HK1058518B - Substituted phenyl-piperazine derivatives, their preparation and use - Google Patents

Description

Substituted phenyl-piperazine derivatives, their preparation and use

The present invention relates to the efficient binding of 5-HT_1ANovel substituted phenyl-piperazine derivatives of the receptor, pharmaceutical compositions containing these compounds and their use for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the present invention are also potent inhibitors of 5-hydroxytryptamine reuptake and/or D₃/D₄Ligands, and thus they are believed to be particularly useful in the treatment of depression and psychosis.

Background

Clinical and pharmacological studies have shown that 5-HT_1AAgonists and partial agonists are useful for the treatment of various affective disorders, such as generalized anxiety disorder, panic disorder, obsessive compulsive disorder, depression and aggression.

5-HT has also been reported_1AThe ligands may be used to treat ischemia.

Schechter et al (Serotonin, 1997, vol.2, No. 7) reviewed 5-HT_1AAntagonists and potential therapeutic targets based on preclinical and clinical data for these antagonists. It is described that 5-HT_1AThe antagonists may be used to treat schizophrenia, senile dementia, dementia associated with alzheimer's disease, and depression in combination with SSRI antidepressants.

5-HT reuptake inhibitors are well known anti-depressant drugs and can be used for panic disorder and social phobia.

Several studies evaluated the combined administration of a compound that inhibits 5-hydroxytryptamine reuptake and 5-HT_1ATherapeutic efficacy of receptor antagonists (Innis, R.B. et al, Eur.J.Pharmacol., 1987, 143, p.195-204, Gartside, S.E., Br.J.Pharmacol.1995, 115, p.1064-1070, Blier, P.et al, Trends Pharmacol.Sci.1994, 15, 220). These studies found that 5-HT was used in combination_1AReceptor antagonists and 5-hydroxytryptamine reuptake inhibitors produce a more rapid therapeutic effect.

Dopamine D₄The receptors belong to dopamine D₂Subfamily receptors, which are thought to be involved in the antipsychotic action of neuroleptics. Antipsychotics are mainly through antagonism of D₂The receptor exerts its action, and its side effect is known to be due to antagonism of D in the striatal region of the brain₂Due to the receptor. However, dopamine D₄Receptors are located primarily in brain regions outside the striatum, suggesting dopamine D₄The receptor antagonists have no extrapyramidal side effects. This can be illustrated by the antipsychotic drugs clozapine, clozapine on D₄Higher affinity of the receptor (with D)₂Receptor comparison) and no extrapyramidal side effects (Van Tol et al, Nature 1991, 350, 610; hadley Medicinal research reviews 1996, 16, 507-.

A number of hypotheses have been demonstrated for selectivity D₄D of receptor antagonists (L-745, 879 and U-101958)₄The ligands have antipsychotic potential (Mansbach et al, Psychopharmacology 1998, 135, 194-200). However, it has recently been reported that the above compounds are part D in various in vitro potency assays₄Receptor agonists (Gazi et al, Br. J. Pharmacol.1998, 124, 889-896; Gazi et al, Br. J. Pharmacol.1999, 128, 613-620). Furthermore, clozapine, an effective antipsychotic drug, was demonstrated to be a silent antagonist (Gazi et al, Br. J. Pharmacol.1999, 128, 613-.

Thus, is part D₄D receptor agonists or antagonists₄The ligands may have a beneficial antipsychotic effect.

Dopamine D₄Antagonists may also be useful in the treatment of cognitive deficits (Jentsch et al, Psychopharmacology 1999, 142, 78-84).

Also proposed is dopamine D₄Antagonists may be useful in alleviating dyskinesia associated with L-dopa therapy in Parkinson's disease (Tahar et al, Eur. J. Pharmacol.2000, 399, 183-.

Dopamine D₃The receptors also belong to dopamine D₂Subfamily receptors, which are preferentially located in the marginal areas of the brain (Sokoloff et al, Nature, 1990, 347, 146-. In addition, D in the marginal part of the brain of schizophrenic patients has been reported₃Receptor levels are elevated (Gurevich et al, Arch. Gen. Psychiatry 1997, 54, 225-32). Therefore, D₃Receptor antagonists may have the potential to be effective antipsychotic therapy, not primarily by blocking D₂Extrapyramidal side effects of conventional antipsychotic drugs in which the receptor actsAction (Shafer et al, Psychopharmacology 1998, 135, 1-16; Schwartz et al, Brain Research Reviews 2000, 31, 277-287).

And, D₃Receptor blockade produces mild stimulation of the prefrontal Cortex (Merchant et al, Cerebral Cortex 1996, 6, 561-. In addition, dopamine D₃Antagonists may reverse D₂Antagonists cause EPS (Millan et al, Eur. J. Pharmacol.1997, 321, R7-R9) and do not cause prolactin changes (Reaville et al, J. Pharmacol. exp. Ther.2000, 294, 1154-1165). Thus, D of antipsychotic agent₃Antagonistic properties can alleviate the recalcitrant symptoms and cognitive deficits, improving the types of side effects associated with EPS and hormonal changes.

In addition, dopamine D is believed to be₃Agonists are useful in the treatment of schizophrenia (Wustow et al, Current Pharmaceutical Design 1997, 3, 391-404).

Therefore, it is considered to act on 5-HT_1ADrugs for receptors, including agonists and antagonists, have potential utility in the treatment of both neurological and psychiatric disorders, and there is a great need for such drugs. In addition, it has effective 5-hydroxytryptamine reuptake inhibiting activity and/or D₄And/or D₃The active antagonists are particularly useful in the treatment of various psychiatric and neurological disorders.

Compounds of similar structure to the compounds of the present invention have been previously described.

WO 9902516 describes the use of thiophene derivatives as 5-HT_1AA receptor ligand.

WO 9726252 describes piperazinyl derivatives for use as pesticides.

WO 9514004 describes substituted alkylamino-indole derivatives as 5-HT_1A、5-HT_1BAnd 5-HT_1D-a derivative.

It has now been found that certain types of compounds of phenyl-piperazine derivatives have high affinityForce binding 5-HT_1AA receptor. In addition, many of these compounds were found to have other very beneficial properties, namely effective 5-hydroxytryptamine reuptake inhibition activity and/or activity on D₄And/or D₃The receptor has an affinity.

Summary of The Invention

Accordingly, the present invention relates to novel compounds of formula I:

wherein Z is NH, NR', O or S; r' is hydrogen, C_1-6-an alkyl group;

R⁷and R⁸Independently of one another hydrogen, halogen, C_1-6Alkyl radical, C_3-8-cycloalkyl, CN, CF₃Or C_1-6-an alkoxy group; or R⁷And R⁸Together form a 5-or 6-membered aryl or heteroaryl group fused to a phenyl ring;

y is N, C or CH;

the dotted line is an optional bond;

R⁶and R^6’Is H or C_1-6-an alkyl group;

x is-O-or-S-;

n is 2, 3, 4 or 5;

m is 2 or 3;

R¹、R²、R³、R⁴and R⁵Independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6-alkenyl, C_1-6-alkynyl, C_3-8Cycloalkyl, aryl, hydroxy-C_1-6Alkyl radical, C_1-6-alkoxy, C_3-8Cycloalkoxy, C_1-6Alkylthio, acyl, NR⁹R¹⁰Wherein R is⁹And R¹⁰Independently of each other is hydrogen, C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-8-cycloalkyl or aryl; or R⁹And R¹⁰Together with the nitrogen to which they are attached form a 1-morpholinyl, 1-piperidinyl, 1-homopiperidinyl, 1-piperazinyl, 1-homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or pyrazolyl group, all of which may be further substituted by C_1-6-alkyl substitution; or R¹-R⁵Wherein two adjacent substituents together form a ring selected from the group consisting of:

wherein W is O or S, R 'and R' are hydrogen or C_1-6-an alkyl group.

Compounds of the invention para 5-HT_1AThe receptor has affinity. Accordingly, the present invention provides:

the above compounds for use as a medicament;

a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt or prodrug thereof in admixture with one or more pharmaceutically acceptable carriers or diluents.

The present invention provides the use of a compound of formula I as defined above or an acid addition salt or a prodrug thereof in the manufacture of a pharmaceutical formulation for the treatment of the above-mentioned diseases.

