EA009417B1

EA009417B1 - 4-(2-phenyloxyphenyl)-piperidine or -1,2,3,6-tetrahydropyridine derivatives as serotonin reuptake inhibitors

Info

Publication number: EA009417B1
Application number: EA200501580A
Authority: EA
Inventors: Бенни Банг-Андерсен; Фридрих Кролл; Ян Келер
Original assignee: Х. Лундбекк А/С
Priority date: 2003-04-04
Filing date: 2004-04-02
Publication date: 2007-12-28
Also published as: IS7901A; KR20050119682A; CL2004000726A1; AR043966A1; CN1767829A; UA81469C2; ZA200505031B; EA200501580A1

Abstract

The invention provides compounds represented by the general formula (I)wherein the substituents are defined in the application as well as pharmaceutical compositions based thereon useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder social anxiety disorder, post traumatic stress disorder, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.

Description

The present invention relates to new compounds that are inhibitors of serotonin reuptake and are actually effective in the treatment of depression and anxiety.

Technical field

Selective serotonin reuptake inhibitors (hereinafter referred to as 88BI) were the first choice of therapeutic agents in the treatment of depression, some forms of anxiety states and social phobias, as they are effective, well tolerated and have a favorable safety profile compared to classic tricyclic antidepressants.

However, clinical studies of depression show that there is a significant lack of response to 88B! up to 30%. Another factor that is often not taken into account in antidepressant treatment is patient compliance with a medication regimen that has a strong and profound effect on the patient's motivation to continue drug therapy.

Firstly, there is a delay in the therapeutic effect of 88ΡΙ. Sometimes symptoms even worsen during the first weeks of treatment. Secondly, the usual side effect for 88B1 is an impaired sexual function. Without addressing these problems, real progress in the medical treatment of depression and anxiety-related illnesses seems to be less likely.

In clinical studies evaluated the combined effect of serotonin reuptake inhibition and inhibition of norepinephrine uptake of depression of compounds such as Duloxetine (Mopd, OYoheype (ΕΥ-248686): an shYyog Og kegoYupsh apy pogaygepaype ir ake apy an apyyergekkap ygid eapy1ya1e - Ehrey Orshyup!. Op 1peekydayopa1 Egidk, 1998, 7, 10, 1691-1699) and venlafaxine (K1apA e! a1., Uep1aGahshe sh yergekkey oi1rayep 18. Rkusjorjagastoy Villup, 1991, 27, 141-144).

The present invention provides new compounds that have a combined effect of inhibiting serotonin reuptake and inhibiting norepinephrine absorption in the treatment of affective diseases such as depression, anxiety states, including general anxiety, social anxiety, post-traumatic shock, obsessive compulsive disorder, panic disorder , panic attacks, specific phobias, social phobia and atraphobia.

Summary of Invention

The present invention provides compounds of general formula I

where the dotted line, B ¹ , B ² , B ³ , B ⁴ , B ⁵ , B ⁶ , B ⁷ , B ⁸ and B ⁹ have the meanings defined below.

The invention provides a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent.

The invention provides the use of a compound as described above, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of affective diseases such as depression, anxiety states, including general anxiety, social anxiety, post-traumatic shock, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.

The invention also provides a method for treating affective diseases such as depression, drug conditions, including general anxiety, social anxiety, post-traumatic shock, compulsive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in animals, including in humans, which comprises administering a therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable acid addition thereof. willow salt.

Determination of substituents

Halogen means fluorine, chlorine, bromine or iodine.

The definition of C _1-6 alkyl refers to branched or unbranched alkyl groups containing from one to six carbon atoms, including, but not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2- butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.

Definitions of C1 _-6- alkyloxy- and halo-C1 _-6- alkyl means those groups in which C1 _-6- alkyl has the meaning as defined above. Halogen means halogen.

- 1 009417

Description of the invention

The present invention relates to 4- (2-phenyloxyphenyl) piperidine derivatives or -1,2,3,6 tetrahydropyridine, which are serotonin reuptake inhibitors and are essentially effective in treating, for example, depression and anxiety states. In particular, piperidines are also good inhibitors of norepinephrine uptake.

Thus, the present invention relates to a derivative of 4- (2-phenyloxyphenyl) piperidine or -1,2,3,6-tetrahydropyridine of the general formula I

where the dotted line —— means a single bond or a double bond;

K ¹ , B ² , B ³ , B ⁴ , B ^{5 are} independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkyloxy, halo C _1-6 alkyl; or

B ² and B ³ together form a heterocycle condensed with a phenyl ring, selected from —Λ and B ¹ , B ⁴ , B ⁵ , as defined above;

or to its salt.

In one embodiment of the compound of formula I, the substituent B ^{1 is} selected from hydrogen, halogen, C1.6 alkyl, C1-6 alkyloxy, halo C1-6 alkyl. An additional illustration without limiting the invention is the variant where the substituent B ¹ is hydrogen; in another embodiment, B ¹ is C 1-6 alkyl, such as methyl; in another embodiment, B ¹ is a halogen, such as fluorine or chlorine.

In yet another embodiment of the compound of formula I, the substituent B ^{2 is} selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkyloxy, halogen-C 1-6 alkyl. An additional illustration without limiting the invention is the variant where the substituent B ² is hydrogen; in another embodiment, B ² is C1-6 alkoxy, such as methoxy; in another embodiment, B ² is halo-C 1-6 alkyl, such as trifluoromethyl; in yet another embodiment, the substituent B ² is C1-6 alkyl, such as methyl; in another embodiment, B ² is a halogen, such as chlorine.

