acid addition salts include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylene salicylic 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, glycolic acid, p-amino-benzoic acid, glutamic acid, penzensulfonic acid and Theophylline acetic acid, as well as salts with 8-halotheophylline, such as 8-bromo-theophylline. Examples of such inorganic acid addition salts are salts with hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.

Furthermore, the compounds of the present invention can exist in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered to correspond to the unsolvated forms for the purposes of this invention.

The compounds of the present invention contain several chiral centers and such compounds are isomers (
That is, it exists in the form of a mirror image). The present invention includes all such isomers and all mixtures thereof, including racemic mixtures.

The optical antipodes of the racemic form are known, for example by separating their diastereomeric salts with an optically active acid and treating with a base to liberate the optically active amine compound. Can be divided into Another method of resolving racemates to their optical antipodes is based on chromatographic methods on an optically active matrix. The racemates of the present invention can also be resolved into their optical antipodes, for example by fractional crystallization of the d- or l- salt (tartrate, mandelate or cynosulfonate). The compounds of this invention can also be resolved by the formation of diastereomeric derivatives.

Other methods of optical isomer resolution known to those of skill in the art may be used. Such a method is
Jaques J. Collet A, and Wilen S, "Enantiomers, Racemates, and Resolutio
ns ", John Wiley and Sons, New York (1981).

Optical active compounds can also be prepared from optical active starting compounds.

[0063]   Finally, formula (I) includes all antipodal forms of the compounds of the invention.

[0064]   The compounds of this invention can be made by one of the following methods: a) Formula (III)

[0065]

[Chemical 25] (Wherein R ³ -R ¹² , W and the dotted line are as defined above) to reduce the carbonyl group of the compound; b) Formula (IV)

[0066]

[Chemical formula 26] (In the formula, R ⁷ -R ¹² , W and the dotted line are as defined above.) The amine of the formula (V) G- (CH ₂ ) _n -Z- (CH ₂ ) _m -A (V) ( Where A, Z, n and m are as defined and G is an agent with a suitable leaving group such as halogen, mesylate or tosylate.) C) Formula (IV)

[0067]

[Chemical 27] (In the formula, R ⁷ -R ¹² , W and the dotted line are as defined above.) The amine of formula (VI) E- (CH ₂ ) _n -Z- (CH ₂ ) _m -A (VI) ( Wherein A, Z, n and m are as defined above and E is either an aldehyde group or a carboxylic acid group.) Reductive alkylation with a reagent; d) Cyclic amine of formula (I) Corresponds to the double bond of the indole ring that is attached to the moiety
Reduction to obtain the 2,3-dihydroindole derivative; e) Formula (VII)

[0068]

[Chemical 28] (Wherein R ⁷ -R ¹² , A, Z, n, m and the dotted line are as defined above), the double bond of the tetrahydropyridine is reduced to give the corresponding piperidine derivative; f) General formula (VIII)

[0069]

[Chemical 29] (In the formula, R ⁷ -R ¹² , A, Z, W, n, m and the dotted line are as defined above.
) Reducing the amide group of the compound of g); g) reducing and eliminating one or more of the halogen substituents R ³ -R ⁹ or R ¹¹ -R ¹² in the compound of the general formula (I); One or more of these substituents is selected from chlorine, bromine or iodine; h) formula (IX)

[0070]

[Chemical 30] (Wherein R ⁷ -R ¹² and the dotted line are as defined above), the amine of formula (X)

[0071]

[Chemical 31] Where A, Z, n and m are as defined above and G is a suitable leaving group such as halogen, mesylate or tosylate. Dialkylate with a reagent of: i) Formula (XI) H ₂ N- (CH ₂ ) _n -Z- (CH ₂ ) _m -A (XI) (wherein A, Z, n and m are as defined above) is replaced with an amine of formula (XII),

[0072]

[Chemical 32] (Wherein R ⁷ -R ¹² , W and the dotted line are as defined above, G is a suitable leaving group, such as halogen, mesylate or tosylate) and dialkylated with a reagent; j) Formula A compound of (I), wherein R ¹⁰ is hydrogen, and / or X and / or
Y is NH. 1) alkylating, arylating or acylating one or two indole nitrogen atoms of the compound of formula (I); or k) the compound of formula (I) wherein R ⁷ , R ⁸ or R ⁹ is an alkoxycarbonyl group. ) Is reduced to give the corresponding hydroxymethyl group; the compound of formula (I) is then isolated as the free base or in the form of its acid addition salt.

The reduction of process a) is preferably carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran in the presence of lithium aluminum hydride at reflux temperature. The starting compounds of formula (III) are generally amines of formula (IV) and 3-chlorooxazolyl indole (Houben-Weyl, Methodender Organisch in the presence of a base such as triethylamine or potassium carbonate).
enChemie, VolE6B2, p. Manufactured as described in 1058).

The alkylation of method b) is carried out in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably at the reflux temperature in the presence of an organic or inorganic base (potassium carbonate or triethylamine). It is advantageous.

Indolylpiperazine derivatives of formula (IV) are described by Martin et al., J. Med. Chem., 1989.
, 32, 1052 or Kruse et al., Rec. Trav. Chim. Pays-Bas, 1988,
Advantageously, it is prepared from the corresponding arylamine according to the method described in 107, 303. Starting arylamines are either commercially available or are well documented in the literature.

Indolyltetrahydropyridine derivatives of the formula (IV) are known from the literature (French Patent No. 2458549). 1-protected 4,5,6 or 7-
Bromoindoles were lithiated with BuLi as outlined in the example below to give 1-
It is advantageous to add the protected 4-piperidone and then dehydrate. Starting bromoindoles are commercially available or are well documented in the literature. Reagents of formula (V) are commercially available or prepared by literature methods, eg by reducing the corresponding carboxylic acid derivative to the corresponding hydroxy derivative and converting the hydroxy group to group G in a conventional manner. can do.

The reductive alkylation of method c) is usually carried out by the methods described in the literature.
This reaction is carried out in two steps: the derivative of formula (IV) and the reagent of formula (VI) are coupled via a carboxylic acid chloride in a conventional manner or with a coupling agent such as dichlorohexylcarbodiimide, and then It is carried out by reducing the obtained amide with lithium aluminum hydride or alane. The reaction can also be carried out by conventional one-pot processing. Carboxylic acids or aldehydes of formula (VI) are commercially available or described in the literature.

The reduction of the indole double bond of method d) is carried out using a diborane or a diborane precursor, eg trimethylamine or a dimethyl sulfide complex, in an inert solvent, eg tetrahydrofuran or dioxane, at a temperature of ⁰ ° C. to reflux, Advantageously, the intermediate borane derivative is then hydrolyzed with an acid catalyst. Alternatively, the reduction may be carried out by treatment with sodium cyanoborohydride in trifluoroacetic acid.

The reduction of the double bond in method e) is most advantageously carried out by hydrogenation in alcohol in the presence of a noble metal catalyst such as platinum or palladium.

