SA05260389B1 - Phenylpiperazines With a combination of affinity for dopamin-D2 receptors and serotonin reuptake sites - Google Patents

Abstract

Abstract: The invention relates to a group of novel phenylpiperazine derivatives with a dual mode of action: inhibition of serotonin reuptake and apoptosis of D2-dopamine receptors and methods for preparing these compounds. The invention also relates to the use of a compound disclosed in this application to manufacture a drug that gives a beneficial effect. The compounds have the general formula (1): where the symbols have the meanings given in the specification. Number of protection elements (10)

Description

Phenylpiperazines with a combination of affinity for dopamine -D2 receptors and serotonin reuptake sites Full description BACKGROUND The invention relates to a group of novel phenylpiperazine derivatives with a dual mode of action Inhibition of (sale) uptake of serotonin to dopamine-D receptors; and methods for preparing these compounds. The invention also relates to the use of a compound disclosed herein for the manufacture of a drug which gives a beneficial effect. In this application the beneficial effect of a person skilled in this field has been disclosed from the specification and from his general knowledge in this field. The invention also relates to the use of the selector compound Approved to manufacture a drug & to prevent or cure Ua ya or 0 condition The invention relates more specifically to a new use for the treatment of a disease or Alla disclosed in this application or seems obvious to a person skilled in this field from the specification and general information in this the field. In embodiments of the invention certain compounds disclosed herein are used in the manufacture of a drug useful in the treatment of disorders in which: (0002:0106-1) receptors and serotonin ¢ reuptake sites are involved or that can be treated by the use of these compounds .

General description of the invention The derivatives of phenylpiperazine with a dual effect as antagonists of dopamine-D2 and inhibitors of serotonin reuptake are known from International Patent No. 10/01 47708 This combination is useful in the treatment of schizophrenia, psychotic disorders This enables a more complete treatment of all symptoms of the disease (such as positive symptoms and negative symptoms). In the specification of the British patent 1778006 issued in 14974, oxime derivatives of halophenyl piperazinyl-alkyl ketones have been revealed that have useful pharmacological activity, especially as analgesic agents + anti-inflammatory agents. 0 And as AL jo agents for local muscle contraction - musculotropic spasmolytic agents, the present invention aims to provide other compounds with a dual effect that act as dopamine-D2 antagonists and serotonin reuptake inhibitors. The invention relates to compounds having the general formula: (1) 3 N _Q ly, pl [Fo + Nx (1) (Ry), Vo YYée

$ A of ¢ or ¥¢ or º or 2 ¢ or ©” or 1 ¢ or l é 1 each are 11 5 m Cua -

Ff oY KR is yellow or OR - “benzyl 5” phenyl J branched or unbranched alkyl (Cig) or “halogen is Ry - or ¢ cyano of” trifluoromethyl branched or unbranched ; or alkoxy (Cr) ° « benzyl or + phenyl or + alkyl (Cy) oJ hydrogen each separately less than sR; - . acetyl or N-A group © is selected from moieties with a molecular structure - l Di YT 0 0 0 0

A H 8 0 0 8 N N 0

CO bur Co 3 0 0 0 0

E F G H

0 Ci x 0 subner jos 0 0 0

HJK

1 Ry),

N 0 N 0 BR (LX 0

L mM N where: or a oY is or Y -

R; - is a halogen “or branched alkyl (Cpe) or unbranched Ae jie or phenyl” or benzyl alkoxy (Cig) 3' branched or unbranched dc jie or trifluoromethyl ¢ or cyano ¢ and tautomers 43 sia ¢ and stereoisomers and N-oxides thereof in addition to pharmacologically acceptable salts and hydrates of the aforementioned compounds of formula (1) and ° tautomers ¢ and stereoisomers stereoisomers ¢ and its N-oxides.

Prodrugs of said compounds are within the scope of the present invention. Prodrugs are therapeutic agents that are inactive, among other things, but are converted into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules used to overcome some of the barriers to using the parent drug molecule. These barriers include, but are not limited to; solubility

0 and transmittance; constancy; pre-systemic metabolism; and Target Limitations (Medicinal Chemistry: Principles and Practice, 1994, ISBN 0-85186-494-5, Ed.: F.

D. King, p. 215; J.

Stella, “Prodrugs as Therapeutics”, Expert Opin.

Ther.

Patents, 14(3), p.

