SK138993A3 - Amidoalkyl - and imidoalkylpiperazines - Google Patents

Abstract

Compounds of general formula (I) wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, R4 is an NO2 group or a group NR7R8 wherein R7 and R8 are the same or different and each is hydrogen or alkyl, R5 is hydrogen, halogen or CF3, R6 is halogen, or CF3, W is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group, an alkoxy group, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, processes and intermediates for their preparation, pharmaceutical preparation containing them and the use of the compounds in the treatment of mental disturbances.

Description

Technical field

The present invention relates to novel 1-aryl-4- (N-amido-1-alkyl) piperazines and 1-aryl-4- (0-o-imido-1-alkyl) piperazines, intermediates for their preparation, processes for their production, pharmaceutical compositions containing these piperazines and the use of these compounds in therapy;

The present invention also relates to novel compounds that will be useful in the treatment of psychiatric disorders such as schizophrenia and other psychoses, anxiety states, depression and manic depressive psychosis.

BACKGROUND OF THE INVENTION

Buspiron is a known substance that has recently been tested in changes caused by diseases of the central nervous system ₀ including depression. This has an affinity for both 5HT1A receptors and D2 receptors.

about

Glennon et al. (RA Glennon, NA Naiman, R. A: Lyon and M. Titeler: Journal of Medicinal Chemistry 31, 1986-1971 (1988)) disclose certain piperazine derivatives including 1- (2-methoxyphenyl) -4- [4- (2 phthalimido) butylpiperazine (NAN190) which binds to 5HT1A receptors as determined by designated ³ H-8-hydroxy-DPAT. In another publication the same group (RK Raghuparthi, L. Rydelek-Fitzgerald, M. Teitler, and RA Glennon, Journal of Medicinal Chemistry 34, 2633-2638 (1991)) describes certain analogs.

5HT1A 1- (2-methoxyphenyl) -4- [4- (2-phthalimido) butyl] piperazine antagonist having affinity for 5HT1A receptors as well as some binding affinity for α1 receptors. Another summary work in a related field has also been written (R. A. Glennon, M. E. Pierson, J.

D. Smith, A. M. Xsmaiel, M. Titeler, and R. A. Lyon, Journal of Medicinal Chemistry 32, 1921-1926 (1989).

SUMMARY OF THE INVENTION

According to this general formula of the invention

I have found that the new compounds

or a pharmaceutically acceptable salt thereof, wherein

R represents a hydrogen atom or a phenyl group, m represents an integer from 3 to 8, _t R ₄ is located at the meta or para position of the ring and represents a nitro group or a group of the formula NR ₇ R _g , i

where R _? and R _g are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R 8 is located in the ortho, meta or para position and represents a hydrogen atom, a halogen atom or a trifluoromethyl group,

R ₆ is ortho, meta or para and represents a halogen atom or a trifluoromethyl group,

W represents an optionally substituted aromatic ring or rings, a heterocyclic ring, a carbocyclic ring or rings, or an optionally substituted methylene group,

A represents a hydrogen atom, a hydroxy group, a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a phenyl group or a phenoxy group, and

B is hydrogen or

A and B together form a carbonyl group, n 1 represents a number 0 or 1 and ₂ represents a number 0 or 1, in racemic or optically active form or as a mixture of diastereoisomers, provided that:

1) if W is an optionally substituted aromatic ring or rings, then

R, m, R ₄ , R g and R g have the meanings given above, n = 1 is 0 or 1, n ₂ is 0 or 1,

A represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxy group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a phenyl group or a phenoxy group, and

B is hydrogen or

A and B together form a carbonyl group,

2) if W is a carbocyclic ring or rings or a heterocyclic ring then

R, m, R ₄ , R 8 and R 8 have the meanings given above, n 1 represents the number 0 or 1, n ₂ represents the number 0 or 1,

A and B are hydrogen or

A and B together form a carbonyl group,

3) if W represents an optionally substituted methylene group, then

R, m, R ₄ , R g and R g have the meanings given above,

Πχ ar \ 2 means number 1 or n- ^ represents number 1 and n ₂ represents zero or n ^ represents zero and n ₂ represents number 1 and

A and B together form a carbonyl group, exhibiting affinity for the D2 and 5HT1A receptors. This effect makes it possible to use the compounds as defined above for the treatment of mental disorders such as psychosis, schizophrenia and depression.

Preferably, the aromatic ring or rings as defined above is or is phenyl or naphthyl which is monosubstituted or disubstituted or monosubstituted or disubstituted, wherein the substituents are preferably selected from hydrogen, halogen, hydroxy, trifluoromethyl, alkyl or C 1 -C 3 alkoxy or C 1 -C 3 alkoxy.

The heterocyclic ring as defined above is preferably furyl, thienyl, pyrrolyl, pyridyl or indolyl.

The carbocyclic ring or rings as defined above represents or represents a monocyclic ring or bicyclic or polycyclic rings of 3 to 12 carbon atoms.

The substituents of the carbocyclic ring or carbocyclic rings as defined above are or are preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

Preferably, the methylene substituent as defined above is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

The halogen atom as defined above is preferably a chlorine, bromine or iodine atom.

A preferred group of compounds are those of formula Ia

(la) or a pharmaceutically acceptable salt thereof, wherein:

R 3 is in the 3 or 4 position and represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a group of formula NO ₂ , COCH ₃ or NR ₂ R ₃ R ₂ and R ₃ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, m represents an integer from 3 to 8;

R ₄ is located at the meta or para position of the ring and represents a nitro or NR _? R _g, wherein R ₇ and _Rg are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R ₅ is located in the ortho, meta or para position and represents a hydrogen atom, a halogen atom or a trifluoromethyl group,

R ₆ is ortho, meta or para and represents a halogen atom or a trifluoromethyl group,

W is preferably selected from groups i to xi (i) wherein the substituents are preferably a halogen atom, a hydroxy group or a methoxy group, particularly preferably a bromine atom, a hydroxy group or a methoxy group in the ortho and / or para position,

Q-

(vii)

(Ix)

wherein the substituents are a halogen atom or a methoxy group, (xi)

If W is selected from one of groups i to xi, then m is preferably an integer from 4 to 6,

R ₄ is preferably an amino group, and preferably R ₄ is an amino group located in the meta or para position,

R ₅ is preferably a hydrogen or halogen atom, with compounds where R ₅ is a hydrogen, chlorine or bromine atom, and most preferably R ₅ is a hydrogen or chlorine atom in the meta or para position,

R 8 is preferably trifluoromethyl or halogen, and further preferred are compounds wherein R 8 is trifluoromethyl or chlorine, most preferably R 8 is ₍ trifluoromethyl or chlorine in the meta position).

