DE3404193A1 - 5-FLUOR-PYRIMIDIN-2-YL-PIPERAZINE COMPOUND, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS - Google Patents

Description

PROF. DR. DR. J. REITSTJÖTTTER ¹ .. * .DR. NAtETiKER KINZEBACH DR. ING. WOLFRAM BUNTE (ιβοβ-ιβτβ)

REITSTÖTTER. KINZEBACH Λ PARTNER PATENT LAWYERS

P.O. Box 7βο. D βοοο Munich 43 APPROVED REPRESENTATIVES AT

EUROPEAN PATENT OFFICE EUROPEAN PATENT ATTORNEYS

TELEPHONE: (OB ») Z 71 OB 83 TELEX: OD2102O · IBAFI D BAUERSTRABSE 22. D-BOOO MUNICH

Munich, February 7, 1984

OUR FILES: M / 25 012

OUR REF:

REFERENCE: RE

BRISTOL-MYERS COMPANY

Park Avenue, New York 10154

UNITED STATES.

5-Fluoro-pyrimidin-2-yl- |) iperazine Compound, Method for their manufacture and pharmaceutical agents

POSTAL ADDRESS; D-BOOO MUNICH 43. POST BOX 78Ο

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The invention relates to e - ^ - ^ - ^ - 1-piperazine] -butyl] -8-azaspiro [4.5] decane-7,9-dione der Formula I.

(D

and their pharmaceutically acceptable acid addition salts, processes for their preparation and pharmaceuticals Means containing these compounds. The compounds of the invention are bioactive and possess antipsychotic effect.

The compounds of the general formula (T)

<KÖ

where η is 4 or 5 and W and Y are different, one ring atom being CH and the other being N; R and R independently of one another from a group of substituents, including a hydrogen and halogen atom, are selected are already known.

M / £ 25,012,

Wu et al. describes in J.Med.Chem., 15/5, 477-479

(1972) and U.S. Patent 3,717,634 compounds this structural type with a tranquilizing effect.

In addition, three further pyrimidinyl derivatives substituted in the 5-position are disclosed. These correspond to the structural formula above, where W stands for N and Y stands for C-NO ₂ , C-NHSO ₂ C ^ Hq and C-OH. However, no 5-halopyrimidine compounds are described.

The following publications relate to a related but less obvious prior art.

U.S. Patent 3,907,801 is a divisional application to the aforesaid U.S. Patent 3,717,634 and relates to pyrldinyl compounds (e.g., W and Y are each CH).

U.S. Patent 3,976,776 is also a disclosure application and relates to the use of these compounds as tranquilizers.

US Pat. No. 4,182,763 describes the use of buspirone (2), one of the above series of compounds Compound, described for the treatment of anxiety.

(2)

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US Pat. No. 3,398,151 describes related compounds in which the pyrimidine ring is substituted by an unsubstituted one 5 or substituted (e.g. by halogen) phenyl radical.

Wu et al. reports in Journal Medicinal Chemistry, 12/4, 876-881 (1969), on work with these phenyl analogs. In this publication, however, there are no fluorine-substituted substances in either the examples or the tables PhenyIderivate mentioned.

The application 06/334 688 relates to 1- [4- (4,4-dialkyl-2,6-piperidindion-1-yl) butyl] piperazines, which have 2-pyrimidinyl substituents in the 4-position and have anxiolytic properties. The pyrimidine ring in this series of compounds can either be unsubstituted or by a fluorine or chlorine atom or a hydroxy or trifluoromethyl group may be mono-substituted.

Surprisingly, it has now been found that so far ■ unknown compound 8- [4- [4- (5-fluoro-pyrimidin-2-yl) -1 -piperazinyl] -butyl] -8-azaspiro [4.5 i-decane-7,9-dione Has long-lasting antipsychotic activity. This pharmacological activity is different di © compound according to the invention from the related Prior art pyrimidiny compounds. These known compounds are mainly anxiolytics with only a very low antipsychotic effect and have only a short duration of action.