In yet another embodiment of the compound of Formula I, the substituent B ^{3 is} selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkyloxy, halogen-C 1-6 alkyl. An additional illustration without limiting the invention is the variant where the substituent B ³ is hydrogen; in another embodiment, the substituent B ³ is C 1-6 alkyl, such as methyl; in yet another embodiment, substituent B ³ is C1-6 alkoxy, such as methoxy; in yet another embodiment, B ³ is halogen, such as chlorine or fluorine; in another embodiment, B ³ is halo-C 1-6 alkyl, such as trifluoromethyl.

In yet another embodiment of the compound of formula I, the substituents B ² and B ³ together form a heterocycle condensed with a phenyl ring selected from '—O · ⁹ '.

In yet another embodiment of the compound of Formula I, the substituent B ^{4 is} selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkyloxy, halogen-C 1-6 alkyl. An additional illustration without limiting the invention is the variant where the substituent B ⁴ is hydrogen; in another embodiment, B ⁴ is C1-6 alkoxy, such as methoxy; in another embodiment, B ⁴ is halo-C 1-6 alkyl, such as trifluoromethyl; in another embodiment, B ⁴ is C 1-6 alkyl, such as methyl; in another embodiment, B ⁴ is halogen, such as chlorine.

In yet another embodiment of the compound of Formula I, the substituent B ^{5 is} selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkyloxy, halogen-C 1-6 alkyl. An additional illustration without limiting the invention is the variant where the substituent B ⁵ is hydrogen; in another embodiment, the substituent B ⁵ is C 1-6 alkyl, such as methyl; in another embodiment, the substituent B ⁵ is halogen, such as chlorine or fluorine.

In yet another embodiment of the compound of formula I, the dotted line —— indicates a simple bond.

In yet another embodiment, the compounds of formula I, the dotted line indicates the double bond.

Typically, a compound of formula I has at least one substituent on the phenyl ring selected from any of the substituents B ¹ -B ⁵ that is different from hydrogen, for example, 1, 2, 3, or 4 substituents on the phenyl ring, selected from any of the substituents B ¹ -B ⁵ , which (s) differs (s) from hydrogen, and the remaining substituents are hydrogen. To illustrate these options without limiting the invention, here are some typical variations of the compounds.

Thus, in another embodiment of the compound of formula I, there is one substituent which is B ² , as defined above, with the exception of hydrogen. In another embodiment, with

- 009417 Unity of Formula I contains one substituent, which is B ³ , as defined above, with the exception of hydrogen. In yet another embodiment, the compounds of formula I contain two substituents representing B ¹ and B ² , where B ¹ and B ^{3 are} defined above, with the exception of hydrogen. In yet another embodiment, the compounds of formula I contain two substituents representing B ² and B ³ , where B ² and B ^{3 are} defined above, with the exception of hydrogen, in this connection the substituents B ² and B ³ can together form a heterocycle as defined above. In each of the above options, the remaining substituents are hydrogen.

In another embodiment of the compound of formula I, said compound is selected from the following compounds:

4- [2- (2,4-dimethylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine,

4- [2- (4-chlorophenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (4-fluoro-2-methylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (4-fluorophenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (4-methylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2 - (4-methoxyphenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (2,4-dimethylphenoxy) phenyl] piperidine,

4- [2- (4-chlorophenoxy) phenyl] piperidine,

4- [2- (4-fluoro-2-methylphenoxy) phenyl] piperidine, 4- [2- (4-fluorophenoxy) phenyl] piperidine,

4- [2- (4-methylphenoxy) phenyl] piperidine,

4- [2- (4-chloro-2-methylphenoxy) phenyl] piperidine, 4- [2- (2-chloro-4-methylphenoxy) phenyl] piperidine,

4- [2- (2,4-dichlorophenoxy) phenyl] piperidine,

4- [2- (benzo [b] thiophen-5-iloxy) phenyl] piperidine,

4- [2- (benzo [1,3] dioxol-5yloxy) phenyl] piperidine,

4- [2- (4-methoxy-2-methylphenoxy) phenyl] piperidine, 4- [2- (3,4-dichlorophenoxy) phenyl] piperidine, 4- [2- (3,4-dimethylphenoxy) phenyl] piperidine, 4- [2- (2,3,4,5-tetramethylphenoxy) phenyl] piperidine, 4- [2- (4-trifluoromethylphenoxy) phenyl] piperidine, 4- [2- (4-methoxyphenoxy) phenyl] piperidine, 4- [2- (2-chloro-4-methoxyphenoxy) phenyl] piperidine, 4- [2- (3,4-dimethoxyphenoxy) phenyl] piperidine, 4- [2- (4-chloro-3-trifluoromethylphenoxy) phenyl] piperidine or their pharmaceutically acceptable salts.

Each of these compounds is considered a specific embodiment of the invention and may be subject to separate claims.

As mentioned above, most of the tested compounds have a combined effect of inhibiting serotonin reuptake and inhibiting norepinephrine uptake, however, several compounds are selected from the following:

4- [2- (2,4-dimethylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (4-chlorophenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (4-fluoro-4-methylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (4-fluorophenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (4-methylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- (4-methoxyphenoxy) phenyl] -1,2,3,6-tetrahydropyridine, 4- [2- ( 3,4-dimethylphenoxy) phenyl] piperidine, 4- [2- (2,3,4,5-tetramethylphenoxy) phenyl] piperidine, 4- [2- (3,4-dimethoxyphenoxy) phenyl] piperidine performed in this work tests really show inhibition of serotonin reuptake, but show inhibition of norepinephrine uptake.