When W is a group of formulas (I) to (x), then R preferably represents a hydrogen atom.

When W is a group of formula (i), then n 1 is preferably zero and n ₂ is preferably zero or a number

1, with n ₂ being zero, and most preferably

A preferably represents a hydrogen atom, a methoxy group or an hydroxy group in the ortho position.

When w is a group of formula (ii), then n is preferably zero.

When W is a group of formulas iii to vii, then n j. is preferably zero,

A preferably represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and

B preferably represents a hydrogen atom.

If W represents a group of formula (viii), then n-j and n ₂ preferably represent zero and

A and B preferably form a carbonyl group.

If W represents a group of formula (Ix), then n 1 and n ₂ are preferably the number 1 a

A and B preferably form a carbonyl group.

If W represents a group of formula x, then n and n and ₂ are preferably zero and

A and B preferably form a carbonyl group.

The following compounds are particularly preferred:

ABOUT

o cf ₃

Both organic and inorganic acids can be used in the preparation of non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric acid, nitric acid, phosphoric acid, oxalic acid, hydrochloric acid, formic acid, hydrobromic acid, citric acid, acetic acid, lactic acid, tartaric acid, pamoic acid, ethanedisulfonic acid, sulfamic acid, succinic acid, acid propionic, glycolic acid, malic acid, mandelic acid, gluconic acid, pyruvic acid, phenylacetic acid, 4-aminobenzoic acid, anthranilic acid, salicylic acid, 4-aminosalicylic acid, 4-hydroxybenzoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, naphthalenesulfonic acid, ascorbic acid, cyclohexylsulfamic acid, fumaric acid, maleic acid and benzoic acid. These salts are readily prepared by methods known in the art.

Methods of making compounds

Compounds of formula I

ABOUT

II

in which

R represents a hydrogen atom or a phenyl group, m represents an integer from 3 to 8,

R 4 is located in the meta or para position of the ring and represents a nitro or NR ₇ R ₈ group wherein R ₇ and R 8 are the same or different and each represents a hydrogen atom or a C 1 -C 3 alkyl group,

- 13!

R ₅ is located in the ortho, meta or para position and represents a hydrogen atom, a halogen atom or a trifluoromethyl group,

R 8 is located in the ortho, meta or para position and represents a halogen atom or a trifluoromethyl group,

W represents an optionally substituted aromatic ring or rings, a heterocyclic ring, a carbocyclic ring or rings, or an optionally substituted methylene group,

A represents a hydrogen atom, a hydroxy group, a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a phenyl group or a phenoxy group, and

B is hydrogen or

A and B together form a carbonyl group, η 1 represents the number 0 or 1 and ₂ represents the number 0 or 1, in racemic or optically active form or as a mixture of diastereoisomers, provided that:

1) if W is an optionally substituted aromatic ring or rings, then

R, m, R ₄ , R 8 and R 8 have the meanings given above, n 1 represents the number 0 or 1, n ₂ represents the number 0 or 1,

A represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxy group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a phenyl group or a phenoxy group, and

B is hydrogen or

A and B together form a carbonyl group,

2) if W is a carbocyclic ring or rings or a heterocyclic ring then

R, m, R _4, R ₅ and R ₆ are as defined above, is 0 or 1, is 0 or 1,

A and B are hydrogen or

A and B together form a carbonyl group,

3) if W represents an optionally substituted methylene group, then

R, m, R _4, R ₅ and R are as defined above, n £ n ₂ is 1 or n -] _ is 1 and _n2 is zero or

Π], represents zero and ₂ means the number 1 a

A and B together form a carbonyl group, and are produced by any of the following alternative methods.

A) Compound of formula II

II

N- [CH ₂ ] _m -X (II)

CH in which

R, m, W, A, B, η ^ _ n ₂ are as defined above and a is a suitable leaving group such as a halogen atom, an aryl or alkyl radical, is reacted with a compound of formula III

H— N

R (III) wherein

R4, Rg and Rg have the meanings given above in a suitable solvent such as alcohol, dimethylformamide, acetonitrile or dimethylsulfoxide in the presence of a base such as triethylamine, sodium hydroxide or potassium carbonate in the presence of a catalytic amount of sodium or potassium halide such as potassium iodide, at room temperature or at a higher temperature for an extended period of time.

B) Compound of Formula IV

CH (—A t

R

(IV) in which

R, m, R, R, W, A, B, n · n ^ ₂ are as defined above, and

Y is in the meta or para position and represents a group that can be converted to the group R4I where it is in the meta or para position of the ring and represents a group of formula NR ₇ R _g where R ₇ and R _g have the meanings given above , reduction, electrochemical or other known methods. Compounds of formula (IV) may be prepared according to Method A. The Y groups may be selected from readily cleavable amides, carbamates, imines, benzylamines or other suitably protected amino groups. Such groups can be trifluoroacetamido, formamido, tert-butoxycarbonylamino or N-benzylamino.

In addition, Y may be a group such as nitro, azido, hydroxyamino, hydrazone, amido or imino, which may be converted to R 6 by known reduction methods.