Ettmayer et al., “Lessons learned from marketed and investigational prodrugs, 2004, 277-280”, J.Med.Chem., 47, 2393-2404, 2004 Compounds which, when administered to humans by any route, are metabolized into compounds of formula (1); belonging to the invention. This relates specifically to compounds having primary, binary, or 0-amino groups. hydroxy These compounds can react with organic acids to give compounds of formula (1) where there is an additional group that can be removed easily after administration, for example but not limited to enamine camidine or Mannich’s base “or

:; or a hydroxyl-methylene derivative | 00 m X-

The O-(acyloxymethylene carbamate) derivative, carbamate, ester, amide or enaminone. The N-oxides of said compounds are within the scope of the present invention. It may give J tertiary amines. It does not give N-oxides metabolites. The range in which the N-oxidation edie occurs ranges from negligible amounts to conversion close to quantitative yield 0 N-oxides may be more effective than their corresponding tertiary amines oe or less effective. While N-oxides can easily be reduced to their corresponding tertiary amines by chemical means; This happens in the human body to varying degrees. Some N-oxides undergo reductive conversion close to the quantitative product to the corresponding tertiary amines; In other cases, conversion is just a minimal or non-existent interaction: (ML.H.

Bickel: “The pharmacology and Biochemistry of N-oxides”, Pharmaco-logical Reviews, 21(4), 325 - 355, 1969) Ve. The preferred compounds of the invention are compounds with formula (1) where JY ans ) am for or of or 8 and 2x )¢ and 2 4-fluoro or 4-triflucromethyl ¢ and bcao each separately represent hydrogen or Sis methyl select group Q of fragments have the molecular structures M- or © ; or l or not and 7 is 1 and .18 is Ae jie alkoxy (Crs) or unbranched; and 00 tautomers ¢ and stereoisomers and N-oxides; In addition to pharmaceutically acceptable hydrates of the aforementioned compounds of formula (1) and their enantiomers and analogues and N-Ad oxides, it was found that the compounds of the invention show a high affinity for both the dopamine-D receptor and the site of re-uptake. serotonin The compounds show activity as antagonists at dopamine-D receptors.

1 in mice. The apomorphine compounds also appear to effectively counteract the climbing behavior induced by 5-HTP potentiation of the behavior that Cua serotonin seeks to be effective as inhibitors of reuptake in rats. The compounds are effective in sensitive therapeutic models of antipsychotic drugs with conditioned withdrawal response; Jie of close clinical relevance and antipsychotic drugs Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67°): for depressants or anxiolytics (such as stress-induced suppression) in contrast to antidepressants (van der Poel er. Psycho-pharmacology, 1989). , 97: 147-148) of close clinical relevance. The compounds mentioned have a natural tendency to induce dopamine-D receptor sclerosis in rodents. Extrapyramidal side effects are also likely to occur less than serotonin soley uptake. Current agents Antipsychotics The inhibitory potency0 inherent in these compounds may be responsible for the therapeutic effects seen in behavioral paradigms or anxiolytics The compounds can be used to treat depression Sensitive to antidepressants Central nervous system diseases caused by disturbances in the systems “anxiety disorders” and “aggression disorders” such as: serotonin-dopaminergic aggression, cognitive disorders, depression, vertigo depression, vertigo, autism, and automatic ve

Parkinson’s and Parkinson’s disease » disturbances of cognition or memory or other memory. Psychotic disorders or psychotic disorders, schizophrenia, especially disease

A general pictures of the synthesis: In this patent as mentioned in the scheme of piperazine the synthesis of all derivatives can be carried out as mentioned in 4 phenylpiperazine FY compounds can be obtained Preparation of the compound: Patent Hartog , J et al., 1985: 'New pharmaceutical compositions having a psychtropic ° activity'; Feenstra, R.W.; de Moes, J.P.; Hofma, J.; Kling, H.; Kuipers, W; Long, S.K.;

Tulp, M.T.M.; Van der Heyden, J.A.M and Kruse, C.G.; ‘New I-aryl-4- (biarylmethylene) piperazines as potential atypical antipsychotics sharing dopamine D; receptor and serotonin SHT in receptor affinities. Bioorg. & Med. Chem. Lett., 2001, 11, 2345-2349 and WO 01/14330 Ye Commercially available. Y alkylphenone derivatives: 21 chart 13 mg A <0