The reduction of the amide group in process f) is carried out with lithium aluminum hydride or alane in an inert organic solvent such as tetrahydrofuran or diethyl ether at a temperature of 0 ⁰ C to reflux.

Removal of the halogen substituents of method g) is carried out by catalytic hydrogenation in alcohols in the presence of palladium catalysts or by treatment with ammonium formate in alcohols at elevated temperature in the presence of palladium catalysts. Advantageously, this is done.

The dialkylation of the amines of processes h) and i) is most advantageously carried out in an inert solvent such as chlorobenzene, toluene, N-methylpyrrolidinone, dimethylformamide or acetonitrile at elevated temperature. This reaction may be carried out in the presence of a base such as potassium carbonate or triethylamine. The starting compounds for methods h and i) are either commercially available or can be prepared using conventional methods.

The indole N-alkylation or N-acylation is carried out in an inert solvent such as an alcohol or ketone at elevated temperature in the presence of a base such as potassium carbonate or triethylamine. Alternatively, a phase transfer reagent may be used. Most preferably the corresponding N-arylation is carried out under Ullmann conditions as described in the literature.

Most advantageously, the reduction of the alkoxycarbonyl group of method k) is carried out with lithium aluminum hydride or alane in an inert organic solvent such as tetrahydrofuran.

The invention is illustrated in more detail by the examples below. However, the invention is not limited to these examples.

EXAMPLES Melting points (Mp) were measured on a Buechi B-540 instrument and are uncorrected. Mass spectra were acquired using a Quattro MS-MS system from VG Biotech, Fisons Instruments or Pe.
Obtained with the Sciex API 150EX from rkin Elmer. Spectra are acquired using electrospray ionization at two standard sets of operating conditions. One is to obtain the molecular weight conformation (MH +) (20eV),
The other is set to trigger the fragmentation pattern (70-100eV). The background is subtracted. The relative intensity of the ions is obtained from the fragmentation pattern. If the intensity is not shown for the molecular ion (MH +), this ion is only present under the first installation of processing conditions. ¹ H NMR spectrum at 250 MHz
Record all new compounds on Bruker AC 250 or Bruker DRX500 instrument at 500 MHz. Deuterated chloroform (99.8% D) or dimethyl sulfoxide (
99.9% D) is used as solvent. Use TMS as internal reference standard. Chemical shifts are expressed in ppm-value. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qv = quintet, h = septet, dd = doublet. Double line, dt = double triplet, dq = double quartet, tt = triple triplet, m = multiple line, b = wide. The NMR signals corresponding to acidic protons are omitted to some extent. The water content in the crystalline compound is measured by Karl Fischer titration. A unique elemental analysis is obtained for all target compounds. Standard work-up refers to extraction from a suitable aqueous solution with the indicated organic solvent, drying of the combined organic extracts (anhydrous MgSO ₄ or Na ₂ SO ₄ ), filtration and evaporation under reduced pressure. ing. Column chromatography of type Kieselgel 60 against silica gel 60
Use ASTM 40-60 mesh.

Preparation of Intermediate A. 1- (1H-Indol-4-yl) piperazine: 1- (1H-Indol-4-yl) piperazine dinitrotoluene (25 g) is dissolved in DMSO (60 ml). Triton-
B (40% methanol solution, 6.4 ml) is added resulting in a dark purple solution. The mixture was heated to 30 ° C. and paraformaldehyde (4.5 g) in DSMO (40 ml).
) Is slowly added. After the addition, the mixture is heated to 65 ° C for 1.5 hours. Usual workup with ethyl acetate gives 2- (2,6-dinitrophenyl) ethanol (29 g) as a dark red oil. The oil (27 g) was replaced with ethanol (2
50 ml) and palladium on charcoal (3 g) is added. The mixture is reacted with hydrogen gas at 3 atmospheres on a Parr apparatus for 16 hours. Filtered,
The solvent was removed under reduced pressure to give 2- (2,6-diaminophenyl) ethanol (19.4 g) as a brown oil. The oil crystallizes on standing. A portion of this product (15.8 g) is dissolved in toluene (250 ml) and tris (triphenylphosphine) ruthenium (II) chloride (2.9 g) is added. Mix 8
Reflux in a water separator for hours and then remove the solvent under reduced pressure. The remaining reaction mixture is
Purification by flash chromatography (eluent: heptane / ethyl acetate 3: 1) gives 4-amino-1H-indole (7.6 g) as a crystalline solid.
The solid is dissolved in chlorobenzene (150 ml), bis (2-chloroethyl) amine hydrochloride (9 g) is added and then refluxed for 90 hours. Filtration gave a crystalline product (9.2 g) which was concentrated aqueous ammonia (50 ml) and ethyl acetate (2 g).
Heat in a mixture of 00 ml) for 15 minutes. The organic phase is separated, dried and evaporated to give the target compound (5.6g) as a crystalline substance.

The following piperazine is similarly prepared: 1- (6-methoxycarbonyl-1H-indol-4-yl) piperazine 1- (6-t-butyl-5-methoxy-1H-indol-4-yl) Piperazine 1- (6-t-butyl-7-methoxy-1H-indol-4-yl) piperazine 1- (6,7-dihydro-6,6,8,8-tetramethylcyclopent (g) -1H- Indole-4-
Yl) piperazine 1- (1H-indole-5-yl) piperazine This piperazine is prepared by converting the 5-aminoindole into bis (2- (1H-indole-4-yl) piperazine by the same procedure as described above. It is prepared by treatment with chloroethyl) amine.

1- (3-cyano-1H-indol-4-yl) piperazine Tetrahydrofuran (25 ml) and 1- (1H-indole in water (25 ml)
The mixture with -4-yl) piperazine hydrochloride (1 g) and potassium carbonate (2.9 g) was stirred for 15 minutes and the di-t-butyl dicarbonate (2 g) was added to a 1: 1 mixture of tetrahydrofuran and water (20 ml). A solution having 0.3 g) is added. The mixture is stirred at 50 ° C. for 16 hours. Usual work up with ethyl acetate gives 1-t-butoxycarbonyl-4- (1H-indole-4-yl) piperazine (1.1 g) as heavy oil.

The oil is dissolved in acetonitrile (50 ml) and chlorosulfonyl isocyanate (1 ml) is added dropwise at -20 ° C. Dimethylformamide (5
ml) is kept cold during the dropwise addition. Finally the mixture is stirred for 30 minutes at 0 ° C. Aqueous sodium carbonate solution (30 ml) is added and the mixture is stirred for 30 minutes. The aqueous phase is separated, dried and concentrated. The resulting oil was purified by column chromatography (eluent: ethyl acetate / heptane / methanol 16: 3: 1) to give 1-t-butoxycarbonyl-4- (3-cyano-1H-indole) as a yellow oil.
-4-yl) Piperazine (0.5 g) is obtained.

The oil is dissolved in methanol (2 ml) and ethereal hydrochloric acid (20 ml) is added. Stir for 2 hours and filter to obtain the target compound (0.34 g) as a crystalline substance.