C) Compound of Formula V

ABOUT

II

C H - A

B (V)

in which

R, m, W, A, B, n _ n ^ ₂ are as defined above and is hydrogen, hydroxy, halogen, or alkoxy, is reacted with a compound of formula III

H -

n (III) wherein

R ₄ , R ₅ and R ₆ have the meanings given above, in the presence of a suitable reducing agent, such as sodium cyanoborohydride or lithium aluminum hydride, in a direct or sequential manner.

D) Compound of Formula VI

ABOUT

II / ^CH 2V ^C \

(VI)

CH — A ⁿ 2 in which

W, n _1z n ₂ and A have the meanings given above and

T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or an acid derivative such as a halide, ester, imide, anhydride or other acid-activated group is reacted with a compound of formula VII h, n- ,] ^J m

(VII) wherein m, R ₄ , R 5 and R 8 have the meanings given above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, tetrahydrofuran or the like, at about room temperature or elevated, for an extended period of time.

E) Compound of formula VIII

ABOUT

II

(VIII)

R n ₂ in which

R, m, R _4, W, A, B, n? and n ₂ have the meanings given above and represents a hydrogen atom, a halogen atom or a trifluoromethyl group, and is reacted with a suitable halogenating agent such as sulfuryl chloride or sulfuryl bromide in a suitable solvent such as chloroform or dioxane.

F) Compound of Formula IX

CH I

R (IX) from ^tCH 2> n, -C wherein

W, nl and _n2 are as defined above,

A and B together represent a carbonyl group and

M is a suitable alkali metal such as sodium or potassium is reacted with a compound of formula X

N ~ \ N N

(X) in which

X, R ₄ , R ₅ and R ₆ have the meanings given above, in a suitable solvent such as dimethylformamide, acetonitrile or dimethylsulfoxide, in the presence of a base such as triethylamine, sodium hydroxide or potassium carbonate, at room temperature or above for extended periods of time period.

intermediates

Compound of Formula II

ABOUT

II - - ^{CH 2} U - ^x c (II)

CH

I

R

n.

in which

R, m, W, A, B, n-jL, n ₂ and X have the meanings given above, can be prepared by reacting a compound of formula VI _from (CH ₂

W \

CH

O il

(VI) ⁿ 2 in which

W, np n ₂ and A have the meanings given above and

T independently or together with A represents a suitable aliphatic, cycloaliphatic, aromatic or heterocyclic acid derivative or an acid derivative such as a halide, ester, imide, anhydride or other acid-activated group with a compound of formula XI

H ₂ N- (CH ₂ ) _m -OH (XI) wherein m is as defined above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, tetrahydrofuran or the like, at about room temperature or at elevated temperature, during for an extended period of time and then reacting the intermediate of formula XII

CH

I

R-CCH ₂ ] _m -OH (XII) wherein

R, m, W, A, B, and have the meanings given above, with a suitable halogenating agent, such as thionyl chloride, phosgene, oxalyl chloride or phosphorus tribromide, or a suitable sulfonating agent, such as tosyl chloride or other arylsulfonyl chloride or alkylsulfonyl chloride.

Compound of Formula III ¹ /

H — N \

/

in which

R 4 ^1, R and R are as defined above can be prepared from compound XIII

(XIII) in which

Y, Rg and Rg have the meanings given above in an analogous manner to that described under B.

Compound of Formula XIII (XIII)

in which

R ₅ and R ₆ have the meanings given above and

Y is nitro, may be prepared by reacting a compound of formula XIV

in which

Rg and Rg have the meanings given above,

Y is nitro and

U represents a halogen atom, with piperazine or a suitable monosubstituted piperazine, the substituent of which is readily cleavable, such as a benzyl or ethoxycarbonyl group, or by reaction of a compound of formula XV

(XV) in which

R ₅ and R ₆ have the meanings given above and

Y is nitro, with a compound of formula XVI ch ₂ ch ₂ x

VN ch ₂ ch ₂ x (XVI) in which

X is as defined above and

V represents a hydrogen atom or a readily cleavable group such as a benzyl or ethoxycarbonyl group.

Compound of Formula X [CH

(X) in which

X, m, R ₅ and R 8 have the meanings given above, can be prepared by reacting a compound of formula XVII ^X - [CH ₂ ] _m - _x (XVII) wherein:

X and m have the meanings given above, with a compound of formula III

H-N

R (III) wherein

R ₄ , R ₅ and R 8 have the meanings given above, under suitable reaction conditions. conditions analogous to Method A.

Pharmaceutical compositions

According to the invention, the compounds of the formula I are usually administered orally, rectally or by injection, in the form of a pharmaceutical composition containing the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic acid addition salt such as hydrochloride, hydrobromide, lactate, acetate, sulfate, sulfamate, citrate, tartrate, oxalate, and the like, in association with a pharmaceutically acceptable dosage form. The dosage form may be a solid, semi-solid or liquid composition. The active ingredient will generally comprise from 0.1 to 99% by weight of the composition, more specifically from 0.5 to 20% by weight for the compositions contemplated for injection and from 0.2 to 50% by weight for the compositions suitable for oral administration.

For the manufacture of pharmaceutical compositions comprising a compound of formula I in the form of a dosage unit for oral administration, the selected compound may be admixed with a solid excipient such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone; and a glidant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffinic substances and the like, and then compressed into tablets. If coated tablets are required, the cores produced as described above may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, titanium dioxide and the like. In another embodiment, the tablets may be coated with a polymer known to those skilled in the art, dissolved in a readily volatile organic solvent, a mixture of such solvents or in water. Dyestuffs can be added to the coatings to easily distinguish between tablets containing different active substances or different amounts of compounds.

For the production of soft gelatine capsules, the active ingredient can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active ingredient with any of the above-mentioned tablet excipients, for example sucrose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Hard gelatine capsules can also be filled with drug substances in the form of liquids or semi-solid products.

Dosage units for rectal use may be solutions or suspensions or may be presented in the form of suppositories containing the active ingredient in admixture with a neutral fat base, or in the form of gelatin rectal capsules containing the active ingredient in admixture with vegetable oil or paraffin oil.