LL) CX) ~~ AJ -~ F, no 0 | 0

Llc is a solution

LA, hee) () 672 ne i I

I 3 0 Sil D A 3 . 1 Bi a l 8 oF NF arene © 1 "WH,

Factors and conditions: (5) (DIPEAKLCHLON, reflux A, 0, 0 p 010 (HNO-CH CH NH, 2HCI, reflux. Alien) Selection of specific synthesis procedures on agents known to those skilled in the art Jie The compatibility of functional groups with the agents used; the possibility of using protective groups; catalysts; 0, activating agents and coupling agents; and the extreme structural features present in the final compound being prepared. Pharmacologically acceptable salts can be obtained using standard procedures known in the art; For example, by mixing the compound of the present invention with a suitable acid such as an inorganic acid, hydrochloric acid, inorganic acid, or with organic acid. al Auxiliary materials Jie liquid or solid carrier material . The pharmaceutical formulations of the invention can be administered enterally, orally, or through the digestive system (intramuscularly, intramuscularly). or in (intravenously + ll » or in 0 rectally or locally (topically . It can be given in the form of solutions ¢ or Jf 0 powders tablets or capsules Jad microcapsules ointments (creams or gel) or suppositories suitable excipients ll formulations are Al wd Al liquid or solid fillers pharmaceutically standard and extenders; and solvents; Yyée

Ne, flavorings, flavorings, lubricants, lubricants, emulsifiers, and emulsifiers Frequently used pH adjuvants or pH regulators / 5 colorings mannitol, ne, lactose, and titanium dioxide and hydrogen carbonate; starch, starch ¢ gelatin, “lactoprotein ¢ talc and other types of sugars” and their derivatives; vegetable and animal oils such as fish liver oil; or sunflower oil” or cellulose©; solvents such as sterile water; polyethylene glycol; peanut oil; or sesame oil; and .glycerol fis mono- or polyhydric alcohols. The compounds of the present invention are generally given as pharmaceutical compositions and are important and new embodiments of the invention because of the presence of the compounds and more specifically because of the presence of certain compounds disclosed herein. The types of pharmaceutical formulations that can be used include, for example; chewable tablets; and chewable tablets, such as, but not limited to, tablets and solutions that are given through the digestive system “solutions”; Solutions, capsules and other types, then “suspensions and suspensions” suppositories and suppositories ¢ parenteral solutions disclosed in this application or seem clear to a person skilled in this field from the specification and from general information in this field. In the embodiments of the present invention a pharmaceutical package or set is provided that includes one or more containers filled with one or more components of the pharmaceutical composition Instructions for use; or Jie for the invention. These containers may be accompanied by various written materials; a notice issued by a government agency regulating their manufacture or use; or selling pharmaceutical products; This notification reflects; Agency certification of manufacturing; or use; Or selling animals for the purpose of giving to humans or veterinary giving

-11- Pharmacological methods: Laboratory. Dopamine-D; Determining the affinity for receptors using the aforementioned dopamine-Dy receptor binding experiment, and then determining the affinity of compounds for receptors: by I. Creese, R. Schneider and 5.11. Snyder: “I'H]-Spiroperidol labels dopamine receptors ° in rat pituitary and brain”, Eur.J Pharmacol., 46, 377 - 381, 1977. Laboratory: serotonin uptake (Bale) determines propensity to sites Using the serotonin binding experiment, the propensity of the compounds to the reuptake sites mentioned by: the receptor was determined.

E. Habert et al. “Characterisation of ['H]-paroxetine binding to rat cortical Ye membranes”, Eur.J Pharmacol., 118, 107 — 114, 1985 Dosages and Sites of Reabsorption of dopamine-D ,; The affinity of the compounds of the invention to receptors was determined from the binding affinity of Aad as mentioned before. One can estimate the lowest theoretical serotonin dose

Kid of at a concentration of the compound equal to double . (1) The volume for a given compound of formula 1

SA from the receptors by the compound. by converting 7 001 measured; It is possible that from milligrams of the compound per kg of patient weight the lowest theoretical effective dose is obtained; Assuming optimal bioavailability. May alter pharmacokinetics and pharmacodynamics;