8- [4- [4- (5-fluoro-pyrimidin-2-yl) -1 -piperazinyl] -butyl] -8-azaspiro [4.5] decane-7,9-dione (I), hereinafter referred to as

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-S-

MJ 14594 and its pharmaceutically acceptable Salts have useful antipsychotic activity with long lasting effects. The inventive Compound has the following structural formula

W \ i

(D

The preparation of the compound according to the invention can according to a general procedure comprising various embodiments (A, B and C). It. it is also obvious to the person skilled in the art that the compound according to the invention can also be modified by modifying this Process can be made in slightly different ways. The preferred embodiments are explained by way of example.

General procedure

Y-

II

III

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In the above formulas, W stands for JTO, ^ NH or ^ N- (CH ₂ J ₄ -X and Y stands for H ₂ N- (CH ₂ J ₄ -, XI

5 - θ

or H. There is between W and Y fol

gender relationship: method A

if W stands for:

then Y stands for:

(Ha)

H ₂ N- (CH ₂ ) ₄ -CHIa)

(Hb)

X- (CH ₂ ) ₄ - o.

(HIb) (HIb ¹ )

- (CH ₂ ) _A -X (lic)

H CIIIc)

X denotes a suitable leaving group such as chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate. In practice, the interconnection HIb easily transforms into the connection IHb ¹ , this being the only isolable form. However, the two compounds are equivalent for use as intermediates

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1
method A. fr
-Μ- • * * ^: .. ^: . ::. ^: .: - 'Ύ 3404193 0
t oQ ) ⁺ v " \ ■ .. 11. * ^ - ^F Δ
dry
solvent

IIa

Method B.

DÖ-

lib

2. Hb +

Method c

DO

HIa

IHb

Illb *

Hc

HIc

-> I.

35

L = Γ "L =. :: ü" O ^: t 340A193

Μ / 25 012 Τ

The condensation process according to Method A is carried out by refluxing the reactants in a dry, reaction-inert medium such as pyridine or xylene. Methods B and C are carried out under reaction conditions which are suitable for the preparation of tertiary amines by alkylation of secondary amines. The reactants are heated in a suitable organisehen liquid at temperature of about 60 ⁰ C to about 150 ° C in the presence of an acid-binding agent. Preferred organic, liquid reaction media are benzene, dimethylformamide, ethanol, acetonitrile, toluene and n-butyl alcohol. The preferred acid scavenger is potassium carbonate, but other inorganic and tertiary organic bases such as other alkali and alkaline earth metal carbonates, bicarbonates or hydrides and tertiary amines can be used. All three methods have been extensively reviewed by Wu et al. in the above-mentioned patents and publications, which are hereby incorporated by reference.

As an example of a modification of the method of making the same compounds on something different The following procedure is available. So you can use an N-substituted [4- (1-piperazinyl) butyl] azaspirodecanedione (V) react with a suitable pyrimidine compound to form the compound of formula (i), e.g .:

ΓΛ

The preferred process described below for the preparation of the compound of the formula (I) is based on this procedural modification.

The spiro-glutaric anhydrides used as an intermediate or imides of the formula (II) are commercially available in the publications mentioned above or described in the context of the present invention.

The pyrimidinylpiperazine intermediates (III) are described in the aforementioned Wu et al. and certain publications cited therein. Even if this method is based on the production of 5-fluoropyrimidinylpiperazine compounds can be used which are not in the publications mentioned are disclosed, but for the method according to the invention as intermediates are required below the synthesis of the compound (HIc) explained in more detail using a working example. The intermediates (purple) and (HIb) are easily derived from (HIc) using the method used by Wu et al. standard methods described available.

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H H H

% l

P *

© H

O O

CM

Pooh

JL

O A3 O

9.

• <1 '

"-": 3404193 M / 25 012

The synthesis takes place, starting from 5-fluorouracil, via known reaction stages and leads to the desired th piperazine intermediate. Although the route via the carbethoxypiperazine is more complex, it is due to it the higher yield of (IIIc) and because of the lack of By-products preferred.

In practice it has proven to be expedient to prepare (I) from (rv) and (V) according to the following scheme.