The present invention provides methods for treating human diseases and conditions caused by abnormalities of the 5-hydroxytryptamine system of the central nervous system comprising administering an effective amount of a compound of formula I as described above.

The compounds of the invention are believed to be useful in the treatment of affective disorders such as depression, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia, and eating disorders, psychiatric and neurological disorders such as ischemia and senile dementia.

The invention also relates in particular to the use of a compound of formula I as defined above or an acid addition salt thereof for the preparation of a pharmaceutical preparation for the treatment of affective or neurological diseases and disorders in humans caused by abnormalities of the 5-hydroxytryptamine system in the central nervous system, wherein said diseases are depression, psychosis, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, impulse control disorder, alcoholism, aggression, ischemia, senile dementia and social phobia.

Detailed description of the invention

A preferred embodiment of the present invention are the above compounds of formula I: wherein Z is NH and the resulting indole is attached at position 3;

another preferred embodiment of the present invention are the compounds of formula I above: wherein R is⁷And R⁸Independently selected from hydrogen, halogen, C_1-6-alkyl or R⁷And R⁸Together form a fused pyridyl ring;

another preferred embodiment of the present invention are the compounds of formula I above wherein n is 2, 3 or 4;

yet another preferred embodiment of the present invention are the compounds of formula I above wherein m is 2;

yet another preferred embodiment of the present invention is where R is⁶And R^6’Compounds of formula I above, all of which are hydrogen;

yet another preferred embodiment of the present invention are the compounds of formula I above wherein Y is N;

another preferred embodiment of the present invention are the compounds of formula I above: wherein R is¹、R²、R³、R⁴And R⁵Independently selected from hydrogen, alkoxy, NRR⁴Wherein R is³And R⁴Independently of each other is hydrogen, C_1-6-an alkyl group; or R³And R⁴Together form a 1-morpholinyl group; or R¹、R²、R³、R⁴And R⁵Two adjacent groups in (a) together form a fused ring consisting of:

-O-CH₂-O-，

-O-CH₂-CH₂-O-, or

-CH₂-CH₂-CH₂-；

Another preferred embodiment of the present invention are the compounds of formula I above: wherein R is¹、R²、R³、R⁴、R⁵1 or 2 groups in (a) are not hydrogen;

the most preferred embodiment of the present invention is a compound of formula I as described above, said compound being:

1- {1- [3- (dimethylamino) phenoxy ] phenyl } -4- [2- (1H-indol-3-yl) ethyl ] piperazine;

1- [1- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [2- (1H-indol-3-yl) ethyl ] piperazine;

1- {1- [3- (dimethylamino) phenoxy ] phenyl } -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [1- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-6-yloxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-6-yloxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [4- (1H-indol-3-yl) butyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [4- (1H-indol-3-yl) butyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [2- (6-chloro-1H-indol-3-yl) ethyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [2- (6-chloro-1H-indol-3-yl) ethyl ] piperazine;

1- [2- (3- (dimethylamino) phenoxy) phenyl ] -4- [2- (6-chloro-1H-indol-3-yl) ethyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [4- (1H-indol-3-yl) butyl ] piperazine;

1- [2- (4-methoxyphenoxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (3- (dimethylamino) phenoxy) phenyl ] -4- [4- (1H-indol-3-yl) butyl ] piperazine;

1- (2-phenoxyphenyl) -4- [2- (6-chloro-1H-indol-3-yl) ethyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3- (dimethylamino) phenoxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (7-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (7-chloro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5, 7-difluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (7-bromo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3- (dimethylamino) phenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (1H-pyrrolo [3, 2-H ] quinolin-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5, 7-difluoro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (1H-pyrrolo [3, 2-H ] quinolin-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (1H-pyrrolo [3, 2-H ] quinolin-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (morpholin-4-yl) phenoxy ] phenyl } -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-ethoxyphenoxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3- (diethylamino) phenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (morpholin-4-yl) phenoxy ] phenyl } -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (morpholin-4-yl) phenoxy ] phenyl } -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (morpholin-4-yl) phenoxy ] phenyl } -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (7-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5, 7-dimethyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (7-bromo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3, 4, 5-trimethoxyphenoxy) phenyl ] -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine.

Some of the compounds of formula I may exist as optical isomers thereof, and such optical isomers are also included within the scope of the present invention.

Term C_1-6Alkyl refers to a branched or straight chain alkyl group having 1 to 6 carbon atoms (including 1 and 6 carbon atoms), for exampleSuch as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.

Likewise, C_2-6Alkenyl and C_2-6Alkynyl refers to such groups having 2 to 6 carbon atoms (including 2 and 6 carbon atoms), respectively, and the groups each have at least one double or triple bond.

Halogen means fluorine, chlorine, bromine or iodine.

Term C_3-8Cycloalkyl means a monocyclic or bicyclic carbocyclic ring having 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferred embodiments are cyclopropyl, cyclopentyl, cyclohexyl.

Term C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_3-8By cycloalkoxy is meant a group C wherein alkyl is as defined above_1-6The radical of an alkyl group.

Acyl means CHO and C wherein alkyl is as defined above_1-6-CO-alkyl of alkyl.

A5-or 6-membered ring which is aryl or heteroaryl means a group such as phenyl, pyrrolyl, pyridyl, pyrimidyl, furyl, thienyl.

Examples of organic acid addition salts according to the invention are the addition salts with: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and theophylline acetate, and also 8-halotheophyllines, for example 8-bromotheophylline. Examples of inorganic acid addition salts according to the invention are the addition salts with: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid. The acid addition salts of the present invention are preferably pharmaceutically acceptable salts with non-toxic acids.

In addition, the compounds of the present invention may exist in the form of non-solvates as well as solvates with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). The solvated forms are generally considered equivalent to unsolvated forms for the purposes of the present invention.

Some of the compounds of the present invention contain a chiral center, and the compounds exist as isomers (e.g., enantiomers). The present invention includes all such isomers and any mixtures thereof, including racemic mixtures.

Racemic form mixtures can be resolved into the optical antipodes using known methods, for example by separating the diastereoisomers from the salts of optically active acids, and treating with a base to liberate the optically active amine compound. Another method for resolving racemates into optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can be resolved into their optical antipodes, for example, by fractional crystallization of the d-or 1- (tartrate, mandelate or camphorsulfonate) salt. The compounds of the present invention may also be resolved by forming diastereomeric derivatives.

Other methods of resolving optical isomers known to those skilled in the art may be used. Such methods include those discussed in j.jaques, a.collet and s.wilen in "enantiomers, racemates and resolution", John Wiley and Sons, New York (1981).

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

The compounds of the present invention may be prepared by one of the following methods, including:

a) reacting a secondary amine of the formula

Wherein R is¹-R^6’X, Y and m are as defined above

With an alkylating agent of the general formula:

R⁷、R⁸z and n are as previously defined, G is a suitable leaving group, e.g. halogen, methanesulfonate, toluenesulfonate;

b) reacting a compound of the formula

Wherein R is¹-R^6’X, Y, n and m are as defined above, Q (OH)₂Is a diol, such as a substituted ethylene or propylene glycol or a polymer-bound diol;

with a hydrazine of the formula

c) Reducing an amide of the formula

Z, R therein¹-R⁸X, Y, n and m are as previously defined;

d) reducing a compound of the formula

Wherein R is¹-R⁸Y, X and m are as defined above.

Alkylation is generally carried out as follows: the reactants are boiled under reflux or heated in a suitable solvent (e.g. acetone, acetonitrile, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N-dimethylformamide, dimethylsulfoxide or 1-methyl-2-pyrrolidone) in the presence of a base (e.g. triethylamine or potassium carbonate) and optionally a catalytic amount of potassium iodide at a fixed temperature.

1)

The secondary amine compound of formula III is prepared according to the reaction sequence outlined above. 2-fluoro-nitrobenzene is reacted with a nucleophile of formula VIII using an organic or inorganic base in an aprotic solvent such as N, N-dimethylformamide at elevated temperature. After reduction of the intermediate nitro compound IX using standard conditions such as palladium-catalyzed hydrogenation or iron in an acidic solvent, the aniline derivative X is converted to the desired secondary amine of formula III. Piperazine is formed by reaction with bis (2-chloroethyl) amine hydrochloride at elevated temperatures or by multistep synthesis according to published methods (Kruse et al, Recl. Trav. Chim. Pays-Bas, 1988, 107, 303-S309).