SY

mg / kg; In this application for treatment of an organism, the term “treatment” refers to the prevention of a disease or condition from occurring in a person (1) or a human disease and includes: Als and preferably © the inhibition of the disease or condition i.e. (1) exposed to the disease but has not yet been diagnosed as infected; stopping its progression; (*) curing the disease or condition, i.e. causing a regression of the condition; (;) curing the conditions caused by the disease, i.e. stopping the symptoms of the disease.‎ In more detail In the following examples. (1) Preparation of compounds of formula EXAMPLES 0 Materials and Methods will now be described: (1) Example Bruker Avance DRX600 on °C and 'H' NMR spectra were recorded

Varian lea or at 0 MHz (£44) Varian UN400 MHz) » or on Tew) tetramethylsilane as solvents with CDCI3 or DMSO-D6) using 0 (VXR200 As an internal standard, the chemical displacements were given in ppm (on a scale of 8) below the 0 Hz range. (J) The expression for the coupling constants a.tetramethylsilane away from (Merck mm) was performed. ... 17 - ...40( 10 silica gel flash chromatograph using 0 record (Merck cae 2718-7 ¥) 01 silica gel column chromatograph using

SAY. Mass spectra were recorded on a WBiichi 3-545 melting points on a MassLynx melting point instrument for data acquisition with Micromass QTOF-2 application software using a quasimolecular jon device and reconstructed it. Exact mass measurement of the submolecular ion was performed

J[M+H]": Synthesis of certain compounds: (1) Example 0: Synthesis of the compound * In a two-step reaction starting from the compound, a suspension of 10 mmol was made.4-)2, 3 dihydro-1,4 benzodioxin-5-yl)-1-piperazine (3i) diisopropylethyl-amine was added ?111 mEq of acetonitril in (31) equiv (10 mM) piperazine 1 after Stir for ½ minutes at room temperature; 1 eq. (DIPEA) sodium iodide was added and then » 5-chloro-1-(4-trifluoromethyl-phenyl)-pentane-1-one mol) V+ The solvent was removed by evaporation and elu 71 was dissolved and this mixture was stirred at 88 °C for the remaining 0.001 mL dichloromethane before evaporation. The residue was purified by column chromatography and gave 1.4 mmol of the derivative equiv. At 11 this mixture was heated for O-(2-aminoethyl)-hydroxylamine di-HCI and washed with water gave dichloromethane after evaporation of the solvent the residue was dissolved in and evaporation of the solvent purified residue magnesium sulphate Drying of the organic layer using

Yes

Yeo

GIS” by column chromatograph. Salt 110 of the compound was obtained after adding to the purified material. Ethanol in HCL of .7 16 M Total product Ye = 60 Melting point: : Synthesis of compound 7 in a two-step reaction with Starting from the compound A suspension of 4.7 mmol of 1 (71) 2-isopropyloxy-phenylpiperazine was made. ¥ eq. of 1058 and 50 mL acetonitril were added in (7i) phenylpiperazine: eq. a iodide equivalent 1F » 4-chloro-1-(4-trifluoromethyl-phenyl)-butane-1-one This mixture was heated at reflux condensation temperature overnight and the solvent was evaporated the next day The residue was purified by column chromatography to give 7.8 mol of compound 0. Ethanol (#001) ml Ve was added, which was again dissolved in (Tid) A keto eq. pyridine was heated. 1, O-(2-aminoethyl) hydroxylamine di-HCl in equivalent of 1 salt of this mixture was heated at 80 °C for 2 hours. After evaporation of the solvent the residue was purified by column chromatography and gave 1 mmol of orange oil. Dissolving the oily substance in amorphous fumaric salt was obtained. fumaric acid eq. 1 Add Cady Ethanol 0.7 560 after evaporation Total product VS yall

Yves

sulphate and evaporation of the solvent gave a residue that was purified by column chromatography. The fumaric salt of compound 4 was obtained after adding an ethanol solution of 1 mole of fumaric acid to the purifier and then evaporating the solvent; Total product WARY. Synthesis of compound 01 in a two-step reaction with initiation from compound: dihydro-1,4 benzodioxin-5-yl)-1-piperazine (31). A suspension of + mmol phenylpiperazine (30) was made in 560 mL acetonitril. ¥ eq. <DIPEA and 1 eq. of 7-chloro-1-(4-) were added. trifluoromethyl-phenyl)-heptane-1-one" and 1 equivalent potassium iodide This mixture was heated at reflux condensation overnight and the solvent was evaporated the next day. The residue was purified by 0 column chromatography to give 7.; mol of pure keto compound (101) which was again dissolved in Yo ml V+ + (Ethanol 7). 1 eq. of salt was added: O-(2-aminoethyl) hydroxylamine di-HCI. This mixture was heated at Av C for ; hours. After evaporation of the solvent, the residue was purified by column chromatography and gave “mmol of yellowish oil. The oily substance was dissolved in ethanol and 1 mEq of fumaric acid was added. Yo, the unearthly fumaric salt of the compound was obtained 0 after evaporation is the total yield of Joyo Yves