K ₉ CO, IV / \ / \ ^ KX RaNi

iv + v - ± - L>

KJ

CH ₃ CN

EtOH

The psychotropic profile of MJ 14594 was based on based on subsequent screening tests. MJ 14594 is in the process of determining the conditional Escape reflexes (conditioned avoidance response test) according to the method described by Wu et al. in the above patents and publications described method about three times more effective than buspirone.

This test is done on orally treated rats that have been fasted and generally given the tranquilizer Effect of a compound again, without necessarily between anxiolytic and effective differentiate antipsychotically active compounds. Of even greater importance was the fact that MJ 14594 when administered orally at 35 mg / kg compared to buspirone when administered orally of 100 mg / kg results in an approximately three-fold increase in the duration of action.

A more accurate test for determining antipsychotic effectiveness is the apomorphine stereotypical behavior test on rats that were not fasted.

This test determines the ability of centrally acting compounds, the apomorphine-induced stereotypical behavior to block. This preclinical test is a useful indicator to assess potential indicate antipsychotic effectiveness [Janssen et al., Arzneimittel-Forsch., r £: 841 (1966)]. MJ 14594 was roughly the same on the apomorphine stereotypy test as effective as buspirone, but MJ 14594 remained effective for more than 6 hours a 1 to 2 hour duration of action of buspirone in the same test.

It is believed that the antipsychotic drugs control the symptoms of psychosis by acting as post-synaptic dopamine receptor antagonists act. Since the stereotype reversion test has the effect of a Dopamine antagonist reproduces shows a comparison the duration of action of the two drugs, that the antagonistic component (antipsychotic effect) of MJ 14594 persists while that of buspirone decreases rapidly.

An additional prop to classify MJ 14594 as an antipsychotic agent is found in radioreceptors & imgsunt © rsuchungen. Radioreceptor binding assays, with which the inhibition of the binding of different, neuronally active molecules are used to make the tranquilizing effect more specific to determine. Although MJ 14594 only 10 to 20% of the binding

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If buspirone has an affinity for dopaminergic receptors, it appears to be much more antagonist-like in nature. The binding affinity of buspirone for [H JSpiperone-labeled receptors is reduced in the presence of 5 / µM guanine triphosphate (GTP), while the binding affinity of MJ 14594 remains essentially unchanged. Such a GTP-induced change in binding affinity means agonistic activity, while the absence of such a change means antagonistic activity. Further details in connection with dopamine receptor binding assays and their importance for antipsychotic activity can be found in the following publications: Burt, Creese and Snyder, Molecular Pharmacology, 1j2: 800 (1976); Burt, Creese and Snyder, Science, 196 ; 326 (1977); Creese, Burt and Snyder, Science, 192 ; 481 (1976); Creese, Prosser and Snyder, Life Science, 22: 495 (1978); Creese and Snyder, European Journal of Pharmacology, J50: 459 (1978); Creese, Usdin and Snyder, Nature, 2 £ 8: 577 (1979).

An investigation of MJ 14594 using the Vogel model in rats, an anxiolytic behavioral paradigm, shows that the compound has no activity at doses below 5 mg / kg, whereas buspirone has is effective in this anxiolytic screening test at a dose of 1.0 mg / kg. The bird model on rats is a modification of the Vogel Conflict test, which is a useful conflict method for testing anti-anxiety agents [Vogel, Beer and Clody, Psychopharmacologia (Berl.) 21, 1-7 (1971)].

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Further data was obtained from comparative tests on the Obtained based on other CNS screening methods. MJ 14594 causes at doses up to 70 mg / kg (a higher Dosage is toxic) no catalepsy, but, in contrast to buspirone, it does not lead to the reversal of the trifluoperazine-induced Catalepsy. When tested with standard antipsychotic agents on a recently developed wrapped monkey model (described by Kovacic and Domino, J.Clin.Psychopharmacol., 2: 305-307, 1982) showed that MJ 14594 does not qualify for clinical side effects such as extrapyramidal symptoms. Accordingly includes MJ 14594 © inen -significant therapeutic advantage to most other established antipsychotic agents. MJ 14594 has a buspirone similar cortical electroencephalogram in cats, but larger than buspirone Suggesting effectiveness.