1- (1-allyl-1H-indol-4-yl) piperazine 1-t-butoxycarbonyl-4- (1H-indole-4-yl) piperazine (prepared as above) in tetrahydrofuran (50 ml) Solution containing sodium hydride (0.7 g, 60% mineral oil suspension) in tetrahydrofuran (150 ml).
Is added dropwise at room temperature to the suspension with. After stirring for a further 30 minutes, a solution of allyl bromide (3.5 ml) in tetrahydrofuran (50 ml) is added dropwise. After stirring for 48 hours, the mixture is poured onto ice water and the usual workup with ethyl acetate gives an oil. This oil was purified by flash chromatography (eluent: heptane / ethyl acetate 85:15) to give 1-t-butoxycarbonyl-4- (1-
Allyl-1H-indol-4-yl) piperazine (3.2 g) is obtained.

The oil was dissolved in methanol (15 ml) and diethyl ether (100 ml)
A saturated solution with HCl in is added. After stirring for 16 hours at room temperature, the resulting colorless crystals (2.5 g) consisting of the hydrochloride salt of the target compound are collected by filtration and dried under reduced pressure.

The following piperazine is similarly prepared: 1- (1-benzyl-1H-indol-4-yl) piperazine 1- (1-propargyl-1H-indol-4-yl) piperazine B.I. 4- (1H-Indol-4-yl) -1,2,3,6-tetrahydropyridine: A solution of 4-bromo-1H-indole (36g) in dimethylformamide (80ml) in dimethylformamide (200ml). At 20 ° C. with a suspension of NaH (60% mineral oil solution, 6.9 g). After stirring for 30 minutes, the mixture is cooled to −10 ° C., treated with t-butyldimethylsilyl chloride (38 g) in small portions and then stirred for 1 hour at room temperature. Usual workup with ethyl acetate gave an oil which was purified by flash chromatography to give 4-bromo-1- (t-butyldimethylsilyl) -1H-indole (38 g as crystalline compound. ) Is obtained.

The product is dissolved in dry tetrahydrofuran (500 ml), cooled to −78 ° C. and treated portionwise with 1.6 MBuLi (154 ml) in hexane. Three
After stirring for 0 minutes at −78 ° C., a solution of 1-carbethoxy-4-piperidine (18.2 ml) in tetrahydrofuran (200 ml) was added in small portions, and the temperature was gradually raised to room temperature for 16 hours. Stir. Usual work up with ethyl acetate gave an oil which was flash chromatographed (eluent:
Purified with heptane / ethyl acetate / triethylamine 6: 3: 1) to give 1- (t-butyldimethylsilyl) -4- (1-carbethoxy-4-hydroxy-4-) as a crystalline compound.
Piperidinyl) -1H-indole (20.5 g) is obtained.

This product was treated with tritrifluoroacetic acid (methylene chloride (250 ml)
15 ml) at 0 ° C. for 20-30 minutes [reaction followed by thin layer chromatographic separation on silica gel (eluent: ethyl acetate / heptane / triethylamine 1
0: 9: 1)] 2M sodium hydroxide was added, the organic phase was separated, dried and the solvent was removed under reduced pressure to give an oil which was flash chromatographed (TLC).
With an eluent as described above), and 1-carbethoxy-4- (1H-indole-4-yl) -1,2,3,6-tetrahydropyridine (9.1 g as a crystalline compound)
) Is obtained.

After the usual post-treatment, ethanol (150 ml) was used with a small amount of water (2 ml) for 3 days.
In a refluxing treatment with potassium hydroxide (5 g) in
4.5 g) are obtained.

C. 5-Fluorobenzofuran-3-acetic acid: 5-fluorobenzofuran-3-carboxylic acid (56 ml in methanol (600 ml)
g) and a solution of hydrogen chloride gas in saturated ether solution (300 ml) are stirred for 16 hours at room temperature. Further ethereal HCl (300 ml) is added and stirred for 24 hours. Concentrate under reduced pressure to give a dark crystalline compound, methyl 5-fluorobenzofuran-3.
A carboxylate (58 g) is obtained.

Lithium aluminum hydride (15 g) was suspended in tetrahydrofuran (400 ml) under a nitrogen atmosphere, and methyl 5-- was added to tetrahydrofuran (300 ml).
A solution of fluorobenzofuran-3-carboxylate (58 g) is added in portions. During the addition, the temperature rises to 55 ° C. After stirring for 2 hours, the reaction was carried out with water (
30 ml), 15% sodium hydroxide (15 ml), then water (75 ml). Further tetrahydrofuran (500 ml) is added and the mixture is stirred for 1 hour. The mixture is filtered and the precipitate is extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L). Concentrate the combined organic phases in vacuo an oil was obtained which was purified by flash chromatography on silica gel (eluent: methylene chloride / 25% NH ₃ water 99: 1) to subjecting. The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g), crystallizes on standing. 5-fluorobenzofuran-3-ylmethanol (in methylene chloride (250 ml)
14 g) with 5 drops of dimethylformamide and thionyl chloride (28 m
Continuously process in l). After stirring for 16 hours at room temperature, the reaction is concentrated under reduced pressure to give 3-chloromethyl-5-fluorobenzofuran (19.4 g) as an oil.

A suspension of sodium cyanide (10 g) in dimethylsulfoxide (150 ml) was heated to 80 ° C. then 3-fold in dimethylsulfoxide (50 ml).
A solution with chloromethyl-5-fluorobenzofuran (10 g) is added rapidly. The mixture is kept at 80 ° C. for 30 minutes and then poured on ice. Normal work up with ethyl acetate gave the dark crystalline compound, 5-fluorobenzofuran-3-ylacetonitrile (
8.8 g) are obtained.

A solution of 5-fluorobenzofuran-3-ylacetonitrile (8.8 g) in methanol (350 ml) was added to a saturated ethereal solution of hydrogen chloride gas (350 ml).
) And stirred for 16 hours at room temperature. The mixture is concentrated under reduced pressure and the usual workup with ethyl acetate / water gives 5-fluorobenzofuran-3-ylacetate (9.4 g) as an oil.

The obtained methyl ester is dissolved in methanol (200 ml), 6M aqueous sodium hydroxide solution (400 ml) is added, and the mixture is stirred at room temperature for 16 hr. The organic solvent is removed under reduced pressure and acidified with 6M hydrochloric acid. Usual workup with ethyl acetate gives 5-fluorobenzofuran-3-ylacetic acid (9.2 g) as a crystalline compound.

Similarly, the following benzofuran-3-acetic acid is prepared: 2-methyl-4,5,6,7-tetrahydrobenzofuran-3-acetic acid benzofuran-3-acetic acid 6-methylbenzofuran-3-acetic acid 5- Methylbenzofuran-3-acetic acid 4-Methylbenzofuran-3-acetic acid 7-chlorobenzofuran-3-acetic acid 5-chlorobenzofuran-3-acetic acid 5-fluorobenzofuran-3-propionic acid and -butanoic acid, each as above It is manufactured by chain extension treatment. 6-chloroindazole-3-acetic acid was added to J.
Med. Chem. 35 (1992) 2155. 6- (6-Fluorobenz [1,2] isoxazol-3-yl) propionic acid was added to Dr.
ugDesignDiscov. 8 (1992) 225.