The present invention also includes salts of the compounds of the present invention, usually pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium salts, alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Typical examples of suitable inorganic acids are hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids, etc. Typical examples of suitable organic acids are formic, acetic, trichloroacetic, trifluoroacetate, propionic, benzoic, cinnamic, citric, fumaric, glycolic, octanoic, lactic, methanesulfonic, maleic, malic, methanesulfonic, maleic, malic, malonic, almond, oxalic, picnic, oxyphrine, maleic, malic, malic, citric, malic, oxalic methanesulfonic, ethanesulfonic, tartaric, ascorbic,

- 3 009417 pamovi, bismuth

Examples of salts with metals are salts of lithium, sodium, potassium, magnesium, etc.

Examples of ammonium and alkyl ammonium salts are ammonium, methyl, dimethyl, trimethyl, ethyl, hydroxyethyl, diethyl, n-butyl, sec, butyl, tert.-butyl, tetramethyl ammonium salts, etc.

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

The compounds of the present invention may contain one or more asymmetric centers, and it is understood that any of the optical isomers (i.e., enantiomers or diastereomers) that are isolated, pure or partially purified optical isomers and any mixtures thereof, including racemic mixtures, are included in scope of the present invention.

Racemic forms can be separated into their optical antipodes by known methods, for example, by separating diastereomeric salts with an optically active acid and releasing the optically active amine compound by treatment with a base. Other ways of separating racemates into their optical antipodes are based on chromatography on an optically active matrix. The racemic compounds of the present invention can be separated into their optical antipodes, for example, by fractional crystallization of b-or 1-salts (tartrates, mandelates or camphorsulfonates). The compounds of the present invention can also be separated by the formation of diastereomeric derivatives.

Other methods of separating optical isomers known to those skilled in the art can be used. Such methods are condemned in the publication 1. 1dek, A. So11e1, 8. XVPsp Eppapbotekk, Kasetalek apb K.koleukiuk, 1ppP ΧνίΚν apb 8opk, № \ ν Watk (1981).

Optically active compounds can also be obtained from optically active starting materials or by using stereoselective synthesis.

In addition, when a double bond or a fully or partially unsaturated cyclic system is present in the molecule, geometric isomers may exist. It is implied that any of the geometric isomers that are isolated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the present invention. Similarly, molecules having a bond with limited rotation can form geometric isomers. They are also included in the scope of the present invention.

In addition, some compounds of the present invention may exist in different tautomeric forms, and it is understood that all tautomeric forms that the compounds are capable of forming are included in the scope of the present invention.

The invention also includes prodrugs of the compounds of the present invention, which, upon administration, undergo chemical transformation by means of metabolic processes before transformation into pharmacologically active substances. In general, such prodrugs will be functional derivatives of the compounds of general formula (I), which are easily converted into the desired compounds of formula (I). Conventional procedures for the selection and methods for obtaining suitable prodrug forms are described, for example, in the publication Exec Pgobgidk, eb. N. Wipbdaagb, Ekeke, 1985.

The invention also includes active metabolites of the compounds of the present invention.

As mentioned above, the compounds of formula (I) are inhibitors of serotonin reuptake and, therefore, can be used for treatment, including prevention, affective disorders such as depression, anxiety states, including general anxiety, panic disorder and obsessive compulsive disorder.

Thus, in a first aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier or diluent. The composition may include one or more variants of the compounds of formula I, which are described above.

In an embodiment of the pharmaceutical composition, the compound of Formula I is present in an amount from about 0.001 to 100 mg / kg body weight per day.

The present invention also relates to the use of a compound of formula I for the manufacture of a medicament for treating a disease or disorder, where a serotonin reuptake inhibitor has a positive effect. The drug may include one or more variants of the compounds of formula I, which are described above.

In particular, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of affective disorders.

- 4 009417

In yet another embodiment, the present invention also relates to the use of a compound of formula I for preparing a medicament for treating depression.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for treating anxiety disorders.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of a general state of anxiety.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of social anxiety.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of post-traumatic shock.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of an obsessive compulsive disorder.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of panic disorder.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of panic attacks.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of specific phobias.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of social phobia.

In yet another embodiment, the present invention also relates to the use of a compound of formula I for the preparation of a medicament for the treatment of agoraphobia.

In another aspect, the present invention relates to a method for treating a disease or disorder selected from the group including affective disorder, such as depression, anxiety, including general anxiety, social anxiety, post-traumatic shock, obsessive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in animals, including humans, which includes the administration to a patient in need of treatment, therapeutic and an effective amount of the compounds of formula I.

In another aspect, the present invention relates to a method for producing a compound of formula I, which comprises:

a) removing the protective group or cleavage from the polymer substrate of the compounds of formula II

TO*

n where the dotted line, the substituents B ¹ -B ⁹ have previously defined values, and B 'represents a tert-butyl, methyl, ethyl, allyl or benzyl group, or B'OCO is a carbamate group deposited on a solid substrate;

or

where the substituents B ¹ -B ⁹ have the previously defined meanings, and B is either hydrogen, or

- 5 009417 carbamate group KOSO, where K is a tert-butyl, methyl, ethyl, allyl or benzyl group, or KOSO is a carbamate group deposited on a solid substrate; or

C) the restoration of the double bond in the compound of formula IV

K ⁴

IV where the alternates are K ^! -K ⁹ have previously defined values.