2)

Alternatively, the secondary amines of formula III are prepared using monosubstituted cyclic diamines of formula XII as important intermediates. The substituent R is a suitable protecting group such as ethoxy-, methoxy-or 2-methyl-2-propoxy-carbonyl or benzyl, or a suitable carrier such as Merrifield resin or a carrier-supported carbamate group such as wang resin-based carbamate linking group (Zaragoza, Tetrahedron Lett., 1995, 36, 8677-8678). The monosubstituted cyclic diamines of formula XII are prepared using commercially available starting materials or by methods known to those skilled in the art. In an aprotic solvent such as anhydrous tetrahydrofuran, using a suitable base such as potassium carbonate at elevated temperatureNext, a mono-substituted cyclic diamine of the formula XII and n, hexafluorophosphate⁶-1, 2-dichlorobenzene-eta⁵-cyclopentadienyl iron (II). N. hexafluorophosphoric acid⁶-1, 2-dichlorobenzene-eta⁵Cyclopentadienyl iron (II) was prepared analogously to the literature (Pearson and Gelormani, J.org.chem.1994, 59, 4561-4570). The monochloro derivative of formula XIII thus formed is then reacted with a nucleophile of formula VIII in an aprotic solvent such as anhydrous tetrahydrofuran, either by deprotonation of the nucleophile of formula VIII using a suitable base such as potassium carbonate or a base such as sodium hydride prior to the reaction. The desired secondary amine of the formula III, corresponding to the secondary amine of the formula XV of the formula R.H, is obtained by decomplexation according to literature procedures (Pearson et al, J.org.chem.1996, 61, 1297-one 1305), followed by deprotection using methods known to the chemist skilled in the art or cleavage from the support according to literature procedures (Zaragoza, Tetrahedron Lett., 1995, 36, 8677-one 8678; Conti et al, Tetrahedron Lett., 1997, 38, 2915-one 2918). Nucleophiles of formula VIII are commercially available and can be prepared using methods known to chemists skilled in the art or according to literature procedures (Guillamet and Hretani, J.Heterocyclic chem., 26, 193-196, 1989).

Alkylating agents of the formula are prepared according to literature methods (J.Med.chem.1983, 26, 1470-1477, Brodfuehr et al, J.org.chem.1997, 62, 9192-9202, Anelli et al, J.org.chem.1987, 52, 2559-2562, Brodfuehr et al, J.org.chem.1997, 62, 9192-9202) or by methods known to the skilled chemist:

indole formation according to method b proceeds as follows: the acetal of formula IV is reacted with an aryl hydrazine of formula V to form the corresponding hydrazone, which is then converted to the indole by means of Fischer indole synthesis. Preferably, the reaction procedure is carried out in a one-pot process using a Lewis acid catalyst (preferably zinc chloride or boron trifluoride) or a protic acid (preferably sulfuric acid or phosphoric acid) in a suitable solvent (e.g. acetic acid or ethanol) at elevated temperature.

The acetals of the formula IV are prepared by the reaction sequence outlined in 2) above using monosubstituted cyclic diamines of the formula XII, which are important intermediates, in which

The alkylation of a cyclic diamine of formula XI with an acetal of the formula using the conditions described in Process a above gives an important intermediate of formula XII:

the polymer-bound acetal of formula XVI is prepared as follows: reacting the compound of formula G- (CH) using p-toluenesulfonic acid as a catalyst in a suitable solvent such as toluene at elevated temperature₂)_n+1-CHO aldehyde was reacted with commercially available 2, 2-dimethyl-1, 3-dioxolan-4-yl-methoxymethyl polystyrene. 4-Chlorobutanal, 5-chloropentanal and 6-chlorohexanal were prepared in analogy to the procedure described by Normant et al, Tetrahedron 1994, 50(40), 11665.

LiAlH is generally used₄、AlH₃Or diborane in an inert solvent such as tetrahydrofuran, dioxane or diethyl ether at room temperature or slightly elevated temperature. The amides of formula VI are prepared from secondary amines of formula III and substituted indol-3-yl alkyl carboxylic acids or carboxylic acid chlorides using methods known to the chemist skilled in the art. The amides of the formula VII are prepared using 3-unsubstituted indoles and secondary amines of the formula III according to the literature multistep process (Nichols al., Synthesis 1999, 6, 935-938; Speeter and Anthony, J.Am.chem.Soc.1954, 76, 6208-6210).

Examples

All reactions were carried out under positive pressure nitrogen. The melting points were determined using a Buichi SMP-20 apparatus, uncorrected.

Analytical LC-MS data were obtained using a PE Sciex API 150EX instrument equipped with an ion mist source and Shimadzu LC-8A/SLC-10A LC system. The linear elution gradient under LC conditions (5 μm particle size YMC ODS-A of 50X 4.6 mm) was: water/acetonitrile/trifluoroacetic acid (90: 10: 0.05) to water/acetonitrile/trifluoroacetic acid (10: 90: 0.03), 2ml/min, 7 min. The linear elution gradient for LC conditions (Waters Symmetry, 30 × 4.6mm, C183.5 my particle size) for compounds 3C, 3e, 3f and 31 was: water/acetonitrile/trifluoroacetic acid (90: 10: 0.05) to water/acetonitrile/trifluoroacetic acid (10: 90: 0.03), 2ml/min, 4 min. Purity was determined by integrating the UV spectrum (254 nm). Retention time R_tExpressed in minutes. Preparative LC-MS-separations were performed on the same instrument. The linear elution gradient under LC conditions (5 μm particle size YMC ODS-A of 50X 20 mm) was: water/acetonitrile/trifluoroacetic acid (82: 20: 0.05) to water/acetonitrile/trifluoroacetic acid (10: 90: 0.03), 22.7ml/min, 7 min. Fractions were collected by split flow MS detection.

Recording at 500.13 MHz on a Bruker Avance DRX500 instrument or 250.13 MHz on a Bruker AC 250 instrument¹H NMR spectroscopic data. Deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) was used as solvent. TMS was used as an internal reference standard. Chemical shift values are expressed in ppm. For the number of peaks of the NMR signal, the following abbreviations are used: s-singlet, d-doublet, t-triplet, q-quartet, qui-quintet, h-heptat, dd-doublet, dt-doublet, dq-quartet, tt-triplet, m-multiplet and b-broad singlet. The NMR signal corresponding to the acid proton is generally omitted.

The water content of the crystallized compound was determined using Karl Fischer titration.

Standard work-up procedures refer to extraction from a suitable aqueous solution with the indicated organic solvent, drying of the combined organic extracts (anhydrous magnesium or sodium sulfate), filtration and evaporation of the solvent in vacuo. Column chromatography was performed using Kieselgel type 60 silica gel from 230-. Ion exchange chromatography used the following materials: SCX-column (1g) from Varian Mega Bond Elut *, Cat # Chrompack 220776. The SCX-column was pretreated with 10% acetic acid in methanol (3mL) before use. Reverse phase chromatography used the following materials: c-18 column (1g) from Varian Mega Bond Elut *, catalog No. 220508 for Chrompack. The C-18 column was pretreated with methanol (3mL) and water (3mL) before use. When the decomplexing was performed using irradiation, a UV source (300W) from Philipps was used.