Preparation Example 1 of Compounds of the Invention 1a. 1- (2- (3-benzofuranyl) ethyl) -4- (1H-indol-4-yl) piperazinyl Rajin, oxalate dry tetrahydrofuran (50ml) and dry dimethylformamide (10 m
2- (3-benzofuranyl) acetic acid (0.95 g), 4- (1H-indol-4-yl) piperazine (1.3 g) and N, N-dicyclohexylcarbodiimide (1.3 g) were added to the mixture of 1). The mixture having is stirred for 16 hours at room temperature. Filter and remove the solvent under reduced pressure to give an oil. It was purified by flash chromatography (eluent: ethyl acetate / heptane / triethylamine 10: 9: 1) and as an oil
1- (3-Benzofuranyl) methylcarbonyl-4- (1H-indole-4-yl) piperazine (0.5 g) is obtained. This oil is dissolved in tetrahydrofuran (20 ml), treated with a suspension of lithium aluminum hydride (0.26 g) in tetrahydrofuran (20 ml) under a nitrogen atmosphere at room temperature and refluxed for 4 hours. The reaction mixture was cooled to 0 ° C., water (1 ml), 15% aqueous sodium hydroxide solution (0.
5 ml) and water (2.5 ml). After stirring for 30 minutes, the mixture is filtered and concentrated. The remaining oily substance is dissolved in acetone, oxalic acid is added, and the product is filtered to obtain the target compound (0.4 g) as a crystalline compound.

[0105]

[Outer 1] The following compounds are similarly prepared: 1b. 1- (3-benzofuranylmethyl) -4- (1H-indole-4-yl) piperazine, oxalate.

[0106]

[Outside 2] 1c. 1- (2- (5-fluoro-3-benzofuranyl) ethyl) -4- (1H-indole-4-
Ile) piperazine, oxalate.

[0107]

[Outside 3] 1d. 1- (4- (5-fluoro-3-benzofuranyl) -1-butyl) -4- (1H-indole
-4-yl) Piperazine, oxalate.

[0108]

[Outside 4] 1e. 1- (2- (1H-indole-3-yl) ethyl) -4- (1H-indole-4-yl)
Piperazine, oxalate.

[0109]

[Outside 5] 1f. 1- (3- (1H-indole-3-yl) -1-propyl) -4- (1H-indole-4-yl) piperazine, oxalate.

[0110]

[Outside 6] 1 g. 1- (4- (1H-indole-3-yl) -1-butyl) -4- (1H-indole-4-yl
) Piperazine, oxalate.

[0111]

[Outside 7] 1h. 1- (3- (5-Fluoro-3-benzofuranyl) -1-propyl) -4- (1H-indole-4-yl) piperazine, dihydrochloride.

[0112]

[Outside 8] 1i. 1- (2- (2-methyl-4,5,6,7-tetrafluoro-3-benzofuranyl) ethyl)
-4- (1H-indole-4-yl) piperazine, dihydrochloride.

[0113]

[Outside 9] 1j. 1- (2- (3-indazolyl) ethyl) -4- (1H-indole-4-yl) piperazine, oxalate.

[0114]

[Outside 10] 1k. 1- (2- (6-chloro-3-indazolyl) ethyl) -4- (1H-indole-4-yl
) Piperazine, oxalate.

[0115]

[Outside 11] 1l. 1- (2- (7-cyano-1H-indol-3-yl) ethyl) -4- (1H-indole-4
-Il) piperazine, oxalate.

[0116]

[Outside 12] Example 2 2a. 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4 -yl) piperazine, oxalate.

A solution of 6-chloro-1H-indole (15 g) in diethyl ethanol (300 ml) is cooled to 0 ° C. and treated with a solution of oxalyl chloride (9.4 ml) in diethyl ether (30 ml). . The mixture is stirred for 16 hours at room temperature. Filtration yields 2- (6-chloro-1H-indol-3-yl) -2-oxoacetyl chloride (15.5 g) as a crystalline compound.

A portion of this product (2.5 g) was dissolved in dry tetrahydrofuran (25 ml) and 1H-indole-4-yl) piperazine (1.4 g) and triethylamine (15 ml) in tetrahydrofuran (100 ml). Are added in small portions to the solution containing. After stirring for 16 hours, the reaction mixture is concentrated under reduced pressure. The residual oil was purified by flash chromatography (eluent: ethyl acetate / methanol / triethylamine 85: 10: 5) to give 1- (2- (6-chloro-1H-indol-3-yl) as a crystalline compound. -1,2-Dioxoethyl) -4- (1H-indole-4-yl) piperazine (1.6 g) is obtained. This product was suspended in tetrahydrofuran (25 ml) and dissolved in tetrahydrofuran (50 ml) lithium aluminum hydride (1
． 5 g) are added in portions to the suspension with. The mixture is refluxed for 4 hours, 0
Cool to 0 ° C. and add water (3 ml), 15% aqueous sodium hydroxide solution (1.5 ml), then water (7.5 ml) sequentially. After filtration and usual work-up, a yellow oil is obtained which is added from the acetone solution by addition of oxalic acid to give the desired oxalate (
1.5g).

[0119]

[Outside 13] The following compounds are similarly prepared: 2b. 1- (2- (4-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4
-Il) piperazine, oxalate.

[0120]

[Outside 14] 2c. 1- (2- (5-Fluoro-1H-indol-3-yl) ethyl) -4- (1H-indole
-4-yl) Piperazine, fumarate.

[0121]

[Outside 15] 2 g. 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4
-Yl) -1,2,3,6-tetrahydropyridine, fumarate.

[0122]

[Outside 16] 2h. 1- (2- (5-Fluoro-1H-indol-3-yl) ethyl) -4- (1H-indole
-4-yl) -1,2,3,6-tetrahydropyridine, trifumarate.

[0123]

[Outside 17] 2i. 1- (2- (7-Bromo-1H-indol-3-yl) ethyl) -4- (1H-indole-4
-Ile) piperazine, hemioxalate.

[0124]

[Outside 18] 2j. 1- (1-allyl-1H-indol-4-yl) -4- (2- (6-chloro-1H-indole-3
-Il) ethyl) piperazine, fumarate.

[0125]

[Outside 19] 2k. 1- (1-allyl-1H-indol-4-yl) -4- (2- (5-fluoro-1H-indole
-3-yl) ethyl) piperazine, 1.25 fumarate.

[0126]

[Outside 20] 21. 1- (1-benzyl-1H-indol-4-yl) -4- (2- (6-chloro-1H-indole
-3-yl) ethyl) piperazine, hemifumarate.