Pharmaceutical compositions

The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, or in single or multiple doses. The pharmaceutical compositions of the present invention can be prepared with pharmaceutically acceptable carriers or diluents, as well as with any other known adjuvants and excipients in accordance with conventional techniques, such as those described in the publication Cetchip: T11C 8c1epse apb Rgasbs o! Ryagtasu, 19 Ebyup, Oppago, Eb., Musk RIyIpd So., EaLop. RA, 1995.

Pharmaceutical compositions can be specifically prepared for administration in any suitable manner, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) method, with oral method being preferred. It should be noted that the preferred route of administration will depend on the general condition and age of the patient who is in need of treatment, the nature of the condition being treated, and the selected active ingredient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, lozenges, powders, and granules. When this is acceptable, solid dosage forms can be made with coatings such as enteric coatings, or they can be made to provide controlled release of the active ingredient, such as gradual or sustained release, according to methods known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders that are reconstituted into sterile injectable solutions and dispersions before use. Injectable depot preparations are also intended to be included in the scope of the present invention.

Other suitable forms of administration are suppositories, sprays, ointments, creams, gels, inhalants, dermal patches, implants, etc.

A typical oral dose is in the range of about 0.001 to 100 mg / kg body weight per day, preferably about 0.01 to 50 mg / kg body weight per day, and most preferably about 0.05 to 10 mg / kg body weight per day, which is administered in one or in several dosages, for example, from 1 to 3 dosages. The exact dose will depend on the frequency and method of administration, the sex, age, weight and general condition of the patient in need of treatment, the nature and complexity of the condition being treated, and any associated diseases that require treatment, as well as other factors obvious to a specialist. in this area.

Preparations can usually be obtained in standard dosage forms by methods known to those skilled in the art. A typical unit dosage form for oral administration once or several times a day, for example, from 1 to 3 times a day, may contain from 0.01 to about 1000 mg, preferably from about 0.05 to 500 mg, and more preferably about from 0.5 to 200 mg.

In the case of parenteral routes, such as intravenous, intrathecal, intramuscular, and similar routes of administration, doses are usually about half the dose used when administered orally.

The compounds of the present invention are usually used in the form of a free substance or as

- 6 009417 its pharmaceutically acceptable salt. One example is the acid addition salt of a compound that is used as a free base. When the compound of formula (I) contains a free base, such a salt is obtained in the usual way by reacting a solution or suspension of the free base of formula (I) with a chemical equivalent of a pharmaceutically acceptable acid. Typical examples discussed above.

For parenteral administration, solutions of the novel compounds of formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil can be used. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent must first be made isotonic with a sufficient amount of brine or glucose. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All used sterile aqueous media are readily available by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers are inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, magnesia, sucrose, cyclodextrin, talc, gelatin, agar-agar, pectin, gum arabic, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are refined syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any gradual release material known in the art, such as glycerol monostearate or glycerol distearate, alone or mixed with wax. Pharmaceutical compositions obtained by mixing new compounds of formula (I) and pharmaceutically acceptable carriers are then easily administered in various dosage forms suitable for the administration routes described. Typically, preparations can be obtained in a standard dosage form using methods known in the field of pharmacology.

Formulations of the present invention suitable for oral administration may be presented as separate units, such as capsules or tablets, each of which contains a predetermined amount of the active ingredient, and which may contain a suitable excipient. In addition, orally active preparations can be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil emulsion.

If, in the case of oral administration, a solid carrier is used, the preparation can be a tablet placed in a hard gelatin capsule in powdered or pelletised form, or it can be in the form of a lozenge or lozenge.

The amount of solid carrier will vary widely, but usually ranges from about 25 mg to 1 g.

If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, or a sterile injectable liquid, such as a suspension or solution in an aqueous or non-aqueous liquid.

The compounds of the present invention are prepared by the following general methods or as described in the experimental part of this patent:

a) removing the protective group or cleaving from the polymer substrate the compounds of formula II:

Where the BZ-B ⁹ substituents have the previously defined meanings, and B 'is a tert.-butyl, methyl, ethyl, allyl or benzyl group, or B'OCO is a carbamate group coated on a solid substrate, such as Wang resin bound ( ^ aid hect) carbamate linker;

or

B) dehydration and optionally simultaneous deprotection of the compound of formula III

- 7 009417

where the substituents K ¹ -K ⁹ have the previously defined meanings, and K represents either hydrogen or a carbamate group K'OCO, where K 'represents a tert.-butyl, methyl, ethyl, allyl or benzyl group, or K'OSO is supported on a solid support with a carbamate group, such as a Wanga resin bonded to a carbamate linker; or

C) the restoration of the double bond in the compound of formula IV

where the substituents K'-K ⁹ have previously defined values.

The removal of the protective group in accordance with method a) is carried out according to standard methods known to those skilled in the art and described in detail in the textbook “Prospects for the Conduction of Health and Safety.” T.W. Szepe, R.S.M. HUiK \ UPeu 1n1s8e1epee (1991), Ι8ΝΒ 0471623016. Cleavage from the polymer substrate, for example, associated with the Wang resin, a carbamate linker, in accordance with method a) can be carried out according to the methods described in the literature (Ζ; · ιπ · ι§οζ; · Ι Te! Gayebgop le !!., 1995, 36, 8677-8678, and Sope e! A1., Teyyebgop b le !!., 1997, 38, 2915-2918).

The starting materials of the formula II can be obtained by removing the hydroxyl group of the compounds of the formula III by a number of methods known to those skilled in the art, for example, by using triethylsilane in trifluoroacetic acid and boron trifluoride diethyl etherate (see Epsus1orabi1a £ Keadepé £ og Ogadas ZupShekk, yo1. 7 , Split, eb., 1yup \ Upeu apop, Sysyeyeg, 1995, 51225123). The starting materials of formula II, which are piperidines, can be obtained by reducing the double bond of the corresponding tetrahydropyridines with standard hydrogenation techniques, such as, for example, catalytic hydrogenation at low pressure (<3 atm) in a Parr apparatus.