Due to the in vivo effectiveness, the long effectiveness * - duration and the antagonist-like binding profile of MJ 14594 summarizes that the Pharmacologymar the activity of this antipsychotic Compound clearly distinguishes itself from buspirone and related compounds.

With regard to the pharmacological profile established by the above-mentioned tests, the compound of the formula (I) according to the invention can be described as an effective antipsychotic agent. To alleviate The compounds according to the invention or their pharmaceutically acceptable acid addition-35 are psychoses

salts mammals, including humans _? administered systemically at an effective dose of about 0.01 to 40 mg / kg body weight.

The term "systemic administration" includes oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous) administration. In general, when administered orally, those according to the invention are required Compound, which is the preferred mode of administration, a larger amount of active ingredient to the same To achieve the same effect as with a parenterally administered, smaller amount. It is preferred to administer the Compound according to the invention in a dose which is antipsychotically effective, but without being harmful or cause unwanted side effects.

For therapy, the compound according to the invention can generally be administered in the form of pharmaceutical agents containing an effective antipsychotic amount of MJ 14594 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical ones are preferred Agents containing about 1 to 500 mg of active ingredient / unit dose. They are usually in the form of Tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and formulated aqueous solutions.

Tablets and capsules are the preferred orally administrable compositions which contain common excipients like binders (e.g. syrup, acacia gum, Gelatine, sorbitol, gum tragacanth or polyvinylpyrrolidone), Fillers (e.g. lactose, sugar, corn starch,

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Calciumphosphatg sorbitol or glycine) ₉ lubricant (ζ.Β "magnesium tearatj, talc _s polyethyl @ nglykol or silica), Desintegrationssnittel (z _0, starch) and wetting agent (sodium lauryl sulfate zobo) ο For parenterally administered © means" wi @ an aqueous © Solution for intravenous injection or an oily suspension for intramuscular lajactiong one can use solutions of the suspension of FU 14594 in common pharmaceutical carriers. Such © © means ₉ which must have the necessary stability and applicability Klarheitρ for parenteral ^ purpose is obtained by dissolving O ₀ 1 to 10 Gkäw.tf of the active ingredient in water or a vehicle consisting of ^ © in®m aliphatic polyalcohol, wi © Glyc <BT ± n _g propyl © nglycol and polyethylene glycols _or mixtures thereof o Di © Poly @ thyl © nglycols consist of © inar non-volatile ₀ normally liquid polyethylene © ₀ di © both in water and in organic liquids are soluble and have a molecular weight of around 200 to 1500.

Di © following examples are d®r explanation of the extent Erfinduago ^ otherwise indicated, all temperatures are in ⁰ C. expressed _o

mean the chemical shifting C δ) _f expressed as parts per million (ppm), ^ © βΘηΐΑ ©! ⁵ Tetramethylilane (TMS) as standard. The relative area under the individual signals in the NMR spectrum corresponds to the number of hydrogen atoms of a functional type in the molecule. The multi plizität d © r signal © is expressed as broad singlet (IDE) ₉ singlet (s), multiplet (m) or doublet (d) o Di © v © w © nd © t © n abbreviations Items since DMSO-dg (deutero -

dimethyl sulfoxide), CDCl, (deuterochloroform) and are otherwise common. The infrared (IR) spectra only include those wave numbers (cm) that are important for identifying functional groups. The IR spectra were recorded using potassium bromide (KBr) as the diluent. The elemental analyzes are reported in wt.%.
10

example 1

2-chloro-5-fluoro-4-methylthiopyrimidin-2-one (IV) 5-fluoro-4-thiouracil

A mixture of 5-fluorouracil (26 g, 0.12 mol) and phosphorus pentasulfide (45 g, 0.2 mol) in 500 ml of dioxane is refluxed for 3 hours. The hot reaction mixture is filtered and concentrated in vacuo. The residue is dissolved in 650 ml of water, heated with 5 g of charcoal and filtered. The crystallized upon cooling solid is filtered off to give 25.4 g (88%) of S-fluoro ^ -thiouracil, Fp.269 to 272 ⁰ C, is obtained.