“No. : Synthesis of the + compound in a two-step reaction with starting from the compound A suspension of 0.¥ mmol .4-(2,3 dihydro-1,4 benzodioxin-5-yl)-1-piperazine (31) was made 1, (DIPEA) was added (DIPEA ? equiv. acetonitril) in 560 mL (31) phenylpiperazine of potassium equiv 1, + 6-chloro-1-(4-trifluoromethyl-phenyl)-hexane- 1-one equivalent of overnight ela Yl 10010 was evaporated. This mixture was heated at condensation temperature ©

VY solvent the next day. The remaining material was purified by column chromatography to give

01 ml pure ethanol ((:8); which was again dissolved in keto mol of compound 1 and O-(2-aminoethyl) hydroxylamine di HCl equivalent of 1 salt (0) was added % Yar) This mixture was heated at 868 °C for hours. After evaporation of the solvent, . pyridine eq. mmol of yellow oil was purified. The remaining 0.6 was dissolved by column chromatography and gave 0. Obtaining a fumaric acid salt, and ¥ equivalent of Ethanol was added to the oily substance in 7.48 after evaporation. mmol of compound * 0 was dissolved. 4-(2,3 dihydro-1,4 benzodioxin-5-yl)-1-piperazine 06 : equivalent of 1 was dissolved into this solution. 01 ml in (3ii) C for As and this mixture was heated at O-(N-methyl-2-aminoethyl)-hydroxylamine 01-110 and washed with dichloromethane solution for hours.After evaporation of the solvent it was dissolved The residue in © magnesium the organic layer was dried with 0 followed by sodium bicarbonate brine

Yves

“YY:1) Compounds with the general formula 1: table fs N a N _Q

Ry? 1, | For “Nx (1) ( mN-A where © is one of the fragments with molecular structure 0 ye Ye 0 0 0 0

A H B 0 D / 0

N 8 > mi GOL GO 0 0” Yo 0 3 F G H cl 0

JJ

! J 1©,

N_ 0 Ne Baki B

L M N

“on on Tel © and |« || Fourth, ere ov (AV JER [HE THT] |

TT TAD [Fm aK

Co [TEETH a cp] D HE ACR [HTH Daa ves-ner

CTE oe

Ocho)

Ca [1 TA 46© #8 | es 4 = M H ᴀᴀᴀᴀᴀᴀᴀ geese : b 4 b H H a oe count Co TA em ETE we ee owe ND [sen AR] ee]

YY¢

- 1 -

The particular compounds whose synthesis is mentioned before are intended to describe the invention in greater detail

Therefore, it is not considered a restriction on the scope of the invention in any way. Other models of the invention will appear

clear to those skilled in this field when taking the specification and practicing the invention mentioned in this

request in mind. Therefore, the specification and examples are only examples, while a scope has been clarified

© and the spirit of invention in the elements of protection.

Example (1) Formulation of the Baad ¥ oS pall Animal studies:

For oral administration (P.O) some glass beads have been added to the quantity required

(-20 mg) of the solid compound in a glass tube; The solid material was pulverized by

Spin for two minutes. After adding 1 ml of a solution of methylcellulose 7 1 in water and ? 7 (00 volume) of Poloxamer 188 (Lutrol F68) a suspension was made from the compound by vortexing for 10 minutes

minutes . Then adjust the pH at 1 by a few drops of the 2+L solution of

1. Another suspension was made from the remaining particles in the suspension using an ultrasonic wave bath

acoustic:

For intraperitoneal (M.1) administration: some glass beads were added to the required amount VO — v0 (5 mg) of compound ¥ solid in a glass tube and the solid was pulverized by

Spin for a minute. and after adding 1 mL of mannitol 7 © 5 methylcellulose 7 1 in

cele A suspension of the compound was made by vortexing for 10 minutes. Finally the number is set

pH at 7.