Example 1

1- {2- [3- (dimethylamino) phenoxy ] phenyl } -4- [2- (1H-indol-3-yl) ethyl ] piperazine oxalate (1a)

1-chloro-2-nitrobenzene (15.0g), 3- (dimethylamino) phenol (13.0g) and potassium hydroxide (11.8g) were dissolved in N, N-dimethylformamide (350mL) and boiled under reflux for 18 hours. The reaction was then cooled, poured into water and worked up using ethyl acetate according to standard methods. The crude product was purified by chromatography on silica gel (heptane: ethyl acetate, triethylamine/80: 10). The pure intermediate was dissolved in a mixture of ethanol (200mL) and acetic acid (20 mL). After addition of Pd/C (5%, 4.5g), the reaction mixture was shaken under a hydrogen atmosphere (3bar) for 3 hours. The reaction mixture was filtered, neutralized and worked up with ethyl acetate according to standard procedures to give pure aniline (11.2 g). The crude aniline, bis- (2-chloroethyl) amine hydrochloride (8.6g) and chlorobenzene (200mL) were boiled under reflux for 48 h. The reaction mixture was cooled to room temperature and the volatile solvent evaporated in vacuo to give crude 1- { [3- (dimethylamino) phenoxy ] phenyl } piperazine (18.6 g). A solution of crude piperazine, di-tert-butyl dicarbonate (32g) and potassium carbonate (68g) in tetrahydrofuran: water/1: 1 was heated at 50 ℃ for 18 hours. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The collected organic phases were treated according to standard procedures and then purified by silica gel chromatography (heptane: ethyl acetate/8: 2) to give pure BOC-protected 1- { [ 3-dimethyl) phenoxy ] phenyl } piperazine (9.4 g). A solution of the BOC-derivative in a mixture of anhydrous tetrahydrofuran (30mL) and trifluoroacetic acid (30mL) was stirred at room temperature for 1 hour. The volatile solvent was evaporated in vacuo and ethyl acetate and 1N aqueous sodium hydroxide solution were added. The organic phases were collected and treated according to standard procedures to give pure 1- { [3- (dimethylamino) phenoxy ] phenyl } piperazine (6.0 g). A mixture of partially pure piperazine (1.37g), 3- (2-bromoethyl) -1H-indole (1.0g), potassium carbonate (2.2g), potassium iodide (catalytic amount) and methyl isobutyl ketone was boiled under reflux for 24 hours. The mixture was cooled to room temperature, filtered, the volatile solvent evaporated in vacuo and the oil obtained was purified by silica gel chromatography (heptane: ethyl acetate: triethylamine/26: 70: 4) to give the title compound as an oil. The oxalate salt of the title compound (1.27g) was crystallized from acetone. Mp 210-.

¹H NMR/250 MHz(DMSO-d₆)：2.85(s，6H)；3.00-3.35(m，12H)；6.15(d，1H)；6.35(s，1H)；6.45(d，1H)；6.85(d，1H)；6.95-7.15(m，6H)；7.20(s，1H)；7.35(d，1H)；7.55(d，1H)；10.90(s，1H)。MS：m/z：441(MH+)，144。C₂₈H₃₂N₄Calculated value of O: c, 67.89; h, 6.47; n, 10.56. Measured value: c, 67.34; h, 6.59; and N, 10.30.

The following compounds were prepared using the same general procedure:

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [2- (1H-indol-3-yl) ethyl]Piperazine oxalate (1 b). Mp 221-.¹H NMR(250MHz，DMSO-d₆)：3.00-3.35(m，12H)；6.00(s，2H)；6.40(dd，1H)；6.65(d，1H)；6.80-6.90(m，2H)；6.95-7.15(m，5H)；7.20(d，1H)；7.35(d，1H)；7.55(d，1H)；10.90(s，1H)。MS：m/z：443(MH+)，311，131。C₂₇H₂₇N₃O₃The calculated value of (a): c, 65.10; h, 5.54N, 7.86. Measured value: c, 64.86; h, 5.55; and N, 7.60.

Example 2

1- {2- [3- (methylamino) phenoxy ] phenyl } -4- [3- (1H-indol-3-yl) propyl ] piperazine (2a)

To a suspension of lithium aluminum hydride (8.0g) in tetrahydrofuran (500mL) was added dropwise a solution of 3-indolpropanic acid (20g) in tetrahydrofuran (100 mL). The reaction mixture was stirred at room temperature for 1 hour, then cooled to 5 ℃ and water (16mL), 15% sodium hydroxide, were added sequentiallyAfter stirring the reaction mixture overnight at room temperature after water (8.0mL) and water (40mL), it was filtered. Evaporation of the volatile solvent gave pure 3- (1H-indol-3-yl) propanol oil (19.1 g). 3- (1H-indol-3-yl) propanol (18.6g) and carbon tetrabromide (42.1g) were dissolved in acetonitrile (1L), cooled to 0 ℃ and triphenylphosphine (30.7g) was added in small portions. The reaction was stirred at room temperature for a further 3 hours, the volatile solvent evaporated in vacuo and the remaining oil purified by silica gel chromatography (heptane: ethyl acetate/2: 1) to give 3- (3-bromopropyl) -1H-indole (25.6 g). This intermediate was coupled to a piperazine moiety using the procedure described in example 1 to give the title compound as an isolated amorphous solid.¹H NMR(250MHz，DMSO-d₆)：.1.80(q，2H)；2.25-2.40(m，6H)；2.65(t，2H)；2.85(s，6H)；3.05(m，4H)；6.10(dd，1H)；6.30(t，1H)；6.45(dd，1H)；6.80-7.10(m，8H)；7.30(d，1H)；7.50(d，1H)；10.70(b，1H)。MS：m/z：455(MH+)，295，239，201，130。

The following compounds were prepared using a similar procedure:

1- [2- (1, 3-benzodioxol-5-yloxy)]Phenyl radical]-4- [3- (1H-indol-3-yl) propyl]Piperazine oxalate (2 b). Mp 156-162 ℃.¹H NMR(250MHz，DMSO-d₆)：1.80(q，2H)；2.25-2.40(m，6H)；2.70(t，2H)；3.05(m，4H)；6.00(s，2H)；6.35(dd，1H)；6.55(d，1H)；6.85(d，2H)；6.90-7.15(m，6H)；7.30(d，1H)；7.50(d，1H)；10.75(s，1H)。MS：m/z：456(MH+)，297，201，130。C₂₈H₂₉N₃O₃The calculated value of (a): c, 73.81; h, 6.43; and N, 9.23. Measured value: c, 73.28; h, 6.45; and N, 9.00. 1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [3- (6-chloro-1H-indol-3-yl) propyl]Piperazine dihydrochloride (2 c). Mp 165 deg.C (decomposition).¹H NMR(250MHz，DMSO-d₆)：2.08(m，2H)；2.73(t，2H)；3.02(m，2H)；3.15(m，4H)；3.55(t，4H)；6.00(s，2H)；6.40(d，1H)；6.65(s，1H)；6.80(d，1H)；6.85(d，1H)；7.00(m，2H)；7.05(m，2H)；7.25(d，1H)；7.38(s，1H)；7.55(dd，1H)；10.45(s，1H)；11.00(s，1H)。MS(m/z)：490(MH+)。C₂₈H₃₀Cl₃N₃O₃The calculated value of (a): c, 59.73; h, 5.38; and N, 7.47. Measured value: c, 59.13; h, 5.36; and N, 7.26. 1- [2- (2-methoxyphenoxy) phenyl]-4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine dihydrochloride (2 d). Mp 183-189 ℃.¹H NMR(500MHz，DMSO-d₆)：2.12(m，2H)；2.73(t，2H)；3.05-3.25(m，6H)；3.55(d，2H)；3.65(d，2H)；3.75(s，3H)；6.53(m，1H)；6.88-7.20(m，9H)；7.27-7.40(m，3H)；11.05(s，2H)。MS(m/z)：460(MH+)。C₂₈H₃₂Cl₂FN₃O₂The calculated value of (a): c, 63.16; h, 6.06; and N, 7.89. Measured value: c, 63.04; h, 6.07; and N, 7.88.

1- [2- (1, 4-benzodioxan-6-yloxy) phenyl]-4- [3- (1H-indol-3-yl) propyl]Piperazine (2 e).¹H NMR(250MHz，CDCl₃): 1.90(qui, 2H); 2.40-2.60(m, 6H); 2.79(t, 2H); 3.15(t, 4H); 4.22(s, 4H); 6.45(m, 2H); 6.77(d, 1H); 6.85-7.22(m, 7H); 7.35(d, 1H); 7.60(d, 1H); 7.92(s, 1H). MS (m/z): 470(MH +). 1- [2- (1, 4-benzodioxan-5-yloxy) phenyl]-4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine (2 f).¹H NMR(250 MHz，CDCl₃): 1.90(qui, 2H); 2.38-2.53 (m, 6H); 2.73(t, 2H); 3.16(t, 4H); 4.26(s, 4H); 6.38(dd, 1H); 6.60-6.75(m, 2H); 6.83-7.10(m, 6H); 7.23-7.30(m, 3H); 7.92(s, 1H). LC/MS (m/z): 488(MH +), Rt 2.53, purity 99.8%.