[0127]

[Outside 21] 2 m. 1- (1-benzyl-1H-indol-4-yl) -4- (2- (5-fluoro-1H-indol-3-yl) ethyl) piperazine, fumarate.

[0128]

[Outside 22] 2n. 1- (1-benzyl-1H-indol-4-yl) -4- (2- (5-bromo-1H-indole
-3-yl) ethyl) piperazine, fumarate.

[0129]

[Outside 23] 2o. 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1-propargyl-1
H-Indol-4-yl) Piperazine.

[0130]

[Outside 24] 2p. 1- (2- (1H-Indol-3-yl) ethyl) -4- (1-propargyl-1H-indol-4-yl) piperazine, hemifumarate.

[0131]

[Outside 25] 2q. 1- (2- (5-Fluoro-1H-indol-3-yl) ethyl) -4- (1-propargyl
-1H-Indol-4-yl) Piperazine.

[0132]

[Outside 26] 2r. 1- (2- (5-Bromo-1H-indol-3-yl) ethyl) -4- (1-propargyl-1
H-Indol-4-yl) Piperazine.

[0133]

[Outside 27] 2s. 1- (1-benzyl-1H-indol-4-yl) -4- (2- (1H-indole-3-yl) piperazine, hemifumarate.

[0134]

[Outside 28] 2t. 1- (2- (5-Bromo-1H-indol-3-yl) ethyl) -4- (1H-indole
-5-yl) Piperazine, fumarate.

[0135]

[Outside 29] 2u. 1- (2- (5-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole
-5-yl) Piperazine, hemifumarate.

[0136]

[Outside 30] Example 3 3a. 1- (2- (5-Fluoro-1H-indol-3-yl) ethyl) -4- (6-hydroxymethyl -1H-indol-4-yl) piperazinetetrahydrofuran (50 ml) 1- (2- ( 5-Fluoro-1H-indol-3-yl) -1,2-dioxoethyl) -4- (6-methoxycarbonyl-1H-indol-4-yl
) Piperazine (1.8 g, 2- (5-fluoro-1 by the method of treatment described in Example 2)
H-indol-3-yl) -2-oxoacetyl chloride and 1- (6-methoxycarbonyl-1H-indol-4-yl) piperazine) was added to a solution of lithium aluminum hydride (125 ml) in tetrahydrofuran (125 ml). 1.7 g) is added in small portions at room temperature and then refluxed for 4 hours. Reaction mixture 5
Cooled to ℃, water (3.4 ml), 15% aqueous sodium hydroxide solution (1.7 ml)
Then, water (8.5 ml) is sequentially added. Filtration and removal of the solvent under reduced pressure gave an oil which was purified by flash chromatography (eluent: ethyl acetate / methanol / triethylamine 85: 10: 5) to give the desired product (0.9g).
) Occurs. The product is crystallized from diisopropyl ether.

[0137]

[Outside 31] The following compounds are similarly prepared: 3b. 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (6-hydroxymethyl-1H-indol-4-yl) piperazine.

[0138]

[Outside 32] 3c. 1- (2- (5-Bromo-1H-indol-3-yl) ethyl) -4- (6-hydroxymethyl-1H-indol-4-yl) piperazine.

[0139]

[Outside 33] Example 4 4a. 1- (3- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-propyl) -4- (1H-indole-4-yl) piperazine, fumarate.

3- (3-Bromo-1-propyl) -6- in 4-methyl-2-pentanone (100 ml)
Fluoro-1,2-benzisoxazole (1.1 g), 1- (1H-indol-4-yl) piperazine (1.0 g), potassium carbonate (1.9 g) and potassium iodide (
The solution with 50 mg) is refluxed for 16 hours. Filtration and removal of the solvent under reduced pressure gave an oil which was purified by flash chromatography (eluent: heptane / ethyl acetate / triethylamine 75: 20: 5) to give an oil (1.0 g). Occurs. This is crystallized as the target fumarate by adding fumaric acid.

[0141]

[Outside 34] The following compounds are similarly prepared: 4f. 1- (2- (1H-indole-3-yl) ethyl) -4- (6-methoxycarbonyl-1
H-indol-4-yl) piperazine, oxalate.

[0142]

[Outside 35] 4 g. 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (6-methoxycarbonyl-1H-indol-4-yl) piperazine, oxalate.

[0143]

[Outside 36] 4h. 1- (2- (5-Fluoro-3-benzofuranyl) ethyl) -4- (6-methoxycarbonyl-1H-indol-4-yl) piperazine, oxalate.

[0144]

[Outside 37] 4l. 1- (5-Fluoro-3-benzofuranylmethyl) -4- (1H-indole-4-yl) piperazine, dihydrochloride.

[0145]

[Outside 38] 4 m. 1- (3-cyano-1H-indol-4-yl) -4- (2- (1H-indole-3-yl
) Ethyl) piperazine, fumarate.

[0146]

[Outside 39] 4n. 1- (3-cyano-1H-indol-4-yl) -4- (2- (5-fluoro-3-benzofuranyl) ethyl) piperazine, hemifumarate.

[0147]

[Outside 40] 4o. 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (3-cyano-1H-indol-4-yl) piperazine, hemifumarate.

[0148]

[Outside 41] 4p. 1- (2- (3-benzofuranylmethyl) ethyl) -4- (3-cyano-1H-indole
-4-yl) Piperazine, sesquioxalate.

[0149]

[Outside 42] 4q. 1- (1H-indol-4-yl) -4- (2- (5-methyl-3-benzofuranyl) ethyl) piperazine, hydrochloride.

[0150]

[Outside 43] 4r. 1- (1H-indol-4-yl) -4- (2- (4-methyl-3-benzofuranyl) ethyl) piperazine, oxalate.

[0151]

[Outside 44] 4s. 1- (3- (5-fluoro-3-benzofuranyl) -1-propyl) -4- (1H-indole-4-yl) -1,2,3,6-tetrahydropyridine, fumarate.

[0152]

[Outside 45] 4t. 1- (2- (5-chloro-3-benzofuranyl) ethyl) -4- (1H-indole-4-yl) piperazine, oxalate.

[0153]

[Outside 46] 4u. 1- (1H-indol-4-yl) -4- (2- (6-methyl-3-benzofuranyl) ethyl) piperazine, oxalate.

[0154]

[Outside 47] 4v. 1- (2- (7-chloro-3-benzofuranyl) ethyl) -4- (1H-indole-4-yl) piperazine, hemioxalate.

[0155]

[Outside 48] 4x. 1- (2- (4-chloro-1H-indol-3-yl) ethyl) -4- (3-cyano-1H-indol-4-yl) piperazine,

[0156]

[Outside 49] Example 5 5a. A solution containing 2 g (0.5 g) of the 1- (2- (6-chloro-1H-indol-3-yl) -4- (1H-indole-4-yl) piperidine compound is dissolved in glacial acetic acid. (10% loading on charcoal, 10 mg) is added and the mixture is hydrogenated in a Parr apparatus under 3 atmospheres of hydrogen gas for 16 hours Filter and remove the solvent under reduced pressure to give the desired compound as a crystalline compound. (0.4 g) is obtained.