The reaction of dehydration and the optional simultaneous removal of the protective group of the compounds of formula III in accordance with method b) is carried out similarly to the method described in the publication of Para! A1., EM. Sj., 1997, 40, 1982-1989.

The starting materials of formula III are obtained from the corresponding properly substituted 1-bromo-2-phenoxy-benzenes of formula VI (where the substituents K ¹ -K ⁹ are as previously defined, and C is a bromine or iodine atom) by exchanging metal-hydrogen followed by the addition of a suitable electrophile. Formulas V (where K 'has the previously defined meanings) in a manner similar to that described in the publication Para1tege! A1., EM. Sj., 1997, 40, 1982-1989.

- 8 009417

Properly substituted 1-bromo-2-phenoxybenzenes are obtained by reacting properly substituted phenols (sodium salt of phenols are obtained by using sodium hydride) with properly substituted 1-bromo-2-fluorobenzenes in dimethylformamide (DMF) at elevated temperatures. Diaryl ethers can also be obtained using various modifications of this method (see, for example, CLEARING Go! A1., 1. Separate Syet., 1993, 58, 3229-3230; Weidetruck! A1., Taynergate by. , 1994, 35, 5649-5652; 8a \\ sev1 a1., 1. ogd. Siet., 1998, 63, 6338-6343) under the conditions of ulman or through the arylation of phenols with arylboronic acids Be !!, 1998, 39, 2937-2940). Phenols and 1-bromo-2-fluorobenzenes are commercially available.

The reduction of the double bond in accordance with method c) is usually carried out by catalytic hydrogenation at low pressure (<3 atm) in a Parr apparatus. The starting materials of the formula IV can be obtained from compounds of the formula II by deprotection as described above.

Examples

Analytical LC-MS data were obtained on a PE 8c1ex-150EX instrument equipped with an ion injection source, and a 81-Tabhi LC-8A / 8BC-10A HC system. Column: 30x4.6 mm column of Ua! Ect 8-1 C18 with a particle size of 3.5 μm; Solvent system: A = water / trifluoroacetic acid (100: 0.05) and B = water / acetonitrile / trifluoroacetic acid (5: 95: 0.03). Method: elution with a linear gradient from 90% A to 100% B in 4 min at a flow rate of 2 ml / min. Purity is determined by integrating traces of UV (254 nm) and EB8E. Retention time (BT) is expressed in minutes.

Preparative purification using LC-MS carried out on the same device. Column: 50x20 mm UMS ΟΌ8-Α with a particle size of 5 microns. Method: elution with a linear gradient from 80% A to 100% B in 7 minutes and at a flow rate of 22.7 ml / min. The collection of fractions is carried out using MS detection with flow separation.

The reactions carried out in a microwave oven are carried out in Retkop's 8th118up111eCheg company1 Siettstu, operating at 2450 MHz.

Preparation of Intermediates

Obtaining substituted 2-bromo- (substituted phenoxy) benzenes

1-Bromo-2- (2,4-dimethylphenoxy) benzene

A solution of 2,4-dimethylphenol (2.4 g) in dry dimethylformamide (DMF) (10 ml) is added dropwise to a mixture of sodium hydride (1.0 g, 60% in mineral oil) and dry DMF (25 ml), and the resulting mixture was stirred at 100 ° C for 30 minutes. To the mixture was added 1-bromo-2-fluorobenzene (3.5 g) in dry DMF (5 ml) and the mixture was stirred at 150 ° C for 6 hours. The mixture was then poured onto an ice / water mixture and the aqueous phase was extracted with diethyl by ether. The combined organic phase is washed with 2 n. sodium hydroxide, dried (MD8O ₄ ), filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluent: heptane) to give a crude product (1.2 g, 70% purity). The crude product is used in the next step without further purification.

The following compounds are obtained in a similar way:

1-bromo-2- (4-chlorophenoxy) benzene

1-bromo-2- (4-fluoro-2-methylphenoxy) benzene

1-bromo-2- (4-fluorophenoxy) benzene

1-bromo-2- (4-methylphenoxy) benzene

1-bromo-2- (4-methoxyphenoxy) benzene

Preparation of alkyl 4- [2- (substituted phenoxy) substituted phenyl] -4-hydroxypiperidine-1-carboxylates tert.-Butyl-4- [2- (2,4-dimethylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate

A solution of 1-bromo-2- (2,4-dimethylphenoxy) benzene (0.7 g) in dry tetrahydrofuran (THF) (3 ml) is added to a solution of n-ViE1 (1.6 M in hexane, 2 ml) in dry THF (15 ml) at -78 ° C. The resulting mixture was stirred at -78 ° C for 1 hour and then a solution of tert.-butyl 4-oxopiperidine-1-carboxylate (1.0 g) in dry THF (3 ml) was added. The mixture is stirred for 16 hours at room temperature and then poured into a saturated solution of ammonium chloride. The aqueous phase is extracted with diethyl ether and

- 9 009417 the combined organic phase is washed with water and brine, then dried (MgO0 ₄ ), filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (eluant: heptane / ethyl acetate, 4: 1) to give a crude product (0.55 g). The crude product is used in the next step without further purification.