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl]-4- [3- (6-chloro-1H-indol-3-yl) propyl]Piperazine (2 g).¹H NMR(250 MHz，CDCl₃): 1.90(qui, 2H); 2.35-2.50(m, 6H); 2.75(t, 2H); 3.18(t, 4H); 4.28(s, 4H); 6.40(dd, 1H); 6.60-6.75(m, 3H); 6.80-7.08(m, 6H); 7.32(d, 1H); 7.50(d, 1H); 7.95(s, 1H). LC/MS (m/z): 504(MH +), Rt 2.60, purity 99.6%.

1- [2- (1, 4-benzodioxan-6-yloxy) phenyl]-4- [3- (6-chloro-1H-indol-3-yl) propyl]Piperazine (2 h).¹H NMR(250MHz，CDCl₃): 1.90(qui, 2H); 2.35-2.55(m, 6H); 2.75(t, 2H); 3.15(t, 4H); 4.23(s, 4H); 6.45(m, 2H); 6.78-6.15(m, 7H); 7.32(d, 1H); 7.50(d, 1H); 7.92(s, 1H). LC/MS (m/z): 504(MH +), Rt 2.62, 99.7% purity.

1- [2- (2-methoxyphenoxy) phenyl]-4- [3- (6-chloro-1H-indol-3-yl) propyl]Piperazine (2 i). 6-chloro-3- (3- {4- [2- (2-methoxy-phenoxy) -phenyl]-piperazin-1-yl } -propyl) -1H-indole¹HNMR(250MHz，CDCl₃): 1.90(qui, 2H); 2.35-2.50(m, 6H); 2.73(t, 2H); 3.19(t, 4H); 3.83(s, 3H); 6.70-7.08(m, 10H); 7.32(d, 1H); 7.49(d, 1H); 7.94(s, 1H). LC/MS (m/z): 476(MH +), Rt 2.59, 99.8% purity.

1- [2- (3-methoxyphenoxy) phenyl]-4- [3- (6-chloro-1H-indol-3-yl) propyl]Piperazine (2 j).¹H NMR(250MHz，CDCl₃): 1.89(qui, 2H); 2.33-2.60(m, 6H); 2.73(t, 2H); 3.13(t, 4H); 3.75(s, 3H); 6.49(m, 2H); 6.58(dd, 1H); 6.95-7.20(m, 7H); 7.32(d, 1H); 7.49(d, 1H); 7.92(s, 1H). LC/MS (m/z): 476(MH +), Rt 2.64, purity 99.7%.

Example 3

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine (3a)

4- [ (4-Nitrophenoxy) carbonyloxymethyl ] phenoxymethyl polystyrene (267.0g, 235mmol) was suspended in anhydrous N, N-dimethylformamide (2L). N-methylmorpholine (238.0g, 2.35mol) and piperazine (102.0g, 1.17mol) were added and the reaction mixture was stirred at room temperature for 16 hours. The resin was filtered off and washed with N, N-dimethylformamide (2X 1L), tetrahydrofuran (2X 1L), water (1X 500mL), methanol (2X 1L), tetrahydrofuran (2X 1L), methanol (1X 1L). Finally, the resin was washed with dichloromethane (3X 500mL) and dried in vacuo (25 ℃, 36 h) to give an almost colorless resin (240.0 g).

The thus-obtained partial resin (115.1g, 92mmol) was suspended in anhydrous tetrahydrofuran (1.6L), and hexafluoro-fluoride was addedPhosphoric acid eta⁶-1, 2-dichlorobenzene-eta⁵Cyclopentadienyl iron (II) (76.0g, 184mmol) and then potassium carbonate (50.9g, 368mmol) was added. The reaction mixture was stirred at 60 ℃ for 16 hours. After cooling to room temperature, the resin was filtered off and washed with tetrahydrofuran (2X 500mL), water (2X 250mL), methanol (2X 250mL), dichloromethane (2X 500mL), methanol (2X 250 mL). Finally, the resin was washed with dichloromethane (3X 500mL) and dried in vacuo (25 ℃, 36 h) to give a dark orange resin (142 g).

To a solution of 2-hydroxyanisole (2.2g, 17.7mmol) in tetrahydrofuran (50mL) at room temperature was carefully added pure sodium hydride (15.5mmol) (caution: generation of hydrogen). After hydrogen generation ceased, the mixture was stirred for an additional 30 minutes. Then, part of the resin obtained above (2.8g, 1.72mmol) was added, and the mixture was stirred at 40 ℃ for 12 hours. After cooling to room temperature, the resin was filtered off and washed with tetrahydrofuran (2X 50mL), tetrahydrofuran/water (1: 1) (2X 50mL), N-dimethylformamide (2X 50mL), water (2X 50mL), methanol (3X 50mL), tetrahydrofuran (3X 50 mL); the resin was then washed with methanol and tetrahydrofuran (50mL each, 5 cycles). Finally, the resin was washed with dichloromethane (3X 50mL) and dried in vacuo (25 ℃, 12 h).

The resin thus obtained (3.0g, 1.84mmol) and a 0.5M solution of 1, 10-phenanthroline in a pyridine/water (3: 1) mixture (20mL) were added to a light-transmitting reaction tube. For decomplexing, the suspension was vortexed and irradiated with visible light for 12 hours. The most prominent feature of the decomplexing step is that the liquid phase appears dark red during irradiation. The resin was filtered off, washed with methanol (2X 25mL), water (2X 25mL) and tetrahydrofuran (3X 25mL) until the washings remained colorless (5 cycles), and the irradiation process was repeated until the decomplexation was complete (5 cycles). After complete decomplexation, the resin was washed with dichloromethane (3X 25mL) and dried under vacuum (25 ℃ C., 12 h).

The resin (ca. 2.5g, 1.84mmol) was suspended in a 1: 1 mixture of trifluoroacetic acid and dichloromethane (25mL) and stirred at room temperature for 2 h. The resin was filtered off and washed with methanol (1X 5mL) and dichloromethane (1X 5 mL). The liquid phases were combined and the volatile solvent was evaporated to give a dark brown oil (1.5 g).

The oil was dissolved in acetonitrile (10 mL). To the solution thus obtained, potassium carbonate (46mg, 0.33mmmol) and 3- (3-bromopropyl) -1H-indole (33mg, 0.14mmol) were added, and the mixture was heated at 70 ℃ for 12 hours. Isocyanomethyl polystyrene (250mg, 0.29mmmol) was added and the mixture was slowly cooled to room temperature. The resin was filtered off and washed with methanol (1X 2mL) and dichloromethane (1X 2 mL). The volatile solvent in the combined liquid phases was evaporated to give a dark brown oil. The crude product was purified by preparative reverse phase HPLC chromatography. The resulting solution was then loaded onto a pretreated ion exchange column. The column was washed with methanol (4mL) and acetonitrile (4mL), then the product was eluted with 4N ammonia in methanol (4.5 mL). The volatile solvent was evaporated to give the title compound 3a as a yellow oil (66 mg). LC/MS (m/z)442 (MH)⁺) And Rt ═ 4.15, purity 93%.

The following compounds were prepared in a similar manner:

1- (2-phenoxyphenyl) -4- [4- (1H-indol-3-yl) butyl]Piperazine (3 b): LC/MS (m/z)426 (MH)⁺) RT ═ 4.36, purity: 79 percent.

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [4- (1H-indol-3-yl) butyl]Piperazine (3 c): LC/MS (m/z)470 (MH)⁺) RT ═ 2.62, purity: 89 percent.

1- [2- (2-methoxyphenoxy) phenyl]-4- [2- (6-chloro-1H-indol-3-yl) ethyl]Piperazine (3 d): LC/MS (m/z)462 (MH)⁺) RT ═ 4.35, purity: 76 percent.

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [2- (6-chloro-1H-indol-3-yl) ethyl]Piperazine (3 e): LC/MS (m/z)476 (MH)⁺) RT ═ 2.64, purity: 89 percent.

1- {2- [3- (dimethylamino) phenoxy]Phenyl } -4- [2- (6-chloro-1H-indol-3-yl) ethyl]Piperazine (3 f): LC/MS (m/z)475 (MH)⁺) RT ═ 2.32, purity: 91 percent.

1- [2- (2-methoxy)Phenoxy) phenyl]-4- [4- (1H-indol-3-yl) butyl]Piperazine (3 g): LC/MS (m/z)456 (MH)⁺) RT ═ 4.31, purity: 90 percent.