[0157]

[Outside 50]   Pharmacological test   5-HT_1AThe affinity of the compounds of the present invention for the receptor was determined by 5-HT as shown in the test below._1A The inhibition of radioligand binding at the receptor is measured and examined. Human 5-HT_1ATo the receptor³H-5-CT binding inhibition   Transfected HeLa cells (HA7) (Fargin, A. et al., J. Biol. Chem., 1989, 264,
 14848) stably expressed and cloned human 5-HT_1A5-HT to receptor _1A Agonist³H-5-Carboxamide tryptamine (³(H-5-CT) bond to the drug
Thus inhibition is measured in vitro by this method. The assay
(assay) is Harrington, M.A. et al. J. Pharmacol. Exp. Ther., 1994, 268, 1098.
As a modification of the method described in. Human 5-HT_1AReceptor (cell homogen
Nart 40 μg) for 15 minutes 37⁰C in 50 mM Tris buffer at pH 7.7³Existence of H-5-CT
Incubate in the presence. Non-specific binding was measured including metergoline 10 μM
To be done. Reactions are filtered by Unifilter GF / B on Tomtec Cell Harvester.
Finish by rapid filtration. Count the filters on a Packard Top Counter. So
The results of are shown in Table 1:

[0158]

[Table 1]
^* Comparative compounds The compounds of the invention are also tested in the following test for their effect on the reuptake of serotonin. Inhibition of ³ H-5-HT Reuptake into Rat Brain Synaptosomes This method is used to measure the ability of agents to inhibit ³ H-5-HT accumulation in rat whole brain synaptosomes in vitro. The assay is based on Hyttel, J., Psychophar.
Done as described by macology, 1978, 60, 13.

[0159]

[Table 2] ^* Comparative compound, nt = not tested Healer cells (HA7) loaded with 5-HT _1A antagonistic activity of some compounds of the invention.
Evaluated in vitro with the 5-HT _1A receptor, which was stably expressed in and cloned. In this test, 5-HT _1A antagonism is evaluated by measuring the ability of compounds to antagonize the 5-HT-induced inhibition of forskolin-induced cAMP accumulation. The assay is performed as a modification of the method described by Pauwels, PJ et al., Biochem. Pharmacol. 1993, 45, 375.

Some of the compounds of the present invention have also been described by Sanchez. C. et al., Eur. J. Pharmacol. 1996, 315.
, pp 245. for its in vivo effect on the 5-HT _1A receptor. In this test, antagonism of test compounds was 5-MeO-DMT-induced 5-
It is examined by measuring the ability of the test compound to inhibit HT syndrome.

[0161]   The compounds of the present invention have important activity as serotonin reuptake inhibitors, _1A Has an antagonistic effect on the receptor. Therefore, the compounds of the present invention are
Uptake inhibition and 5-HT_1ACure diseases and disorders that respond to antagonistic activity at receptors
Considered to be effective in medical treatment. Diseases that respond to inhibition of serotonin reuptake include:
Well-known in the art, including affective disorders such as depression, psychosis, general anxiety symptoms
Anxiety disorder, Panitz disorder, obsessive-compulsive disorder, etc. are included.

As mentioned above, the antagonistic activity of the compounds of the invention at the 5-HT _1A receptor interferes with the negative feedback mechanism elicited by the inhibition of serotonin reuptake, whereby the compounds of the invention are It is expected to improve the action of the serotonin reuptake inhibitory activity of.

Accordingly, the compounds claimed herein are considered to be particularly effective as fast-acting agents to treat depression. These compounds are also effective in treating depression, which is currently unresponsive to SSRI's.

Formulations The pharmaceutical formulations of the invention are manufactured in conventional manner. Example: Tablets are prepared by mixing the active ingredient with the customary excipients and / or diluents and then compressing the mixture in a conventional tablet press. Examples of excipients or diluents: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. For example, it is possible to use all other excipients or additives which are always used for coloring, flavoring and preservation purposes, but which are compatible with the active ingredient.

Injectable solutions are prepared by dissolving the active ingredient and possible additives in an injectable solvent, preferably a portion of sterile water, adjusting the solution to the desired volume, sterilizing the solution, and using a suitable ampoule or glass bottle. It is manufactured by filling. Suitable additives commonly used,
For example, tonicity agents, preservatives, antioxidants and the like are added.

The pharmaceutically acceptable preparations according to the invention or the preparations prepared according to the invention are parenterally administered in any suitable manner, for example orally in the form of tablets, capsules, powders, syrups or in the form of injectable solutions. Can be administered to. To produce such a preparation,
The methods known in the art can be used, and all pharmaceutically acceptable carriers, diluents, excipients or other additives conventionally used can be used.

The compounds of the invention are advantageously administered in a unit dosage form containing the compound in an amount of about 0.01 to 100 mg. The total daily dose is usually about 0.05-500 mg of the active substance of the invention,
Most preferably it is in the range of about 0.1 to 50 mg.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 25/18 A61P 25/18 25/22 25/22 25/24 25/24 43/00 114 43/00 114 C07D 209/16 C07D 209/16 209/42 209/42 401/14 401/14 403/12 403/12 405/12 405/12 405/14 405/14 413/12 413/12 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA ( AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), A , AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX , NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, Z W ( 72) Inventor Krog-Jensen Kristian Denmark, 2100 Copenhagen, Hornmannsgarde, 23 F term (reference) 4C063 AA01 AA03 BB03 BB09 CC11 CC22 CC51 CC76 DD06 EE01 4C086 AA01 AA02 AA03 BC50 BC68 GA02 GA01 MA02 MA12 GA12 MA02 GA12 MA02 GA12 MA04 MA05 NA14 ZA05 ZA12 ZA18 ZC14 ZC41 ZC42 4C204 BB01 BB09 CB03 DB01 DB14 EB01 EB02 FB01 GB01 GB32

Claims (18)