Liquid compositions for oral administration may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 to about 20% by weight of the active ingredient described herein, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Such liquid compositions may optionally contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in the art.

Solutions for parenteral use for injection may be prepared in aqueous solution from a pharmaceutically acceptable salt of the water-soluble active ingredient, in particular at a concentration of from about 0.5 to about 10% by weight. These solutions may also contain stabilizing agents and / or buffers and may usually be formulated into ampoules containing various dosage units.

Suitable daily dosages of the compounds of this invention for the therapeutic treatment of humans are from 50 to 500 mg when administered orally and up to 100 mg when administered parenterally.

It is particularly preferred to administer the compound of formula

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (Method A)

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine dihydrochloride

A mixture of 3.18 g (0.01 mol) of 4-amino-3-trifluoromethylphenylpiperazine, a catalytic amount of potassium iodide, 4.1 g (0.03 mol) of potassium carbonate and 3.0 g (0.01 mol) of N- ( 4-Bromobutyl) phthalimide in 25 mL of DMF was stirred at 100 ° C overnight. Water (500 ml) was added and the mixture was extracted with ether. The extract was washed with water and extracted with dilute hydrochloric acid.

The aqueous layer was separated, basified with sodium hydroxide and re-extracted with ether. The extract was dried (sodium sulfate) and acidified with a solution of hydrogen chloride in ether. The precipitate obtained is filtered off and recrystallized from a mixture of ethanol and ether. 3.0 g of compound are obtained, which corresponds to a yield of 58% of theory. Melting point: 226-227 ° C.

The following compounds were prepared in a similar manner (Examples 2-12).

Example 2

1- (4-Amino-3-trifluoromethylphenyl) -4- (3-phthalimido-1-propyl) piperazine dihydrochloride

Melting point: 167-169 ° C.

Example 3

1- (4-Amino-3-trifluoromethyl-phenyl) -4- [5- (3-methoxy-phthalimido) -1-pentyl] -piperazine oxalate

Melting point: 114-118 ° C.

Example 4

1- (4-Amino-3-trifluoromethylphenyl) -4- [4- (4-chlorophthalimido) -1-butyl] piperazine dihydrochloride

Melting point: 203-204 ° C.

Example 5

1- (4-Amino-3-trifluoromethylphenyl) -4- (5-phthalimido) trihydrochloride

1-pentyl) -piperazine

Melting point: 109-113 ° C.

Example 6 1- (4-Amino-3,5-dichlorophenyl) -4- (4-phthalimido-1-butyl) piperazine

Melting point: 116-119 ° C.

Example 7

1- (4-amino-3-trifluoromethylphenyl) -4- (3- (1,8-naphthalimido) -1-propyljpiperazín

Melting point: 156-158 ° C.

Example 8

1- (4-Amino-3-trifluoromethylphenyl) -4- [4- (3,3-dimethylglutarimido) -1-butyl] piperazine dihydrochloride

Melting point: 235-236 ° C.

Example 9

1- (4-Amino-3-trifluoromethylphenyl) -4- (4- (3,3-tetra methyleneglutarimido) -1-butyl) piperazine dihydrochloride

Melting point: 243-245 ° C.

Example 10

1- (4-Amino-3-trifluoromethyl-phenyl) -4- (5- (3-phenyl-Iglu-tarimido) -1-pentyl) -piperazine hydrochloride

Melting point: 136-140 ° C.

Example 11

1- (3-Amino-4-chlorophenyl) -4- (5- (2-furancarboxamido) -1-pentyl) piperazine oxalate

Melting point: 165-170 ° C.

Example 12

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-cyclohexanecarboxamido) -1-butyl] piperazine

Melting point: 127-128 ° C.

Example 13 (Method B)

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine acetate

9.53 g (20 mmol) of the compound of Example 38 dissolved in 100 ml of ethanol and 50 ml of acetic acid are hydrogenated to 1.0 g of palladium on carbon catalyst for 5 hours. The mixture was filtered, the solvent was evaporated and the residue was crystallized from a mixture of diisopropyl ether and ethanol. This gives 10.0 g of the title compound. Melting point: 101-103 ° C.

The following compounds were prepared in a similar manner (Examples 14-24).

Example 14

1- (4-Amino-3-trifluoromethylphenyl) -4- (6-phthalimido-1-hexyl) piperazine acetate

Melting point: 125-127 ° C.

Example 15

1- (4-Amino-3-trifluoromethylphenyl) -4- (8-phthalimido-1-octyl) piperazine acetate

Melting point: 94-96 ° C.

Example

Zinc acetate

temperature

Example

Zinc acetate

temperature

Example

Zinc acetate

temperature

EXAMPLE 1- (3-Amino-4-chlorophenyl) -4- (4-phthalimido-1-butyl) piperidine m.p .: 159-162 ° C.

1- (3-amino-4-chlorophenyl) -4- (5-phthalimido-1-pentyl) piper: mp 149-150 ° C;

1- (4-amino-3-methylphenyl) -4- (4-phthalimido-1-butyl) piperidine: 123-126 ° C.

1- (3-Amino-4-chlorophenyl) -4- [4- (3,3-tetramethyleneglutarimido) -1-butyl] piperazine

Melting point: 133-136 ° C.

Example 20

1- (4-Amino-3-fluoromethylphenyl) -4- (6- (3-phenoxybenzamido) -1-hexyl) piperazine acetate

Melting point: 128-131 ° C.

Example 21

1- (4-Amino-3-trifluoromethylphenyl) -4- (6-cyclohexane carboxamido-1-hexyl) piperazine dihydrochloride

Melting point: 112-115 ° C.

Example 22

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-adamantanecarboxamido-1-butyl) piperazine dihydrochloride

Melting point: 123-125 ° C.

Example 23

1- (4-amino-3-trifluoromethylphenyl) -4- (4-adamantanacetamido-l-butylJpiperazín

Melting point: 115-116 ° C.