1- [2- (4-methoxyphenoxy) phenyl]-4- [3- (1H-indol-3-yl) propyl]Piperazine (3 h): LC/MS (m/z)442 (MH)⁺) RT ═ 4.18, purity: 90 percent.

1- {2- [3- (dimethylamino) phenoxy]Phenyl } -4- [4- (1H-indol-3-yl) butyl]Piperazine (3 i): LC/MS (m/z)469 (MH)⁺) RT ═ 2.27, purity: 88 percent.

1- (2-phenoxyphenyl) -4- [2- (6-chloro-1H-indol-3-yl) ethyl]Piperazine (3 j): LC/MS (m/z)432 (MH)⁺) RT ═ 4.40, purity: 70 percent.

Example 4

2- (4-chlorobutyl) -1, 3-dioxolan-4-ylmethoxymethyl-polystyrene (4a)

2, 2-dimethyl-1, 3-dioxolan-4-ylmethoxymethyl polystyrene (90g, 72mmol, commercially available from Calbiochem-Novabiochem as (. + -.) -1- (2, 3-isopropylidene) glycerol polystyrene, Cat. No. 01-64-0291) was charged into a 2L round bottom flask. Toluene (900mL), p-toluenesulfonic acid monohydrate (5.0g, 26mmol), sodium sulfate (25g) and 5-chloropentanal (25.5g, 211mmol) were added successively, and the mixture was boiled under reflux for 12 hours. The reflux condenser was replaced by a Dean-Stark apparatus and the mixture was boiled under reflux for 3 hours. After the reaction mixture was cooled to 60 ℃, the resin was filtered off and washed with toluene (200mL), tetrahydrofuran/pyridine (1: 1, 200mL), tetrahydrofuran/water/pyridine (10: 1, 200mL), methanol (200mL), water (200mL), tetrahydrofuran (200mL), dichloromethane (200mL), methanol (3X 200mL) and dichloromethane (3X 200 mL). The resin was dried in vacuo (55 ℃ C., 12 h) to give the title compound 4a (97 g).

The following compounds were prepared in a similar manner:

2- (3-chloropropyl) -1, 3-dioxolan-4-ylmethoxymethyl-polystyrene (4b)

2- (5-Chloropentyl) -1, 3-dioxolan-4-ylmethoxymethyl-polystyrene (4c)

Example 5

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine (5a)

2- (3-chlorobutyl) -1, 3-dioxolan-4-ylmethoxymethyl-polystyrene (70g, 90.3mmol) was suspended in anhydrous N, N-dimethylformamide (700 mL). Sodium iodide (68g, 452mmol) was added followed by diisopropylethylamine (232mL, 1.36mol) and piperazine (117g, 1.36 mol). The reaction mixture was heated with stirring at 80 ℃ for 12 hours. After cooling to room temperature, the resin was filtered off, washed with N, N-dimethylformamide (3X 500mL), methanol (3X 500mL), tetrahydrofuran (3X 500mL), then methanol and tetrahydrofuran (250 mL each, 5 cycles). Finally, the resin was washed with dichloromethane (3X 500mL) and dried under vacuum (25 ℃, 36 h) to give an almost colorless resin (76 g).

Then, the thus-obtained partial resin (50g, 60.6mmol) was suspended in anhydrous tetrahydrofuran (600mL), and η hexafluorophosphate was added⁶-1, 2-dichlorobenzene-eta⁵Cyclopentadienyl iron (II) (48g, 116.2mmol) and then potassium carbonate (32g, 233mmol) was added. The reaction mixture was stirred at 60 ℃ for 12 hours. After cooling to room temperature, the resin was filtered off and washed with tetrahydrofuran (2X 500mL), water (2X 250mL), tetrahydrofuran (2X 500mL), methanol (2X 250mL), dichloromethane (2X 500mL), methanol (2X 250 mL). Finally, the resin was washed with dichloromethane (3X 500mL) and dried in vacuo (25 ℃, 36 h) to give a dark orange resin (70 g).

To a solution of 5-hydroxy-1, 4-benzodioxan (2.8g, 18.4mmol) in tetrahydrofuran (50mL) at room temperature was carefully added pure sodium hydride (15.5mmol) (caution: hydrogen evolution). After hydrogen generation ceased, the mixture was stirred for an additional 30 minutes. Then, part of the resin obtained above (2.8g, 2.3mmol) was added and the mixture was stirred at 40 ℃ for 12 hours. After cooling to room temperature, the resin was filtered off and washed with tetrahydrofuran (2X 50mL), tetrahydrofuran/water (1: 1) (2X 50mL), N-dimethylformamide (2X 50mL), water (2X 50mL), methanol (3X 50mL), tetrahydrofuran (3X 50 mL); then washed with methanol and tetrahydrofuran (50mL each, 5 cycles). Finally, the resin was washed with dichloromethane (3X 50mL) and dried in vacuo (25 ℃, 12 h).

The portion of resin thus obtained (200mg, 0.15mmol) and a 0.5M solution of 1, 10-phenanthroline in a pyridine/water (3: 1) mixture (10mL) were added to a light-transmitting reaction tube. The suspension was vortexed and irradiated for 12 hours. The most prominent feature of the decomplexing step is that the liquid phase appears dark red during irradiation. The resin was filtered off, washed with methanol (2X 10mL), water (2X 10mL) and tetrahydrofuran (3X 10mL) until the washings remained colorless (about 5 cycles), and the irradiation process was repeated until the decomplexation was complete (about 4 cycles). After complete decomplexation, the resin was washed with dichloromethane (3X 10mL) and dried under vacuum (25 ℃ C., 12 h).

The resin thus obtained (160mg, 0.15mmol) and 4-fluorophenylhydrazine hydrochloride (35mg, 0.21mmol) were mixed in a reaction tube. A0.5M solution of anhydrous zinc chloride in acetic acid (1.5mL) was added and the reaction tube was sealed. The reaction mixture was stirred at 70 ℃ for 12 hours. After cooling to room temperature, the reaction mixture was filtered and the residual resin was washed with dimethylsulfoxide (1.5 mL). A saturated aqueous solution of sodium carbonate (1.5mL) was carefully added to the combined filtrates (note: carbon dioxide evolution). The solution was loaded onto a pretreated reverse phase C-18 column. The column was washed with water (4mL) and the product was eluted with methanol (4.5 mL). After evaporation of the volatile solvent, the crude product was purified by preparative reverse phase HPLC chromatography. The resulting solution was then loaded onto a pretreated ion exchange column. The column was washed with methanol (4mL) and acetonitrile (4mL), then the product was eluted with 4N ammonia in methanol (4.5 mL). Evaporation of the volatile solvent gave the title compound 5a as a yellow oil (2 mg). LC/MS (m/z)488 (MH)⁺) And Rt 4.22, purity 84%.

The following compounds were prepared in a similar manner:

1- (2-phenoxyphenyl) -4- [3- (5-methyl-1H-indol-3-yl) propyl]Piperazine (5 b): LC/MS (m/z)426 (MH)⁺) RT ═ 4.44, purity: 88 percent.

1- [2- (2-methoxyphenoxy) phenyl]-4- [3- (5-chloro-1H-indol-3-yl) propyl]Piperazine (5 c): LC/MS (m/z)476 (MH)⁺) RT ═ 4.46, purity: 95 percent.

1- [2- (2-methoxyphenoxy) phenyl]4- [3- (5-bromo-1H-indol-3-yl) propyl]Piperazine (5 d): LC/MS (m/z)522 (MH)⁺) RT ═ 4.52, purity: 91 percent.

1- (2-phenoxyphenyl) -4- [ 3-1H-indol-3-yl) propyl) piperazine (5 e): LC/MS (m/z)412 (MH)⁺) RT ═ 4.25, purity: 98 percent.

1- (2-phenoxyphenyl) -4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine (5 f): LC/MS (m/z)430 (MH)⁺) RT ═ 4.32, purity: 96 percent.

1- (2-phenoxyphenyl) -4- [3- (5-bromo-1H-indol-3-yl) propyl]Piperazine (5 g): LC/MS (m/z)492 (MH)⁺) RT ═ 4.60, purity: 84 percent.