The following compounds were obtained in a similar way: ethyl-4- [2- (2,4-dimethylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate ethyl 4- [2- (4-chlorophenoxy) phenyl] -4-hydroxypiperidine-1 tert.-butyl 4- [2- (4-fluoro-2-methylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate ethyl 4- [2- (4-fluoro-2-methylphenoxy) phenyl] - carboxylate Ethyl 4- [2- (4-fluorophenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate tert.-butyl 4- [2- (4-methylphenoxy) phenyl] -4-hydroxypiperidine 4-hydroxypiperidine-1-carboxylate Ethyl 4- [2- (4-methylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate tert-butyl 4- [2- (4-labels syphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

Preparation of ethyl 4- (2-methoxyphenyl) piperidine-1-carboxylate

To 26 mmol of 4- (2-methoxyphenyl) piperidine (Maubpde) in 28 ml of dry dichloromethane add 28.6 mmol of triethylamine and 78 mmol of ethyl chloroformate at 0 ° C. The solution is stirred at room temperature overnight, washed twice with 0.5 M HCl (125 ml), then dried over MgO ₄ and evaporated. The product is pure enough to be used in the next stage.

Preparation of ethyl 4- (2-hydroxyphenyl) piperidine-1-carboxylate

To 24 mmol of ethyl 4- (2-methoxyphenyl) piperidine-1-carboxylate in 150 ml of dry dichloromethane add 48 mmol of BBr ₃ at 0 ° C. The solution is stirred at room temperature overnight, washed twice with 0.5 M HCl (125 ml), then dried over MgO ₄ and evaporated. The product is pure enough to be used in the next stage.

The compounds of the present invention

Preparation of 4- [2- (substituted phenoxy) substituted phenyl] -1,2,3,6-tetrahydropyridines la. 4- [2- (2,4-Dimethylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine

A mixture of tert.-butyl-4- [2- (2,4-dimethylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate (0.5 g) and a mixture of acetic acid and conc. hydrochloric acid (3: 1) is refluxed for 16 h. The mixture is cooled, poured into alkaline water and extracted with ethyl acetate. The combined organic phase is dried (MgO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant: ethyl acetate / methanol / triethylamine, 8: 2: 1) to give the title compound (11 mg, 3% yield). LC / MS (t / ζ) 280 (MH ⁺ ); NT = 2.16; purity (UV, 1Ί.8Ι)): 85, 97%.

The following compounds are obtained in a similar way:

lb. 4- [2- (4-Chlorophenoxy) phenyl] -1,2,3,6-tetrahydropyridine

From ethyl 4- [2- (4-chlorophenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

LC / MS (t / ζ) 286 (MH ⁺ ); NT '2.10; purity (UV, 1Ί.8Ι)): 85, 95%; yield: 33 mg (6%).

lc. 4- [2- (4-Fluoro-2-methylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine

From tert-butyl 4- [2- (4-fluoro-2-methylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

LC / MS (t / ζ) 284 (MH ⁺ ); NT 2.08; purity (UV, 1Ί.8Ι)): 97, 99%; yield: 100 mg (21%).

16. 4- [2- (4-Fluorophenoxy) phenyl] -1,2,3,6-tetrahydropyridine

From ethyl 4- [2- (4-fluorophenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

LC / MS (t / ζ) 270 (MH ⁺ ); NT = 1.93; purity (UV, 1Ί.8Ι)): 87, 97%; yield: 45 mg (11%).

1e. 4- [2- (4-Methylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine

From tert-butyl-4- [2- (4-methylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate. LC / MS (t / ζ) 266 (MH ⁺ ); HT 2.04; purity (UV, 1Ί.8Ι)): 98, 99%; yield: 250 mg (24%). P. 4- [2- (4-Methoxyphenoxy) phenyl] -1,2,3,6-tetrahydropyridine

From tert-butyl-4- [2- (4-methoxyphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

LC / MS (t / ζ) 282 (MH ⁺ ); NT = 1.95; purity (UV, 1Ί.8Ι)): 79, 99%; yield: 14.7 mg (19%).

Getting 4- [2- (substituted phenoxy) substituted phenyl] piperidine

Method A

2a 4- [2- (2,4-Dimethylphenoxy) phenyl] piperidine

A mixture of ethyl 4- [2- (2,4-dimethylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate (0.6 g), dichloromethane (25 ml), triethylsilane (1 ml), trifluoroacetic acid (0.1 ml) and boron trifluoride diethyl ether (0.2 ml) was stirred at room temperature for 16 hours. The resulting mixture was poured into alkaline water and then extracted with ethyl acetate. The combined organic phase is dried (MgO ₄ ), filtered and concentrated in vacuo (0.4 g). The residue is dissolved in a mixture of conc. hydrochloric acid and acetic acid (1: 3) (25 ml) and refluxed for 16 hours. The mixture was poured into alkaline water and then extracted with ethyl acetate. The combined organic phase is dried (MgO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant: ethyl acetate / methanol / triethylamine, 8: 2: 2) to give the title compound (10.6 mg, 3% yield).

LC / MS (t / ζ) 282 (MH ⁺ ); NT 2.22; purity (UV, 1Ί.8Ι)): 67, 83%.

The following compounds are obtained in a similar way:

- 10 009417

2b. 4- [2- (4-Chlorophenoxy) phenyl] piperidine

From ethyl 4- [2- (4-chlorophenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

LC / MS (t / ζ) 288 (MH ⁺ ); CT = 2.1; purity (UV, EJ): 96, 97%; yield: 41 mg (7%).