Example 24

1- (4-Amino-3-trifluoromethylphenyl) -4- (6-adamantanecarboxamido-1-hexyl) piperazine ¹ H NMR Spectrum (CDCl 3) δ 7.00 (s, 1H). 6.96 (dd, 1H), 6.70 (d, 1H), 5.57 (broad singlet, 1H), 3.26 (broad singlet, 2H), 3.24 (m, 2H), 3.08 (m, 4H), 2.61 (m, 4H), 2.39 (m, 2H), 2.04 (broad singlet, 3H), 1.84 (broad singlet, 6H), 1.71 (broad singlet) 6H), 1.52 (m, 4H), 1.34 (m, 4H) ppm.

Example 25 (Method B)

1- (4-Amino-2-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine dihydrochloride

To a mixture of 7.8 g (0.01 mol) of 1- (4-nitro-2-trifluoromethylphenyl) 4- (4-phthalimido-1-butyl) piperazine in 200 ml of ethanol and 60 ml of water is added 11.2 g of dithionate. sodium, in portions with stirring and heating to 100 ° C. The mixture was refluxed for 1 hour and then the ethanol was evaporated. The residual aqueous solution was basified with sodium hydroxide and extracted with ether. The extract was washed with water, dried and the ether was evaporated. The resulting oil was dissolved in dry ether (100 mL) and the dihydrochloride precipitated by addition of hydrogen chloride in ether. The salt obtained is recrystallized from a mixture of ethanol and ether. 2.3 g of compound are obtained. Yield: 44%. Melting point: 243-244 ° C.

Example 26 (Method B)

1- (4-Diethylamino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine

1.0 g (2 mmol) of the compound of Example 13 dissolved in 5 ml of acetic acid was added to a mixture of 304 mg (8 mmol) of sodium borohydride and 20 ml of toluene. Heat the mixture at 80 ° C for 6 hours and cool. The mixture was then contacted with 50 mL of water and 50 mL of ether and basified with 2M sodium hydroxide solution. The organic phase is dried and evaporated. The residue was recrystallized from hexane to give 440 mg of the title compound. Melting point: 70-71 ° C.

Example 27 (Method B) 1- (4-Amino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine

4.9 mg (0.01 mmol) of 4- (4-acetamino-3-trifluoromethylphenyl) -1- (4-phthalimido-1-butyl) piperazine dissolved in 2 ml of ethanol and 0.2 ml of 2M hydrochloric acid are added. Heat at 80 ° C for 5 hours. The solvent was evaporated and the residue, as determined by gas chromatography, was identical to the compound of Example 1.

Example 28 (Method C)

4- (4-Amino-3-trifluoromethylphenyl) -1- (4-phthalimido-1-butyl) piperazine

To a solution of 0.713 g (3.25 mmol) of 4-phthalimido-1-butanal and 0.804 g (3.25 mmol) of N- (4-amino-3-trifluoromethylphenyl) piperazine in 10 ml of refluxing chloroform, 10 ml of 98% formic acid in chloroform are added dropwise over a period of minutes. The solution is refluxed for 2 hours, then the solvent is evaporated and the residue, purified by TLC and GC, is identical to the compound of Example 1.

Example 29 (Method D) 1- (4-Amino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine mg (0.1 mmol) 4- (4-amino-3-trifluoromethylphenyl) - 1- (4-aminobutylpiperazine) and 30 mg (0.2 mmol) of phthalic anhydride dissolved in 1 ml of acetic acid were stirred at 75 ° C for 3 hours. The solvent was evaporated and the residue, as shown by gas chromatography and thin layer chromatography, was identical to the compound of Example 1.

Example 30 (Method D)

1- (4-Amino-3-trifluoromethylphenyl) -4- (4- (5-bromo-2,3-dimethoxybenzamido) -1-butyl) piperazine dioxalate

3.3 g (6.4 mmol) of the compound of Example 1 are dissolved in 60 ml of ethanol, basified with 2M sodium hydroxide solution and the base is heated with 2.0 ml of hydrazine hydrate at 75 ° C for 3.5 hours . After cooling, the solution is acidified with 27 ml

Of 2M hydrochloric acid and evaporated. The residue is dissolved in 75 ml of water and 75 ml of ether. The aqueous phase was basified and extracted with chloroform. The solvent was evaporated to give crude 1- (4-aminobutyl-4- (4-amino-3-trifluoromethylphenyl) pipera from in. A solution of 0.52 g (2.0 mol) of 5-bromo-2,3-acid. -dimethoxybenzoic acid in 10 ml of toluene, 2 ml (23 mmol) of thionyl chloride and a few drops of dimethylformamide are heated at 60 DEG C. for 3 hours. ml of dichloromethane and a solution of 0.51 g (1.6 mmol) of the crude amine described above and 0.45 g (3.2 mmol) of triethylamine in 10 ml of dichloromethane are added under cooling, all stirred overnight, the solvent is evaporated and the residue is evaporated. The organic phase was extracted with water and the combined aqueous phases were basified and re-extracted with chloroform, dried (sodium sulfate) and evaporated to give 0.57 g of the compound as an oil, the base was dissolved in acetone and worked up. with oxalic acid ska 0.95 g of the title compound. Melting point: 174-175 "C.

The following compounds were prepared in a similar manner (Examples 31-34).

Example 31

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-benzamido-1-butyl) piperazine

Melting point: 117-120 ° C.

Example 32

1- (4-Amino-3-trifluoromethylphenyl) -4- [5- (5-bromo-2,3-dimethoxybenzamido) -1-pentyl] piperazine dioxalate

Melting point: 151-154 ° C.

Example 33

1- (4-Amino-3-trifluoromethylphenyl) -4- [4- (2-norbornanecarboxamido) -1-butyl] piperazine hydrochloride

Melting point: 77-80 ° C.