1- [2- (2, 6-Dimethoxyphenoxy) phenyl]-4- [3- (5-bromo-1H-indol-3-yl) propyl]Piperazine (5 h): LC/MS (m/z)552 (MH)⁺) RT ═ 4.49, purity: 86 percent.

1- {2- [3- (methylamino) phenoxy]Phenyl } -4- [3- (5-methyl-1H-indol-3-yl) propyl]Piperazine (5 i): LC/MS (m/z)469 (MH)⁺) RT ═ 3.73, purity: 86 percent.

1- (2-phenoxyphenyl) -4- [3- (5-chloro-1H-indol-3-yl) propyl]Piperazine (5 j): LC/MS (m/z)446 (MH)⁺) RT ═ 4.52, purity: 88 percent.

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [3- (5-methyl-1H-indol-3-yl) propyl]Piperazine (5 k): LC/MS (m/z)470 (MH)⁺) RT ═ 4.38, purity: 70 percent.

1- [2- (2-methoxyphenoxy) phenyl]-4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine (5 l): LC/MS (m/z)460 (MH)⁺) RT ═ 4.24, purity: 87 percent.

1- [2- (2-methoxybenzene)Oxy) phenyl]-4- [3- (7-chloro-1H-indol-3-yl) propyl]Piperazine (5 m): LC/MS (m/z)476 (MH)⁺) RT ═ 4.42, purity: 96 percent.

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine (5 n): LC/MS (m/z)474 (MH)⁺) RT ═ 4.25, purity: 99 percent.

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [3- (5-iodo-1H-indol-3-yl) propyl]Piperazine (5 o): LC/MS (m/z)582 (MH)⁺) RT ═ 4.58, purity: 85 percent.

1- (2-phenoxyphenyl) -4- [3- (7-chloro-1H-indol-3-yl) propyl]Piperazine (5 p): LC/MS (m/z)430 (MH)⁺) RT ═ 4.38, purity: 87 percent.

1- (2-phenoxyphenyl) -4- [3- (5, 7-difluoro-1H-indol-3-yl) propyl]Piperazine (5 q): LC/MS (m/z)448 (MH)⁺) RT ═ 4.44, purity: 84 percent.

1- [2- (2-methoxyphenoxy) phenyl]-4- [3- (7-bromo-1H-indol-3-yl) propyl]Piperazine (5 r): LC/MS (m/z)520 (MH)⁺) RT ═ 4.50, purity: 77 percent.

1- {2- [3- (dimethylamino) phenoxy]Phenyl } -4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine (5 s): LC/MS (m/z)473 (MH)⁺) RT ═ 3.63, purity: 96 percent.

1- [2- (2-methoxyphenoxy) phenyl]-4- [3- (5-iodo-1H-indol-3-yl) propyl]Piperazine (5 t): LC/MS (m/z)568 (MH)⁺) RT ═ 4.63, purity: 82 percent.

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [3- (5-chloro-1H-indol-3-yl) propyl]Piperazine (5 u): LC/MS (m/z)490 (MH)⁺) RT ═ 4.45, purity: 90 percent.

1- [2- (2, 6-Dimethoxyphenoxy) phenyl]-4- [3- (5-chloro-1H-indol-3-yl) propyl]Piperazine (5 v): LC/MS (m/z)506 (MH)⁺) RT ═ 4.46, purity: 83 percent.

1- [2- (1, 3-benzodioxyl)Pent-5-yloxy) phenyl]-4- [3- (1H-pyrrolo [3, 2-H)]-quinolin-3-yl) propyl]Piperazine (5 w): LC/MS (m/z)507 (MH)⁺) RT ═ 3.30, purity: 97 percent.

1- [2- (2-methoxyphenoxy) phenyl]-4- [3- (5, 7-difluoro-1H-indol-3-yl) propyl]Piperazine (5 x): LC/MS (m/z)478 (MH)⁺) RT ═ 4.36, purity: 75 percent.

1- (2-phenoxyphenyl) -4- [3- (5-iodo-1H-indol-3-yl) propyl]Piperazine (5 y): LC/MS (m/z)5.38 (MH)⁺) RT ═ 4.69, purity: 92 percent.

1- [2- (2-methoxyphenoxy) phenyl]-4- [3- (1H-pyrrolo [3, 2-H)]Quinolin-3-yl) propyl]Piperazine (5 z): LC/MS (m/z)493.2 (MH)⁺) RT ═ 3.29, purity: 96 percent.

1- [2- (3-methoxyphenoxy) phenyl]-4- [3- (1H-pyrrolo [3, 2-H)]Quinolin-3-yl) propyl]Piperazine (5 aa): LC/MS (m/z)493 (MH)⁺) RT ═ 3.38, purity: 96 percent.

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl]-4- [3- (5-methyl-1H-indol-3-yl) propyl]Piperazine (5 ab): LC/MS (m/z)484 (MH)⁺) RT ═ 4.35, purity: 84 percent.

1- [2- (2, 6-Dimethoxyphenoxy) phenyl]-4- [3- (5-methyl-1H-indol-3-yl) propyl]Piperazine (5 ac): LC/MS (m/z)486 (MH)⁺) RT ═ 4.38, purity: 80 percent.

1- [2- (3-methoxyphenoxy) phenyl]-4- [3- (1H-indol-3-yl) propyl]Piperazine (5 ad): LC/MS (m/z)442 (MH)⁺) RT ═ 4.25, purity: 85 percent.

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl]-4- [3- (1H-indol-3-yl) propyl]Piperazine (5 ae): LC/MS (m/z)471 (MH)⁺) RT ═ 4.13, purity: 83 percent.

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [3- (5-bromo-1H-indol-3-yl) propyl]Piperazine (5 af): LC/MS (m/z)536 (MH)⁺) RT ═ 4.49, purity: 88 percent.

1- {2- [3- (morpholin-4-yl) phenoxy]Phenyl } -4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine (5 ag): LC/MS (m/z)515 (MH)⁺) RT ═ 4.17, purity: 94 percent.

1- [2- (3-methoxyphenoxy) phenyl]-4- [3- (5-chloro-1H-indol-3-yl) propyl]Piperazine (5 ah): LC/MS (m/z)476 (MH)⁺) RT ═ 4.53, purity: 92 percent.

1- [2- (3-ethoxyphenoxy) phenyl]-4- [3- (5-methyl-1H-indol-3-yl) propyl]Piperazine (5 ai): LC/MS (m/z)470 (MH)⁺) RT ═ 4.68, purity: 85 percent.

1- [2- (2, 6-Dimethoxyphenoxy) phenyl]-4- [3- (5-iodo-1H-indol-3-yl) propyl]Piperazine (5 aj): LC/MS (m/z)598 (MH)⁺) RT ═ 4.61, purity: 70 percent.

1- {2- [3- (diethylamino) phenoxy]Phenyl } -4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine (5 ak): LC/MS (m/z)501 (MH)⁺) RT ═ 3.18, purity: 87 percent.

1- [2- (2, 6-Dimethoxyphenoxy) phenyl]-4- [3- (5-fluoro-1H-indol-3-yl) propyl]Piperazine (5 al): LC/MS (m/z)490 (MH)⁺) RT ═ 4.26, purity: 88 percent.

1- {2- [3- (morpholin-4-yl) phenoxy]Phenyl } -4- [3- (5-bromo-1H-indol-3-yl) propyl]Piperazine (5 am): LC/MS (m/z)475 (MH)⁺) RT ═ 4.42, purity: 78 percent.

1- {2- [3- (morpholin-4-yl) phenoxy]Phenyl } -4- [3- (5-chloro-1H-indol-3-yl) propyl]Piperazine (5 an): LC/MS (m/z)531 (MH)⁺) RT ═ 4.34, purity: 81 percent.

1- {2- [3- (morpholin-4-yl) phenoxy]Phenyl-4- [3- (5-iodo-1H-indol-3-yl) propyl]Piperazine (5 ao): LC/MS (m/z)623 (MH)⁺) RT ═ 4.56, purity: 71 percent.

1- [2- (3-methoxyphenoxy) phenyl]-4- [3- (7-fluoro-1H-indol-3-yl) propyl]Piperazine (5 aq): LC/MS (m/z)460 (MH)⁺) RT ═ 4.38, purity: 70 percent.