[Claims] 1. A compound represented by the formula (I): Where W is N, C, CH or COH, the dotted line indicates any bond, and A is of formula (IIA) Wherein X is CR ^1A , CHR ^1A , N, NR ^1B , O or S, where R ^1A is as defined below for R ^{3 to} R ⁹ and R ^1B is related to R ^10. And Y is CR ^2A , CHR ^2A , N, NR ^2B , O or S, wherein R ^2A is as defined below for R ³ to R ⁹ , and R ^2B is as defined below for R ¹⁰ and the dotted line indicates an optional bond, provided that X and Y are not O or S at the same time. ] Or A is of the formula (IIB): Wherein X is CR ^1A , CHR ^1A , N, NR ^1B , O or S, where R ^1A is as defined below for R ^{3 to} R ⁹ and R ^1B is related to R ^10. As defined below, U is C, CH, or N, and the dotted line indicates any bond. ] Or A is of the formula (IIC): Wherein U is C, CH, or N, Y is CR ^2A , CHR ^2A , N, NR ^2B , O or S, where R ^2A is defined below with respect to R ³ to R ^9. And R ^2B is as defined below for R ¹⁰ and the dotted line indicates an optional bond. ], N is 0, 1, 2, 3, 4, or 5, m is 0, 1, 2, 3, 4, or 5, and Z is CH ₂ , O, S, CO, SO or SO ₂ , where n is 0, Z is CH ₂ , R ³ -R ⁹ and R ¹¹ -R ¹² are independently hydrogen, halogen, cyano, nitro, C _{1- 6} alk (/ en / yn) yl, C _1-6 alkoxy, C _1-6 alkylthio, hydrate proxy, hydroxy -C _1-6 alkyl, C _1-6 alkoxycarbonyl, C _3-8 cycloalk (g / Keny) yl, C _3-8 cycloal (ki / keni) yl-C _1-6 alk (ki / keni / quini) yl, C _1-6 alkylcarbonyl, phenylcarbonyl, halogen-substituted phenylcarbonyl, trifluoro Rumethyl, trifluoromethylsulfonyloxy, C _1-6 alkylsulfonyl, aryl and hetero Is selected from the group consisting of aryl and / or, two adjacent groups selected from R ^{3 to} R ⁹ may together form a methylenedioxy group, and / or Adjacent groups R ⁷ -R ⁹ may together form a cyclopentyl or cyclohexyl ring, which may be substituted by one or more methyl groups, and / or R ³ -R ⁹ One of the groups is optionally a group --NR ¹³ R ¹⁴ (wherein R ¹³ is as defined below for R ¹⁰ and R ¹⁴ is hydrogen, C _1-6 ar (ki / keni / yn) yl, C _3-8 cycloalk (g / en) yl, C _3-8 cycloalk (g / en) yl -C _1-6 alk (/ en / yn) yl, aryl, heteroaryl, aryl -C _{1- 6} alkyl or heteroaryl -C _1-6 alkyl.), and, R ¹⁰ is hydrogen, C _1-6 alk (/ en / key ) Yl, C _3-8 cycloalkyl (g / en) yl, C _3-8 Shiruroaru (g / en) yl -C _1-6 alk (/ en / yn) yl, the aryl, heteroaryl, aryl -C _1-6 alkyl or heteroaryl-C _1-6 alkyl, acyl, thioacyl, C _1-6 alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl or heteroarylsulfone, or R ¹⁵ VCO- (formula in, V is O or S, R ¹⁵ is C _1-6 alk (/ en / yn) yl, C _3-8 cycloalk (g / en) yl, C _3-8 cycloalk (g / en) yl -C _1-6 alk (/ en / yn) yl, Ru Oh aryl or heteroaryl. ) Or where group R ¹⁶ R ¹⁷ NCO-- or R ¹⁶ R ¹⁷ NCS @ - (wherein, R ¹⁶ and R ¹⁷ are independently hydrogen, C _1-6 alk (/ en / yn) yl, C _3-8 cycloal (ki / keni) yl, C _3-8 cycloar (ki / keni) yl-C _1-6 ar (ki / keni / quini) yl, heteroaryl or aryl or selected from R ¹⁶ and R ¹⁷ together with the N-atom to which they are attached form a pyrrolidinyl, piperidinyl, morpholinyl or perhydroazepine group.). } The substituted 4,5,6 and 7-indole and indoline derivative represented by these or its acid addition salt. 2. A is of formula (IIA) The compound according to claim 1, which is a residue represented by the formula: wherein X, Y, dotted lines and R ³ -R ⁶ are as defined in claim 1. 3. A is of the formula: The compound according to claim 2, which is a residue represented by the formula: wherein R ³ -R ⁶ and the dotted line are as defined in claim 2. 4. A is of the formula: The compound according to claim 3, which is represented by the formula: wherein R ³ -R ⁶ and the dotted line are as defined in claim 3. 5. A compound represented by the formula (II): The compound according to claim 1, wherein R ⁷ -R ¹² W, A, Z, n, m and the dotted line are as defined in claim 1. 6. The compound according to claim 1, wherein Z is CH ₂ and n + m is 0, 1, ₂ , 3, 4, 5 or 6. 7. The compound according to any one of claims 1 to 6, wherein W is N. 8. A compound of formula (II): [Wherein R ⁷ -R ¹² , W, Z, n, m and the dotted line are as defined in claim 1, and A is of formula (IIA) (In the formula, X, Y, dotted lines and R ³ -R ⁶ are as defined in claim 1.). ] The compound of Claim 1 which has these. 9. A is of the formula: The compound according to claim 8, which is a residue represented by the formula: wherein R ³ -R ⁶ and the dotted line are as defined in claim 8. 10. A is of the formula: The compound according to claim 9, which is a residue represented by the formula: wherein R ³ -R ⁶ and the dotted line are as defined in claim 9. 11. Z is CH ₂ , n + m is 0, 1, ₂ , 3, 4, 5 or 6, and R ³ -R ⁹ and R ¹¹ -R ¹² are hydrogen, halogen, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxycarbonyl and trifluoromethyl, R ¹⁰ being hydrogen. The compound according to. 12. The compound according to any one of claims 8 to 11, wherein W is N. 13. 1- (2- (3-Benzofuranyl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (3-benzofuranylmethyl) -4- (1H-indole-4) -Yl) piperazine, 1- (2- (5-fluoro-3-benzofuranyl) ethyl) -4- (1H-indole-4-yl)
Piperazine, 1- (4- (5-fluoro-3-benzofuranyl) -1-butyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (1H-indole-3-yl) ethyl ) -4- (1H-Indol-4-yl) piperazine, 1- (3- (1H-Indol-3-yl) -1-propyl) -4- (1H-Indol-4-yl) piperazine, 1- (4- (1H-indole-3-yl) -1-butyl) -4- (1H-indole-4-yl) piperazine, 1- (3- (5-fluoro-3-benzofuranyl) -1-propyl) -4- (1H- indole-4-
Yl) piperazine, 1- (2- (2-methyl-4,5,6,7-tetrafluoro-3-benzofuranyl) ethyl) -4- (1H
-Indole-4-yl) piperazine, 1- (2- (3-indazolyl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (6-chloro-3-indazolyl) ethyl ) -4- (1H-Indol-4-yl) piperazine, 1- (2- (7-cyano-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl)
) Piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl
) Piperazine, 1- (2- (4-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl
) Piperazine, 1- (2- (5-fluoro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (6-chloro-1H-indole -3-yl) ethyl) -4- (1H-indole-4-yl