Example 34

(R, Endo) -1- (4-amino-3-trifluoromethylphenyl) -4- (4- (2-norbornancarboxamido) -1-butyl)] piperazine hydrochloride

Melting point: 142-146 ° C.

Example 35

1- (4-Amino-5-bromo-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine oxalate

1.0 g (2 mmol) of the compound of Example 13 was dissolved in 20 mL of dioxane and 5 mL of methanol. To the solution was added 350 mg (2.2 mmol) of bromine dissolved in 3 mL of dioxane and the mixture was stirred at room temperature for 5 hours, the solvent was evaporated and the residue basified with 2M sodium hydroxide solution and extracted with methylene chloride. The solvent was evaporated and the residue was dissolved in diisopropyl ether. Oxalic acid dissolved in ethanol was added to the solution to give a precipitate of the title compound. Melting point: 172-175 ° C.

Example 36 (Intermediate, Compound of Formula II)

N- (5-Bromo-pentyl) -3-methoxy phthalimide

3.0 g (16.8 mmol) of 3-methoxyphthalic anhydride and 1.7 g (16.8 mmol)

The 5-amino-1-pentanol was stirred and heated at 120 ° C for hours. After cooling, 3.5 g (13 mmol) of phosphorus tribromide are added to the reaction mixture and the resulting mixture is heated at 110 ° C for 2 hours, poured out on ice, extracted with ethyl acetate and the organic phase is separated, dried and the solvent evaporated. The residue was crystallized from ethyl acetate / hexane. Melting point: 65-67 ° C.

Example 37 (Intermediate, Compound of Formula II)

N- (5-tosyloxypentyl) -5-bromo-2,3-dimethoxybenzamide

A solution of 1.56 g (6.0 mmol) of 5-bromo-2,3-dimethoxybenzoic acid in 25 mL of toluene, 6 mL (70 mmol) of thionyl chloride and a few drops of dimethylformamide was heated at 60 ° C for hours. The solvent was evaporated and the residue was dissolved in 20 ml of dichloromethane and evaporated again. The resulting acid chloride was dissolved in 20 mL of dichloromethane and added to a solution of 1.8 g (18 mmol) of 5-aminopentanol and 4 mL (28 mmol) of triethylamine in 30 mL of dichloromethane at -35 ° C and allowed to rise to 0 ° C. for hours. The solution is washed with dilute hydrochloric acid, the organic phase is separated and the solvent is evaporated. 2.2 g of a crude oil are obtained. This oil was dissolved in 20 mL of dichloromethane, 4 mL (28 mmol) of triethylamine and 1.33 g (7 mmol) of tosyl chloride were added, and the mixture was stirred at room temperature overnight. Ethyl ether (100 ml) was added to the reaction mixture, and the organic phase was washed with sodium carbonate and water. After drying, the

cypher nej v phase evaporated. 2.7 g of a title oil are obtained. (5.5 mmol) compound pomenova- ¹ H NMR Spectrum (CDCl ₃ ) δ 7.9 (broad singlet, 1H) 7.81 (d, 1H), 7.77 (d, 2H); 7.34 (d, 2H); 7.13 (d, 1H), 4.03 (t, 2H) 3.89 (S, 3H), 3.87 (s, 3H), 3.42 (q, 2H) 2.44 (s, 3H), 1.73

1.40 (m, 6H) ppm.

Example 38 (Intermediate, Compound of Formula IV) 1- (4-Nitro-3-trifluoromethylphenyl) -4-phthalimido-1-butyl) piperazine

8.5 g (30 mmol) of the compound of Example 39, 11.1 g (40 mmol)

4-bromobutylphthalimide, 5.0 g (36 mmol) of potassium carbonate and a catalytic amount of potassium iodide are heated at 90 ° C in 80 ml of dimethylformamide for 6 hours. The mixture was poured into 500 ml of water and extracted with methylene chloride. The organic layer was dried, the solvent was evaporated and the residue triturated with a mixture of ethanol and diisopropyl ether. A yellow, crystalline solid is obtained. The compound has a melting point of 152-154 ° C.

Example 39 (Intermediate, Compound of Formula XIII)

1- (4-Nitro-3-trifluoromethylphenyl) piperazine

A mixture of 22.4 g (0.1 mol) of 4-nitro-3-trifluoromethyl-1-chlorobenzene, 50.0 g (0.58 mol) of anhydrous piperazine and a catalytic amount of potassium iodide in 80 ml of 1-propanol is stirred and heated at 100 ° C overnight. After cooling, 1 liter of ice water was added with stirring. The precipitate obtained is filtered off, washed with water and dried. Yield: 26.6 g (94%). The compound has a temperature of 81-83 ° C.

Example 40 (Intermediate, Compound of Formula XIII)

4-Amino-2,6-dichlófenylpiperazín

10.4 g (50 mmol) of 2,6-dichloro-4-nitroaniline dissolved in 100 ml of methanol and 10 ml of 2M hydrochloric acid are hydrogenated with platinum on carbon catalyst at room temperature and normal pressure for 8 hours. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in ether and basified. 5.1 g (29 mmol) of a gray crystalline powder are obtained. This material was treated with 5.4 g (30 mmol) of bis- (2-chloroethyl) -amine hydrochloride while heating at 100 ° C in n-butanol with three times 1 g (30 mmol) of sodium carbonate for 26 hours. The solvent was evaporated, the residue was taken up in ether and basified. 3.4 g of compound are obtained in the form of an oil. Yield: 48%.

¹ H NMR Spectrum (CDCl ₃ ) δ 6.82 (s, 2H), 4.10 (s, 2H), 3.02 (m, 8H), 1.82 (s, 1H) ppm.

Process for the production of pharmaceutical compositions

The following examples illustrate suitable pharmaceutical compositions for use in the method of the invention. The following compositions may be used to prepare tablets.