^ -Fluoro-4-methylthiopyrimidin-2-one

Methyl iodide is added dropwise to a solution of 5-fluoro-4-thiouracil (25 »4 g, 0.174 mol) in 350 ml of 0.15N NaOH (59.4 g, 0.348 mole). The mixture is stirred at room temperature for 2 hours, cooled in an ice bath and filtered. The isolated solid is triturated with hot methanol, 18.5 g (66%) of the product, m.p. 205 to 207 ° C.

A mixture of 5-fluoro-4-methylthiopyrimidin-2-one (21.1 g, 0.132 mol), phosphorus oxychloride (126.4 g,

Μ / 25 012 3-7

Q "S24 mol) and N ₈ M-dimethylaniline (27 _s O g, 0 _p 224 mol), _ö ΐ / IRD 2 h wat®r reflux heated Dl © mixture is cooled in an ice bath δ, simultaneously being in ice di © R © aktionsffiischung are _ΰ and then with ether xtrahi © © rt ₀ the ether extract is dried (MgSQ ^) and is added to inen © v © residue rdampft _s in two 100 ml-P © @ n rtion hot Skelly B. The üb rst © © © h nd © Skelly B is insoluble material dekantiertg, filtered and einge- © © NGTP with carbon wherein one 2O S ₉ g (88%) of compound (IV).

3®iSOi © 12

S- [4- (piperazinyl) »butylj => 8-azaspiro [4 _o 5 decane-7 ₉ 9» dione

ν © »3o3 ^ra T @ tr ^> amethyl @ nglutapimid (50.2 g, </ _ΰ 3> WA ₁ J ₅ -j _s ^ ~ Difero! Bbutane (130 g ₉ 0 ^ 6 mol) and waterfe @ d» iC ^ CO- (S 6 ₅ 7 ₉ O ₉ J mol) in 500 al of toluene is unt® .20 3h? refluxed wad _ΰ vacuum filtered © inge restricted B © 2? residue is distilled (165 to 170 ° C / iif © b @ i was 64 _ß 1 g 8 ~ [4 ~ (1-bromo) butyl] -8-aza} ά <$ Ό®Μ ~ 7f> 9 "d ± ÖN _s ®rhält together with piperazine (90 _p 4 g ₉ 1.05 mol) and K ₂ CO ₃ (145.5 g ₉ 1.05 mol) in 900 ml of toluene, heated under reflux for 18 h , filtered and concentrated in vacuo. The residue is distilled {ieO- 20 ° C / O _g O1 ram) ₀ whereby 52.7 g (82Ji) of (V) are obtained.

Hydration s 8- [4- [4- = · (5-fluoro-2-pyrimidinyl) -1-piperasine

won IV (4.47 g ₉ 0.025 mol), V (7.7 g,

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0.025 mol), K ₂ CO ₃ (10.37 g, 0.07 mol) and KI (catalytic amount) in 100 ml of acetonitrile is refluxed for 18 h. The mixture is filtered, concentrated in vacuo and the residue chromatographed on 230 g of silica gel using 2% ethanol-chloroform as the eluent. Removal of the solvent gives 9.0 g (80%) of 8- [4- [4- [5-fluoro-4- (methylthio) -2-pyrimidinyl] -1-piperazinyl] -butyl] -8-azaspiro [4.5] decan-7,9-dione.

A 3.5 g portion (0.008 mol) and moist Raney nickel (1.5 teaspoons full) is refluxed in 70 ml of ethanol for 3 h, filtered and the solvent is evaporated off. The residue is heated in acetonitrile, filtered and concentrated in vacuo. This residue is then heated with Skelly B on a steam bath. The supernatant liquid is decanted from insoluble material and cooled, 1.8 g (59%) of the compound (I) in hydrated form, melting point 83 to 85 ^° C., being obtained.

Analysis: for C ₂₁ H ₃₀ FN ₅ O ₂ .0.1 H ₂ O

Calculated: C, 62.23%, H, 7.51%, N, 17.28% found: 62.17, 7.46, 16.88.

Example 4

MJ 14594 in the form of Hydrochlorld

The hydrochloride of the compound (I) is obtained by a modification of the above procedure, whereby 8- [4- [4- [5-fluoro-4- (methylthio) -2-pyrimidinyl] -1 - piperazinyl] -butyl] -8-azaBplro [4.5] decane-7,9-dione (9.0 g,

* O

Μ / 25 012 ν?