1- (2-phenoxyphenyl) -4- [3- (5, 7-dimethyl-4H-indol-3-yl) propyl]Piperazine (5 ar): LC/MS (m/z)440 (MH)⁺) RT ═ 4.64, purity: 78 percent.

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl]-4- [3- (7-bromo-1H-indol-3-yl) propyl]Piperazine (5 as): LC/MS (m/z)534 (MH)⁺) RT ═ 4.46, purity: 75 percent.

1- [2- (3, 4, 5-trimethoxyphenoxy) phenyl]-4- (5-bromo-1H-indol-3-yl) propyl]Piperazine (5 at): LC/MS (m/z)580 (MH)⁺) RT ═ 4.34, purity: 81 percent.

Pharmacological test

The compounds of the invention were tested using known reliable methods. The test was performed as follows.

To pair³H-YM-09151-2 and human dopamine D₄Inhibition of receptor binding

The method is used for measuring the drug pair in vitro³H]YM-09151-2(0.06nM) and human clone dopamine D expressed in CHO cells_4.2Inhibition of receptor membrane binding. The method used was an improvement of NEN Life Science Products, Inc., technical documentation PC 2533-10/96. IC (integrated circuit)₅₀The results are shown in Table 1 below.

Para 2³H]-spiperone with human D₃Inhibition of receptor binding

The method is used for measuring the drug pair in vitro³H]Spiroperone (0.3nM) and human clone dopamine D expressed in CHO cells₃Inhibition of receptor membrane binding. The method used was an improvement of r.g. mackenzie et al, eur.j.pharm. -mol.pharm.sec., 1994, 266, 79-85. IC (integrated circuit)₅₀The results are shown in Table 1 below.

By detecting the coupling of radioligand to 5-HT as described in the following assay_1AInhibition of receptor binding, thereby determining the binding of the compounds of the invention to 5-HT_1AThe affinity of the receptor.

To pair³H-5-CT and human 5-HT_1AInhibition of receptor binding

The method is applied to in vitro determination of 5-HT of the drug_1AAgonists³H-5-carboxamidochramine(s) ((³H-5-CT) and cloned human 5-HT stably expressed in transfected HeLa cells (HA7) (Fargin, A. et al, J.biol.chem., 1989, 264, 14848)_1AInhibition of receptor binding. The assay was performed according to a modification of the method described in Harrington, m.a. et al, j.pharmacol.exp.ther., 1994, 268, 1098. Human 5-HT_1AThe receptor (40. mu.g of cell homogenate) was incubated in 50mM Tris buffer (pH7.7) containing 3H-5-CT at 37 ℃ for 15 minutes. Nonspecific binding was determined by addition of 10. mu.M of ergoline. The reaction was stopped by rapid filtration through a Uniflter GF/B filter on a Tomtec cell harvester. Filters were counted using a Packard Top counter. The results obtained are shown in table 1 below.

Uptake of brain synaptosomes in rats³Inhibition of H-5-HT

In vitro determination of drug pairs using this method³Inhibitory capacity of H-5-HT accumulation in synaptosomes throughout rat brain. The assay was performed as described in Hyttel, j., Psychopharmacology 1978, 60, 13. The results obtained are shown in table 1 below.

TABLE 1

Compound numbering	To pair3Inhibition of H-5-CT binding IC50(nM)	To pair3Inhibition of H-5-HT uptake IC50(nM)
			1b	7.8	130
2b	16	2.8
			3c	16	Inhibition was 27% at 100nM
3e	24	Inhibition of 40% at 100nM
			5a	19	14
5e	10	13
			5f	10	4.8
5h	10	Inhibition of 55% at 100nM
			5i	10	Inhibition at 100nM, 46%
51	13	4.7
			5x	18	33
5ae	26	Inhibition of 42% at 100nM
			5ag	26	23
5ai	28	Inhibition at 100nM, 34%

Thus, since the compounds of the present invention show affinity in said tests, they are considered useful for the treatment of affective disorders, such as depression, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social phobia and eating disorders, psychiatric and neurological disorders such as ischemia and senile dementia.

Claims (6)

1. A compound represented by the general formula I:

wherein R is⁷And R⁸Independently selected from hydrogen, halogen, C_1-6-alkyl, or R⁷And R⁸Together form a pyridyl ring fused to the phenyl ring;

n is 2, 3 or 4; and is

R¹、R²、R³、R⁴And R⁵Independently selected from hydrogen, C_1-6Alkoxy, NR^3’R^4’Wherein R is^3’And R^4’Independently of each other is hydrogen, C_1-6-an alkyl group; or R^3’And R^4’Together form a 4-morpholinyl group; or R¹、R²、R³、R⁴And R⁵Wherein two adjacent radicals together are composed of-O-CH₂-O-or-O-CH₂-CH₂-O-fused rings.

2. The compound of claim 1, wherein R¹、R²、R³、R⁴And R⁵One or both of which are not hydrogen.

3. The compound of claim 1, which is:

1- {2- [3- (dimethylamino) phenoxy ] phenyl } -4- [2- (1H-indol-3-yl) ethyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [2- (1H-indol-3-yl) ethyl ] piperazine;

1- {2- [3- (dimethylamino) phenoxy ] phenyl } -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-6-yloxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-6-yloxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (6-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [4- (1H-indol-3-yl) butyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [4- (1H-indol-3-yl) butyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [2- (6-chloro-1H-indol-3-yl) ethyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [2- (6-chloro-1H-indol-3-yl) ethyl ] piperazine;

1- [2- (3- (dimethylamino) phenoxy) phenyl ] -4- [2- (6-chloro-1H-indol-3-yl) ethyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [4- (1H-indol-3-yl) butyl ] piperazine;

1- [2- (4-methoxyphenoxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (3- (dimethylamino) phenoxy) phenyl ] -4- [4- (1H-indol-3-yl) butyl ] piperazine;

1- (2-phenoxyphenyl) -4- [2- (6-chloro-1H-indol-3-yl) ethyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ]4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (dimethylamino) phenoxy ] phenyl } -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (7-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (7-chloro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5, 7-difluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (7-bromo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3- (dimethylamino) phenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (1H-pyrrolo [3, 2-H ] quinolin-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (5, 7-difluoro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2-methoxyphenoxy) phenyl ] -4- [3- (1H-pyrrolo [3, 2-H ] quinolin-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (1H-pyrrolo [3, 2-H ] quinolin-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 4-benzodioxan-5-yloxy) phenyl ] -4- [3- (1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (morpholin-4-yl) phenoxy ] phenyl } -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-ethoxyphenoxy) phenyl ] -4- [3- (5-methyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3- (diethylamino) phenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- [2- (2, 6-dimethoxyphenoxy) phenyl ] -4- [3- (5-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (morpholin-4-yl) phenoxy ] phenyl } -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (morpholin-4-yl) phenoxy ] phenyl } -4- [3- (5-chloro-1H-indol-3-yl) propyl ] piperazine;

1- {2- [3- (morpholin-4-yl) phenoxy ] phenyl } -4- [3- (5-iodo-1H-indol-3-yl) propyl ] piperazine;

1- [2- (3-methoxyphenoxy) phenyl ] -4- [3- (7-fluoro-1H-indol-3-yl) propyl ] piperazine;

1- (2-phenoxyphenyl) -4- [3- (5, 7-dimethyl-1H-indol-3-yl) propyl ] piperazine;

1- [2- (1, 3-benzodioxol-5-yloxy) phenyl ] -4- [3- (7-bromo-1H-indol-3-yl) propyl ] piperazine; or

1- [2- (3, 4, 5-trimethoxyphenoxy) phenyl ] -4- [3- (5-bromo-1H-indol-3-yl) propyl ] piperazine.

4. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I according to any one of claims 1 to 3 or a pharmaceutically acceptable acid addition salt thereof in admixture with one or more pharmaceutically acceptable carriers or diluents.

5. Use of a compound of formula I according to any one of claims 1 to 3 or an acid addition salt thereof for the preparation of a pharmaceutical formulation for the treatment of affective or neurological diseases and disorders in humans caused by abnormalities of the 5-hydroxytryptamine system in the central nervous system.

6. The use of claim 5, wherein the disorder is depression, psychosis, generalized anxiety disorder, panic disorder, obsessive compulsive disorder, impulse control disorders, alcoholism, aggression, ischemia, senile dementia, and social phobia.