Mixture 1

Example 1 compound 50 g lactose 85 g Potato starch 40 g polyvinylpyrrolidone 5 g Microcrystalline cellulose 18 g Magnesium stearate 2 g

Mixture 2

Example 1 compound 100 g lactose 90 g Potato starch 50 g polyvinylpyrrolidone 5 g Microcrystalline cellulose 23 g Magnesium stearate 2 g

From the above mixtures, 1000 tablets can be prepared, each containing 50 and 100 mg of active ingredient. If desired, the obtained tablets may be film-coated, for example with hydroxypropylmethylcellulose dissolved in an organic solvent or with water.

pharmacology

It is generally accepted that drugs that bind to dopamine receptors and are antagonists of these receptors will be clinically effective as antipsychotic agents (e.g. in schizophrenia). It is also believed that serotoninergic (5HT1A) receptor affinity as an antagonist may be a useful property manifested by decreasing the incidence of extrapyramidal side effects and enhancing the efficacy of agents in psychosis. By having a certain ratio of D2 and 5HT1A binding, these agents will maintain the antipsychotic effect together with a reduced incidence of side effects and improved efficacy.

Table 1 illustrates the binding affinities (K i values, in nmol) of some compounds at the dopamine (D2) and serotin (5HT1A) receptors and the D2 / 5HT1A ratios.

Pharmacological procedures are described below.

D2 Receptor Binding Assay

Tissue preparation

The rats are sacrificed by severing the head and the corpus striatum is separated and placed on ice. The tissue is homogenized at 0 ° C in 20 ml of 0.05 molar Tris-HCl buffer at pH 7.7 using a Branson B30 ultrasonic device. The homogenate is centrifuged at 4 ° C for 10 minutes at 48,000 g in a SOrvall RC-5B refrigerated super-centrifuge. The granules are resuspended and centrifuged again. Finally, the granules are resuspended in an incubation buffer, (0.05 mol Tris-HCl buffer, pH 7 containing 0.1% ascorbic acid, 120 mmol sodium chloride, 5 mmol potassium chloride, 2 mmol calcium chloride, 1 mmol magnesium chloride and 10 µmol pargyline), to a final concentration of 2.5 mg (expressed as wet weight) in 0.5 ml volume. The homogenate is heated at 37 ° C for 10 minutes.

Receptor Binding Assay

The test compound at various concentrations, the ligand (1 nmol @ 1 H-Raclopride) and the homogenate are incubated for 60 minutes at room temperature. No specific binding is established when 1 μπιοί (+) - butaclamol is added. Incubation is terminated by rapid filtration through glass fiber paper (Whatman GF / B) and then the filter cake is washed with cold incubation buffer using a cell capture device. The radioactivity of the filtrate is measured in a Packard 2200CA liquid scintillation counter. Values are analyzed by non-linear regression using the LIGAND program and are reported as K i values.

5-HT1A receptor binding assay

Tissue preparation

The cerebral cortex and hippocampus are cut from each rat and homogenized in 15 ml of ice-cold solution of 50 mmol Tris-HCl buffer, 4.0 mmol of calcium chloride and 5.7 mmol of ascorbic acid, pH 7.5, using a Utra -Turrax (Jakne & Kunkel, Staufen, SNR) for 10 seconds. The mixture is centrifuged for 12.5 minutes at 17,000 rpm (overload 39,800 g, in a JA-17 cooled rotor Beckman centrifuge (Beckman, Palo Alto, California, USA), and the granules are resuspended in the same buffer. 5 ml of an ice-cold 0.32 molar sucrose solution is added to each granule and homogenized for 5 seconds, and these samples are kept frozen at -70 ° C. Dilute to 8 mg tissue per milliliter and homogenize for 10 seconds Tissue homogenates are allowed to heat at 37 ° C for 10 minutes and then 10 μποοί pargylin is added, after which all the heat is re-tempered for 10 minutes. as described by Peroutka in J. Neurochem, 47, 529-540 (1986), 2 ml of incubation mixture containing 0.25 to 8 nmol of ³ H-8-OH-DPAT, 5 mg / ml tissue homogenate in 50 mmol Tris are used. -HCl buffer solution containing 4.0 mmol calcium chloride and 5.7 mmol ascorbic acid, pH 7.5. 6 different concentrations are analyzed

H-S-OH-DPAT. The binding experiment is initiated by adding tissue homogenate and then incubating at 37 ° C for 10 minutes. The incubation mixtures were filtered through Whatman CF / B glass filters using a Brandel Cell Harvest (Gaithersburhg, Maryland, USA). The filtrates were washed twice with 5 ml of ice-cold 50 mM Tris-HCl buffer each time with a pH value.

7.5 and read for placing with 5 ml Ultima Gold ™ (Packard) in a Beckman LS 3801 scintillation counter. Non-specific binding is measured directly by adding 10 μπιοί 5-HT to the reaction mixture. Binding values are processed by computer analysis based on the determination of nonlinear least squares (Munson and Rodbard, Anal. Biochem. 107, 220-239 (1980)). Values are reported as values (nmol).

Table α:

O σ>

tú / -H • H> p

CL, co

ABOUT)

CM

CM co

P / - / 3Í-Ý-33

Claims (13)