2c. 4- [2- (4-Fluoro-2-methylphenoxy) phenyl] piperidine

From ethyl 4- [2- (4-fluoro-2-methylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

LC / MS (t / ζ) 286 (MH ⁺ ); CT = 2.1; purity (UV, EJ): 89, 99%; yield: 51 mg (8%).

26. 4- [2- (4-Fluorophenoxy) phenyl] piperidine

From ethyl 4- [2- (4-fluorophenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

LC / MS (t / ζ) 272 (MH ⁺ ); CT = 1.97; purity (UV, EE811): 91, 99%; yield: 7 mg (5%).

2nd. 4- [2- (4-Methylphenoxy) phenyl] piperidine

From ethyl 4- [2- (4-methylphenoxy) phenyl] -4-hydroxypiperidine-1-carboxylate.

LC / MS (t / ζ) 268 (MH ⁺ ); CT = 2.12; purity (UV, EE811): 88, 93%; yield: 8 mg (1%).

Method B

Ethyl 4- (2-hydroxyphenyl) piperidine-1 -carboxylate (0.1 mmol) is mixed in 0.5 ml of 1-methylpyrrolidin-2-one with 0.12 mmol of the corresponding aryl bromide or iodide. Cu1 (0.037 mmol) is added as a catalyst and the vessel is sealed before it is heated for 1 hour in a microwave oven at 220 ° C. The solvent is removed from the sample and a solution of KOH in water (3.7 mmol), dioxane and ethanol (99.9%) are added, the mixture is heated at 130 ° C for 1 hour in a microwave oven. Water and solid NaC1 are then added to the sample, extracted with ethyl acetate. The organic phase is evaporated and the crude product is purified by preparative LC-MS. The isolated products are applied to 8CX columns and the free amines are transferred to the test as solutions in DMSO. In the described manner, the following compounds are obtained, for which a specific molecular weight, a specific retention time in HPLC (CT, min) and purity in terms of UV and EB ^ AND (%) are presented in the table.

behind. 4- [2- (4-chloro-2-methylphenoxy) phenyl] piperidine

3b. 4- [2- (3-chloro-2-methylphenoxy) phenyl] piperidine zs. 4- [2- (2-chloro-4-methylphenoxy) phenyl] piperidine zb. 4- [2- (2,4-dichlorophenoxy) phenyl] piperidine

e. 4- [2- (benzo [1,3] dioxol-5-alloxy) phenyl] piperidine

3ί. 4- [2- (4-methoxy-2-methylphenoxy) phenyl] piperidine

3d 4- [2- (3,4-dichlorophenoxy) phenyl] piperidine

311. 4- [2- (3,4-dimethylphenoxy) phenyl] piperidine

31. 4- [2- (2,3,4,5-tetramethylphenoxy) phenyl] piperidine

3). 4- [2- (4-trimethylphenoxy) phenyl] piperidine

3k 4- [2- (4-methoxyphenoxy) phenyl] piperidine

31. 4- [2- (2-chloro-4-methoxyphenoxy) phenyl] piperidine h. 4- [2- (3,4-dimethoxyphenoxy) phenyl] piperidine

3p. 4- [2- (4-chloro-3-trifluoromethylphenoxy) phenyl] piperidine

- 11 009417

Table. A certain molecular weight, a certain retention time in HPLC (W, min) and purity by UV and EBSE (%)

Determination of [ ³ H] -5-NT absorption in rat cortical synaptosomes

The whole brain of male rats (125-225 g), except the cerebellum, is homogenized in 0.32 M sucrose, supplemented with 1 mM nialamide, using a glass / teflon homogenizer. The homogenate is centrifuged at 600 / d for 10 min at 4 ° C. Pellets are removed and the supernatant is centrifuged at 20,000 / d for 55 minutes. The final pellet is homogenized (20 s) in evaluation buffer (0.5 mg of starting tissue / well). Test compounds (or buffer) and 10 nM [ ³ H] -5-NT are added to 96-well plates and shaken gently. The composition of the evaluation buffer: 123 mm No. 1С1. 4.82 mM KC1, 0.973 mM CaCl ₂ , 1.12 mM MgO ₄ , 12.66 mM Na ₂ HPO ₄ , 2.97 mm NaH ₂ PO ₄ , 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid . The buffer is saturated with 95% O ₂ /5% CO ₂ for 10 min at 37 ° C and the pH is adjusted to 7.4. Aging is started by adding tissue to a final estimated volume of 0.2 ml. After 15 minutes of incubation with a radioactive ligand at 37 ° C, the samples are filtered directly on glass fiber filters of ISrHEGO / C (impregnated for 1 hour in 0.1% polyethylene imine) under vacuum and immediately washed with evaluation buffer (3x0.2 ml). Non-specific absorption is determined using citalopram (final concentration 10 μM). Citalopram is included as a standard in all experiments as a dose-response curve.

Determination of [ ³ H] norepinephrine uptake in rat cortical synaptosomes

A fresh cortical layer of male rats (125-225 g) is homogenized in 0.4 M sucrose using a glass / teflon homogenizer. The homogenate is centrifuged at 600 / d for 10 min at 5 ° C. Pellets are removed and the supernatant is centrifuged at 20,000 / d for 55 minutes. The final pellet is homogenized (20 s) in a buffer for evaluation (6 mg of initial tissue / ml = 4 mg / well).