) -1,2,3,6-Tetrahydropyridine 1- (2- (5-fluoro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl) -1,2,3 , 6-Tetrahydropyridin 1- (2- (7-bromo-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl
) Piperazine, 1- (1-allyl-1H-indol-4-yl) -4- (2- (6-chloro-1H-indol-3-yl)
) Ethyl) piperazine, 1- (1-allyl-1H-indol-4-yl) -4- (2- (5-fluoro-1H-indol-3-yl) ethyl) piperazine, 1- (1-benzyl- 1H-Indol-4-yl) -4- (2- (6-chloro-1H-indol-3-yl) ethyl) piperazine, 1- (1-benzyl-1H-indol-4-yl) -4- ( 2- (5-fluoro-1H-indole-3-
1- (1-benzyl-1H-indol-4-yl) -4- (2- (5-bromo-1H-indol-3-yl) ethyl) piperazine, 1- (2- ( 6-chloro-1H-indol-3-yl) ethyl) -4- (1-propargyl-1H-indol-4-yl) piperazine, 1- (2- (1H-indole-3-yl) ethyl) -4 -(1-Propargil-1H-Indole-4
-Yl) piperazine, 1- (2- (5-fluoro-1H-indol-3-yl) ethyl) -4- (1-propargyl-1H-indol-4-yl) piperazine, 1- (2- (5 -Bromo-1H-indol-3-yl) ethyl) -4- (1-propargyl-1H-indol-4-yl) piperazine, 1- (1-benzyl-1H-indol-4-yl) -4- ( 2- (1H-Indol-3-yl) piperazine, 1- (2- (5-Bromo-1H-indol-3-yl) ethyl) -4- (1H-Indol-5-yl) piperazine, 1- ( 2- (5-Chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-5-yl) piperazine, 1- (2- (5-Fluoro-1H-indol-3-yl) ethyl ) -4- (6-Hydroxymethyl
-1H-Indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (6-hydroxymethyl-1
H-indol-4-yl) piperazine, 1- (2- (5-bromo-1H-indol-3-yl) ethyl) -4- (6-hydroxymethyl-1
H-indol-4-yl) piperazine, 1- (3- (6-fluoro-1,2-benzisoxazol-3-yl) -1-propyl) -4- (1H
-(Indole-4-yl) piperazine, 1- (2- (1H-indole-3-yl) ethyl) -4- (6-methoxycarbonyl-1H-indol-4-yl) piperazine, 1- (2- ( 6-Chloro-1H-indol-3-yl) ethyl) -4- (6-methoxycarbonyl)
-1H-indol-4-yl) piperazine, 1- (2- (5-fluoro-3-benzofuranyl) ethyl) -4- (6-methoxycarbonyl-1
H-indol-4-yl) piperazine, 1- (5-fluoro-3-benzofuranylmethyl) -4- (1H-indole-4-yl) piperazine, 1- (3-cyano-1H-indole-4 -Yl) -4- (2- (1H-indole-3-yl) ethyl) piperazine, 1- (3-cyano-1H-indol-4-yl) -4- (2- (5-fluoro-3- Benzofuranyl
) Ethyl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (3-cyano-1H-indol-4-yl) piperazine, 1- (2- (3 -Benzofuranyl) ethyl) -4- (3-cyano-1H-indol-4-yl) piperazine, 1- (1H-indol-4-yl) -4- (2- (5-methyl-3-benzofuranyl) ethyl ) Piperazine, 1- (1H-indol-4-yl) -4- (2- (4-methyl-3-benzofuranyl) ethyl) piperazine, 1- (3- (5-fluoro-3-benzofuranyl) -1- Propyl) -4- (1H-indole-4-
Yl) -1,2,3,6-tetrahydropyridine, 1- (2- (5-chloro-3-benzofuranyl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (1H-indole -4-yl) -4- (2- (6-methyl-3-benzofuranyl) ethyl) piperazine, 1- (2- (7-chloro-3-benzofuranyl) ethyl) -4- (1H-indole-4- Yl) piperazine, 1- (2- (4-chloro-1H-indol-3-yl) ethyl) -4- (3-cyano-1H-indol-4-yl) piperazine, 1- (2- (6- Chloro-1H-indol-3-yl) -4- (1H-indole-4-yl) piperidine, 1- (2- (5-chloro-1H-indol-3-yl) ethyl) -4- (1H- Indole-4-yl) piperazine, 1- (2- (7-bromo-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (4- Chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (6-trifluoromethyl-1H-yne Dole-3-yl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (1H-indole-4-yl) -4- (2- (5-methyl-1H-indole-3- 1- (1H-Indol-4-yl) -4- (2- (6-methyl-1H-indole-3-yl) ethyl) piperazine, 1- (1H-indole-4-yl) ) -4- (2- (7-Methyl-1H-indol-3-yl) ethyl) piperazine, 1- (2- (4,5-dichloro-3-benzofuranyl) ethyl) -4- (1H-indole- 4-Il
) Piperazine, 1- (2- (5-bromo-3-benzofuranyl) ethyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (4-chloro-1H-indol-3-yl ) Ethyl) -4- (1H-indole-4-yl) piperidine, 4- (1H-indol-4-yl) -1- (2- (5-methyl-1H-indol-3-yl) ethyl) piperidine , 4- (1H-indol-4-yl) -1- (2- (1H-indol-3-yl) ethyl) piperidine, 1- (1H-indol-4-yl) -4- (3- (4 -Methyl-3-benzofuranyl) -1-propyl) piperazine, 4- (1H-indol-4-yl) -1- (3- (4-methyl-3-benzofuranyl) -1-propyl) piperidine, 1- ( 3- (4-chloro-3-benzofuranyl) -1-propyl) -4- (1H-indole-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (6-Chloro-1H-indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) eth ) -4- (6-Fluoro-1H-indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (6-cyano-1H-indole -4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (7-chloro-1H-indol-4-yl) piperazine, 1- (2- (6-Chloro-1H-indol-3-yl) ethyl) -4- (7-cyano-1H-indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ) Ethyl) -4- (2-cyano-1H-indol-4-yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1H-indoline-4 -Yl) piperazine, 1- (2- (6-chloro-1H-indol-3-yl) ethyl) -4- (1H-indole-6-yl) piperazine, 1- (2- (6-chloro-1H -Indol-3-yl) ethyl) -4- (1H-indole-7-yl) piperazine or a pharmaceutically acceptable acid addition salt thereof. 14. A pharmaceutical preparation comprising a compound according to any of claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent. . 15. The method according to any one of claims 1 to 13, for producing a drug for treating a disorder or disease that responds to inhibition of serotonin reuptake and antagonism of 5-HT _1A receptor.
A method of using the above compound or a pharmaceutically acceptable acid addition salt thereof. 16. A compound according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of affective disorders such as depression, psychosis, anxiety disorders including general anxiety symptoms, panic disorders and obsessive compulsive disorders. Alternatively, a method of using a pharmaceutically acceptable acid addition salt thereof. 17. A therapeutically effective amount of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof, is administered to an animal body including human. , A method of treating a disorder or disease in an animal body, including a human, which responds to inhibition of serotonin reuptake and impairment of 5-HT _1A receptor antagonism. 18. In an animal body including human, which comprises administering a therapeutically effective amount of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof. A method for treating depression, psychosis, anxiety disorders including general anxiety symptoms, emotional disorders including panic disorder and obsessive-compulsive disorder.