PATENT CLAIMS 1) if W is an optionally substituted aromatic ring or rings, then R, m, R ₄ , R g and R g have the meanings given above, nL is 0 or 1, n ₂ is 0 or 1, A represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having an alkyl group having from 1 to 3 carbon atoms; (C 1 -C 3), phenyl or phenoxy; and B is hydrogen or A and B together form a carbonyl group, 1 a Y is in the meta or para position and represents a group which can be converted to a group R 4 ^1, where R ¹ is in the meta or para ring, and a group of formula NR ₇ R ₈ in the meaning as defined in Claim 1, or C) Compound of formula VO / CH ₂ ] _n -c ABOUT II • c — z (V) CHf-A I R in which R, m, W, A, B, n · n ^ ₂ are as defined in Claim 1 and Z is hydrogen, hydroxy, halogen, or alkoxy, is reacted with a compound of formula III wherein (III) R ₄ , R 8 and R 8 are as defined in claim 1, or D) Compound of Formula VI O / [Ch ₂ ] -C (VI) CH I R wherein w, n 1, n ₂ and A have the meanings given in claim 1 a T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or hetero cyclic acid or an acid derivative, is reacted with a compound of formula VII wherein m, R ₄ , R 8 and R 8 have the meanings given in claim 1, or E) Compound of Formula VIII (VII) ABOUT If R n ₂ CH I R in which W, n-, and n ₉ have the meanings in which R, m, R _4, W, A, B, nl and _n2 are as defined in Claim 1 and R ₅ represents a hydrogen atom, a halogen atom or a trifluoromethyl group, reacted with a suitable halogenating agent, or F) Compound of Formula IX ABOUT II, tCH p] _n -C N —M (IX) I Θ referred to in claim 1, A and B together represent a carbonyl group and M is a suitable alkali metal, is reacted with a compound of the formula (X) - [CH ₂ ] -nn-IN - R, (X) wherein X, R ₄ , R 8 and R ₆ have the meanings set forth in claim 1, and then, if desired, the compound obtained by any of methods A) to F) is converted to its pharmaceutically acceptable salt. 1) if W is an optionally substituted aromatic ring or rings, then R, m, R ₄ , R ₅ and R 8 have the meanings given above, nL is 0 or 1, n ₂ is 0 or 1, A represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxy group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a phenyl group or a phenoxy group, and B is hydrogen or. A and B together form a carbonyl group, A compound of formula I / ^{CH 2 '} ABOUT II -c CH ¹ -A I R (I) or a pharmaceutically acceptable salt thereof, wherein: R represents a hydrogen atom or a phenyl group, m represents an integer from 3 to 8, R ₄ is located in the meta or para position of the ring and represents a nitro group or a group of the formula NR y R g, wherein R ₇ and R g are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ₅ is located in the ortho, meta or para position and represents a hydrogen atom, a halogen atom or a trifluoromethyl group, R 8 is located in the ortho, meta or para position and represents a halogen atom or a trifluoromethyl group, W represents an optionally substituted aromatic ring or rings, a heterocyclic ring, a carbocyclic ring or rings, or an optionally substituted methylene group, A represents a hydrogen atom, a hydroxy group, a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a phenyl group or a phenoxy group, and B is hydrogen or A and B together form a carbonyl group, n 1 represents a number 0 or 1 and n ₂ represents a number 0 or 1, in racemic or optically active form or as a mixture of diastereoisomers, provided that: 2) if W is a carbocyclic ring or rings or a heterocyclic ring then R and m have the meanings given above, is 0 or 1, n ₂ is 0 or 1, A and B are hydrogen or A and B together form a carbonyl group, A compound according to claim 1 having the formula or 2) if W is a carbocyclic ring or rings or a heterocyclic ring then R, m, R ₄ , R g and R g have the meanings given above, nL is 0 or 1, n ₂ is 0 or 1, A and B are hydrogen or A and B together form a carbonyl group, 3) if W represents an optionally substituted methylene group, then R and m are as defined above, nl and _n2 is 1 or nL is 1 and _n2 is zero or is zero nL n ₂ is 1, and A and B together form a carbonyl group, A process for the preparation of a compound of formula I according to claim 1, characterized in that: A) a compound of formula (II) xt ^CH 2) _n -C, CH I R (II) n. wherein, m, W, A, B, n 1 and n 2 are as defined in claim 1 a X is a suitable leaving group, reacted with a compound of formula III H — N N \ _y R, (III) wherein R ₄ , R ₅ and R ₆ have the meanings given in claim 1, or B) Compound of Formula IV ABOUT II (IV) in which: R, m, R ₅ , R ₆ , W, A, B, and n ₂ have the meanings given in the claim 3) if W represents an optionally substituted methylene group, then R, m, R _4, R ₅ and R ₆ are as defined above, and n ^ nj, is 1 or n is 1 ^ n ₂ is zero or is zero nL n ₂ is 1, and A and B together form a carbonyl group, 4. The method of claim 3, wherein the compound of claim 2 is produced. 5. A compound of formula II ABOUT II / II _N ^CH C (II) CH I R n ₂ in which R represents a hydrogen atom or a phenyl group, represents an integer from 3 to 8, represents an optionally substituted aromatic ring or rings, a heterocyclic ring, a carbocyclic ring or rings or an optionally substituted methylene group, represents a hydrogen atom, hydroxy, halogen, trifluoromethyl, alkyl (C 1 -C 3), (C 1 -C 3) alkoxy, phenyl or phenoxy group, and represents a hydrogen atom; or A and B together form a carbonyl group, n 1 represents a number 0 or 1 and ₂ represents a number 0 or 1, in racemic or optically active form or as a mixture of diastereoisomers, provided that: 6. A compound of formula III ¹ / - \ H— N N v_ / R (III ¹ ) in which R 4 ¹ is in the meta or para ring and a group of formula NR ₇ R g, wherein R ₇ and R are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ₅ is located in the ortho, meta or para position and represents a hydrogen atom, a halogen atom or a trifluoromethyl group, R 8 is located in the ortho, meta or para position and represents a halogen atom or a trifluoromethyl group. Pharmaceutical active composition, characterized in that it contains a compound according to any one of claims 1 and 2 as active substance. 8. A pharmaceutical composition according to claim 7 in the form of a dosage unit. Pharmaceutical composition according to either of Claims 8 and 9, characterized in that the active ingredient is present together with a pharmaceutically acceptable carrier. A compound according to any one of claims 1 and 2 for use as a therapeutically active agent. Use of a compound according to any one of claims 1 and 2 for the manufacture of a medicament having an effect against mental disorders. 12. A method of treating mental disorders in a mammal, including a human, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 and 2. *) Compounds and methods and intermediates for the manufacture of these compounds, pharmaceutical compositions comprising the compounds, and their use in the treatment of mental disorders as claimed in claims 1 to 12 inclusive and essentially as described.