Test compounds (or buffer) and 10 nM [ ³ H] -noradrenaline are added to deep 96-well plates and shaken slightly. The composition of the estimated buffer: 123 mM NaC1, 4.82 mM KC1, 0.973 mM CaCl ₂ , 1.12 mM MDO ₄ , 12.66 mM Na ₂ HPO ₄ , 2.97 mM NaH ₂ PO ₄ , 0.162 mM EDTA, 10 mM glucose and 1 mM ascorbic acid. The buffer is saturated with 95% O ₂ /5% CO ₂ for 10 min at 37 ° C and the pH is adjusted to 7.4. Aging is started by adding tissue to a final estimated volume of 1 ml. After 15 minutes of incubation with a radioactive ligand at 37 ° C, the samples are filtered directly on fiberglass filters OB / C (soaked for 1 hour in 0.1% polyethylene imine) under vacuum and immediately washed with evaluation buffer (3/1 ml). Non-specific absorption is determined using talsupram (final concentration 10 μM). Diloxetine is included as a standard in all experiments as a dose-response curve.

The results of the experiments show that the test compounds of the present invention inhibit the reuptake of norepinephrine and serotonin with a CC value of less than 200 nM.

Claims

CLAIM

1. A derivative of 4- (2-phenyloxyphenyl) piperidine or 1,2,3,6-tetrahydropyridine of the general formula I

- 12 009417 where the dotted line —— means a simple bond or a double bond;

K ^1, K ^2, K ^3, K ^4, K ⁵ are independently selected from hydrogen, halogen, C1 _-6 -alkyl, C1 _-6 -alkyloxy, galogenS1 _-6 alkyl; or K ² and K ³ together form a heterocycle condensed with a phenyl ring, chosen from

K ¹ , K ⁴ , K ⁵ are as defined above;

K ⁶ , K ⁷ , K ⁸ , K ^{9 are} independently hydrogen;

or its salt.

2. The compound according to claim 1, where K ^{1 is} selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 -alkyloxy, halogen-C _1-6 alkyl.

3. The compound according to any one of claims 1 and 2, where K ^{2 is} selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 alkyloxy, halogen-C _1-6 -alkyl.

4. The compound according to any one of claims 1 to ³ , where K ^{3 is} selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 alkyloxy, halogen-C _1-6 -alkyl.

5. The compound according to any one of claims 1 and 2, where K ² and K ³ together form a heterocycle condensed with ^ °>

phenyl ring selected from

6. The compound according to any one of claims 1 to 5, where K ^{4 is} selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 alkyloxy, halogen-C _1-6 -alkyl.

7. The compound according to any one of claims 1 to 6, where K ^{5 is} selected from hydrogen, halogen, C _1-6 -alkyl, C _1-6 alkyloxy, halogen-C _1-6 -alkyl.

8. The compound according to any one of claims 1 to 7, where K ⁶ is hydrogen.

9. The compound according to any one of claims 1 to 8, where K ⁷ is hydrogen.

10. The compound according to any one of claims 1 to ⁹ , where K ⁸ is hydrogen.

11. The compound according to any one of claims 1 to ¹⁰ , where K ⁹ is hydrogen.

12. The compound according to any one of claims 1 to 11, where the dotted line indicates a simple connection.

13. The compound according to any one of claims 1 to 11, where the dotted line indicates a double bond.

14. The compound according to claim 1, and the specified connection is

4- [2- (2,4-dimethylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine,

4- [2- (4-chlorophenoxy) phenyl] -1,2,3,6-tetrahydropyridine,

4- [2- (4-fluoro-2-methylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine,

4- [2- (4-fluorophenoxy) phenyl] -1,2,3,6-tetrahydropyridine,

4- [2- (4-methylphenoxy) phenyl] -1,2,3,6-tetrahydropyridine,

4- [2- (4-methoxyphenoxy) phenyl] -1,2,3,6-tetrahydropyridine,

4- [2- (2,4-dimethylphenoxy) phenyl] piperidine,

4- [2- (4-chlorophenoxy) phenyl] piperidine,

4- [2- (4-fluoro-2-methylphenoxy) phenyl] piperidine,

4- [2- (4-fluorophenoxy) phenyl] piperidine,

4- [2- (4-methylphenoxy) phenyl] piperidine,

4- [2- (4-chloro-2-methylphenoxy) phenyl] piperidine,

4- [2- (3-chloro-2-methylphenoxy) phenyl] piperidine,

4- [2- (2-chloro-4-methylphenoxy) phenyl] piperidine,

4- [2- (2,4-dichlorophenoxy) phenyl] piperidine,

4- [2- (benzo [1,3] dioxol-5yloxy) phenyl] piperidine,

4- [2- (4-methoxy-2-methylphenoxy) phenyl] piperidine,

4- [2- (3,4-dichlorophenoxy) phenyl] piperidine,

4- [2- (3,4-dimethylphenoxy) phenyl] piperidine,

4- [2- (2,3,4,5-tetramethylphenoxy) phenyl] piperidine,

4- [2- (4-trifluoromethylphenoxy) phenyl] piperidine,

4- [2- (4-methoxyphenoxy) phenyl] piperidine,

4- [2- (2-chloro-4-methoxyphenoxy) phenyl] piperidine,

4- [2- (3,4-dimethoxyphenoxy) phenyl] piperidine,

4- [2- (4-chloro-3-trifluoromethylphenoxy) phenyl] piperidine,

- 13 009417 or its pharmaceutically acceptable salt.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent.

16. The use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of affective disorders such as depression, anxiety, including general anxiety, social anxiety, post-traumatic shock, compulsive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia.

17. A method of treating affective disorders such as depression, anxiety, including general anxiety, social anxiety, post-traumatic shock, compulsive compulsive disorder, panic disorder, panic attacks, specific phobias, social phobia and agoraphobia in animals, including a human, which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable acid addition salt thereof.