Op02 Mol) and Raneynlck ©! (10 to 15 g) in 200 ml of ethanol heated under reflux for 6 h . _P di © mixture filtered and. © in © ngto Water (50 ml) is added to ₉ , the mixture is made alkaline with 50 NaOH and extracted with Ξΐϊι © 3Γ ₀ D @ s ^a dry © extract (MgSO ^) is evaporated, the ©? Rücketaad ia 20 ml of ethanol dissolved and treated with 2.15 ml of 7N ethanolic HCl "whereby 5.6 g (64%)

LO MJ 14594 ia Foxe ö @ g Hydrochloride ₀ Mp ₀ 224 to 226 ⁰ C _f

15th

0 3 "ϋ ·.

2 _ρ δ1 (4 ₉ S) ₉ 3.02 (4, m), ₀ ^ pw ^ & j, tj, 6 ₉ 9 Ez) ₉ 4.54 (2p m), 8ρ51 (2 _ΰ S) ₀ 11 ₀ 70 (1 ₀ bs)

1250, 1350, 149O ₅ 1560, 16? Ο _$

= 1

Claims (8)

M / 25 012 claims 1. I 8- [4- [4- (5-fluoro-2-pyrimidinyl) -1-piperazine] - "'Butyl J-8-azaspiro [4.5] decane-7,9-dione of the formula I. 10 (D and its pharmaceutically acceptable acid addition salts. 20th 2. Process for the preparation of the compounds according to claim 1, characterized in that one (A) a compound of the general formula II (II) 25th wherein ¥ is> 0, ^ NH or ^ N- (CHg) ₄ -X, where X is a suitable leaving group, with a compound of the general formula III 30th O" (III) 35 Μ / 25 012 2 where Y is H ₂ N- (CH ₂ ) ₄ - Λ ^Λ or H y stands ρ ttfo where X has the above meaning, under suitable reaction conditions to form the Reacts compound of formula (I), wherein (a) when W is> 0, Y is H ₂ N- (CH ₂ ) ₄ - and the compounds of the general formulas (II) and (III) are condensed with elimination of water; (b) when ¥ is ^ NH, then Y is either X © or stands and the connections of the general formulas (II) and (III) are reacted under reaction conditions which are suitable for the preparation of tertiary amines © by alkylation of secondary amines; (c) if ¥ is (CH _{2) 4} -X ^ N-, Y stands for H and di © compounds of the general formulas (II) and (III) is reacted under reaction conditions which zm · preparation of tertiary amines by alkylation of secondary Amines © are suitable, where X in alternatives (b) \ and (c) represents a © suitable leaving group; 25 or (B) the compound of formula (IV) SCH, i P .JDJ (IV) Cl old d @ T V @ rbinding (V) 35 Cl " ^N Ci _H M / 25 012
ι to the compound of the formula (X) reacted, and then the compound (X) with Raney nickel in ethyl alcohol to form the compound of Formula (I) treated, and c) if desired, then the salts of the compound of formula (I) using known processes 3. The method according to claim 2, characterized in that in method (A) of alternative (a) follows and the compounds of the general formulas (II) and (III) in a dry, reaction-inert medium, such as pyridine or xylene, heated to reflux. 4. The method according to claim 2, characterized in that in method (A) the alternatives (b) or (c) follows and thereby the compounds of the general formulas (II) and (III) in a suitable organic Liquid at a temperature (s) in the range of about 60 to about 150 ° C in the presence an acid binding agent heated. M / 25 012 5. A pharmaceutical agent containing at least one of the compounds according to claim 1, optionally in combination with a pharmaceutical carrier and / or Auxiliary materials. 6 "A pharmaceutical agent according to claim 5 in unit dosage form for systemic administration containing a pharmaceutical carrier and a compound according to claim 1 in a non-toxic, antipsychotically effective Meng®. 7. A pharmaceutical agent according to claim 6, containing about 0 ₉ 01 to about 40 mg of the compound according to claim 1 per kg of body weight. 8. Use of the compounds according to claim 1 for the treatment of psychoses «,