Example (4): Pharmacokinetic test results: then insert the data of propensity to the dopamine-D receptor; and La, serotonin re-uptake for the previously mentioned protocols in the following table. Table (1): Laboratory values for the inclination of the compounds of the invention. seus smn, | sim tc Tea YYee

Claims (1)

SY. Claims: 1) Compounds of the general formula 1-1 fs ve m n n mia 1) (Ry), L or O or do Jet Jor JY separately are 1 or Sn ym where -1 «A ¢ FFX or 1 yellow or aX - 8 ¢ phenyl of branched or unbranched alkyl (Cre) or » halogen is Ry - 1 branched or Unbranched. or alkoxy (Cie) or “benzyl L or Z” cyano gl ¢ trifluoromethyl A or “phenyl that” ¢ alkyl (Ci) that “hydrogen represents sas and 8 and is All on - 4 . acetyl 5 ¢ benzyl Ye NCA The group © is selected from the moieties with the molecular structure - “1 a a M A 0 0 0 0 A H 8 0 D N N N © CO Co CA CD 0 0 0 0 Vv E F 8 H o Cl 0 1 $ and b’ b H J K 1 Ry, N 0 N 0 x x ‘e 0” 0 L M N where: 11 7 or a J ay - no ¢ phenyl J ic jie branched or non-alkyl or (Br©) “halogen is 182 ~ YA Jace, ¢ Ji ce alkoxy (Cig) or” benzyl or 5′ and stereoisomers ¢ tautomers and conjugates ¢ cyano or “ trifluoromethyl Yo In addition to pharmaceutically acceptable salts gia N-oxides s stereoisomers on the aforementioned compounds with formula (1) and their YY hydrates. oY ;” where 10 is 5) 12 is (1) compounds of the claim — Y 1 each separately sR; and ¢ 4-fluoro or 4-trifluoromethyl is (¢ and X 50 ¥ « DJA from Q structural fragments and unbranched methyl or hydrogen Jus group is selected; Jd cia alkoxy (Cis) is Ri 5¢) neither nor is JF J ¢ « N-oxides s ¢ stereoisomers and stereoisomers ¢ tautomers and compounds © (1) of the mentioned compounds having the formula hydrates in addition to pharmaceutically acceptable salts N Yye - YY. its. N-oxides stereoisomers and their conjugates tautomers and their conjugates |" compound according to claim (1); chosen from the group: * 1 a we wl w Lr ol alleen nas 0] : ol be bela sa Col eee] us a] ol Lalla 0] ol Labi lem was 0] on 1 in the form Alaa where the symbols are 'Y R 3 N Q rR a and l' | l For NS (1) (Ry), Yves 71 - 1 and the fragments have the molecular structure they are e or © or a NJ H (R,) no / 8 0 1 1 msr J 0 ; 0 1 ; A 0 F N VY tautomers ¢ and stereoisomers of which N-oxides_s stereoisomers are VA in addition to acceptable salts hydrates s Ws of the mentioned compounds of formula (1) 4 and tautomers ¢ and stereoisomers stereoisomers + and N-oxides WY.1;- a pharmaceutical composition comprising in addition to a pharmaceutically acceptable carrier and/or a “- at least one pharmaceutically acceptable adjuvant” a pharmaceutically active amount of at least ¥ of one compound in accordance with claims (1 - “) Or cia salt as an active ingredient .active ingredient ¢ )0 A method for preparing a composition in accordance with claim (8) characterized by the preparation of at least one compound Y in accordance with claims 1 (- “) or a salt thereof in a suitable form 7 for administration p. 1 +- A compound according to any of Claims (1 - ); or a salt thereof for use as a medicine .medicament ~~ Y 1 b Using a compound according to any of the claims) - 0 » to prepare a pharmaceutical composition for the treatment of disorders of the central nervous system ‎015. A - disorders, where it is distinguished that the disorders (oV) use according to the element of protection A) “anxiety disorders” and the aforementioned aggression disorders are “aggression” ov, automatic selfishness ¢, vertigo ¢ and depression depression Disturbances of cognition or memory Parkinson's disease, especially schizophrenia Other psychotic disorders 7) For claim a use 4-1 ,. depression The mentioned is depression Y disorders, where it is distinguished that the disorders 0 (V) use according to the protection element 0 - 1 ¥ mentioned are schizophrenia, psychotic disorders, and others.