SA05260387B1 - Phemylpiperazine derivatives with a combination of paritial dopamine d2 receptor agonism and serotonin reuptake inhibition - Google Patents

Abstract

Abstract: The invention relates to a group of novel phenylpiperazine derivatives that have a dual mode of action: as serotonin reuptake inhibition and as a partial agonist of dopamine-D2 receptors. The invention also relates to the use of the compound disclosed in this application to manufacture a drug that has a beneficial effect. The compounds have the general formula (1): and where the symbols bear the same meanings given in the specification, compounds of tautomers, stereoisomers and N-oxides thereof, in addition to salts, hydrates and solutes Pharmacologically acceptable of the mentioned compounds of formula (1) and their tautomers, their stereoisomers and their N-oxides.

Description

Phenylpiperazine derivatives with a combination of partial dopamine-D; receptor agonism and serotonin reuptake inhibition Full Description Background to the invention

The present invention relates to a group of novel phenylpiperazine derivatives with a dual action mode of inhibiting (sale) serotonin reuptake inhibition and acting as a partial cofactor for 02N0M40-08 receptors. The invention also relates to the use of a compound that is GSS

© About him here in the manufacture of a drug with a beneficial effect. The beneficial effect will be revealed here or it will be obvious to a person skilled in this field after reading the full description and from the general information in

this field. The invention also relates to the use of a compound of the invention in formulating a drug for the treatment or prevention of a disease or condition. And more specifically; The present invention relates to a new use for the treatment of a disease or condition which will either be disclosed herein or would be obvious to an individual experienced in the art

0 After reading the full description and general information in this field 0 and in the models of the invention; the

The specific compounds disclosed herein are used in the manufacture of a drug useful in the treatment of disorders

Involved by dopamine-D receptors; and sale sites of serotonin reuptake

prohibition; Or disorders can be ade by addressing these goals. dual-action compounds such as 0008106-02 antagonists and sale inhibitors of serotonin reuptake inhibition; Known International Order Numbers:

— Y — 00 / JPY EEN and AA / 00 and A / Loe This combination of activities is useful in the treatment of schizophrenia and other psychological disorders and makes it possible to reach a more complete treatment for each symptom the disease. Benzoxazolone derivatives bearing a terminal phenyl group 1 have been disclosed in EP 4009797-1a. However, these compounds; It has a dual effect as it acts as a dopamine-D antagonist, and as a cofactor for the 5-1118¢ receptor, but it does not inhibit serotonin reuptake inhibition. General Description of the Invention The present invention aims to provide other compounds that have a dual effect as partial antagonists of . serotonin reuptake inhibition and dopamine-D; | 1:0) The invention relates to a group of new compounds having the formula

X

R

~~ (Rg),

N N—T 7 1)

Rs or 0; 8=X where: or “alkyl (or -m-©)” OH or “CH,CFs” or “CFs 4” alkyl b is 1l olem©- ©) ¢ cyano or « halogen or ¢ alkyl (C1-C) a » H sR; \o

Yves

— ¢ _ O is 11 Ar alkyl (C)-Ce) ¢ 15 M is JH an alkyl group (C1-Co) optionally substituted by a halogen atom . T is a saturated or unsaturated carbon chain with Y - 1 atoms; Where one carbon atom can be replaced by a nitrogen atom; or optionally substituted by alkyl group (C13) « or «CF; or «CH,CF3 or oxygen atom i.e. sulfur atom and optionally substituted in the chain by one or more substituents chosen from dc gana consisting of (pebr) cyano s “halogen s” alkoxy (Ci) s ¢ alkyl “and trifluoromethyl see “OCF; SCF3 and nitro 3” OCHF; ¢ with is a substitution group chosen from the group consisting of alkoxy (0 1-C3) 3 alkyl (Ci-Cs) 0 and SCF; 5 OCF; trifluoromethyl s cyano s halogen and nitro s OCHF, “d has a value from zero to ©; And tautomers ¢, stereoisomers and 11-0:065_terminators, in addition to salts of 5 hydrates and drug-acceptable solutes of compounds of formula (1) and its stereoisomers 35 and its N-oxides s stereoisomers. Provided that when 0 = X ; R?1 is hydrogen or methyl « and Dk[ is hydrogen 'eo, 1 = n, and Rs is not 4-fluoro . In describing the substituents, the abbreviation alkyl (Cr) means ethyl § « methyl Sle sane » or n-propyl © or isopropyl . Yvea

The prodrugs of the aforementioned compounds fall within the scope of the present invention. Prodrugs are therapeutic agents that are inactive in themselves but convert into one or more active ovulatory products. Prodrugs are reversible biological derivatives of drug molecules used to overcome some of the obstacles to use of the parent drug molecule. These include obstacles. but not limited to 0; to dissolve; permeability; constancy; pre-systemic metabolism; Targeted deficiencies: Medicinal Chemistry: Principles and Practice, 1994, Ed.:F.

D.

King, p. 215; J.

Stella, “Prodrugs as therapeutics”, Expert Opin.

Ther.

Patents, 14(3), 277-280, 2004; P. Ettmayer et al., “Lessons learned from marketed and investigative prodrugs”, J.

Med.Chem., 47, 2393-2404, 2004). which are converted by metabolism to compounds of formula (1); within the scope of the invention. This is especially true for compounds having primary or secondary amino or hydroxy groups (Sas secondary) Reaction of such compounds with organic acids to obtain compounds of formula (1) in which there is an additional group that is easy to get rid of After administration; Jn vo the following groups without limitation: amidine » or enamine » or Mannich base or hydroxyl-methylene ¢ derivative or O-(acyloxy-methylene carbamate) derivative ) “¢ or ester ¢ or amide 6 or 0 enaminone The N-oxides of the foregoing compounds la SS are within the scope of the present invention. Tertiary amines may or may not be metabolized; to N-oxides; the extent to which the conversion rate to Nioxides varies from trace amounts to almost complete quantitative conversion.

The N-oxides may be more or less active than their corresponding tertiary amines. Although N-oxides are easily reducible; by chemical methods; To the corresponding tertiary amines, this occurs in the human body in varying degrees. Some N-oxides undergo an almost quantum reductive transformation; Where it is transformed into the corresponding tertiary amines 0 H. In other cases, the transformation is only a minor reaction or may not occur at all: (M.H.

Bickel: “The pharmacology and Biochemistry of N-oxides”, Pharmaco-logical Reviews, 21(4), 325 - 355, 1969 D; and the serotonin reuptake inhibition site. The compounds have been shown to be effective at the dopamine-D receptors, which have varying degrees of help. The compounds are also active as serotonin reuptake inhibitors where they potentiate behavior induced by 5-1119 in rats: (B.L.

Jacobs., 'An animal behavior model for studying central serotonergic synapses', Life Sci., 1976, 19(6), 777-785)0 In contrast to the use of complete dopamine-Dy receptor agonists. The use of partial help of the dopamine-D receptor provides dynamic therapy that self-adjusts moment by moment to the subconscious state of the patient. Thus, it provides the required flexible modulation of the dopamine lead and avoids many of the adverse effects caused by treatment with complete dopamine-DY receptor agonists Je bromocriptine (hallucinations ¢ and nausea; vomiting ¢ and dysphoria). Yo movement; hypotension, laziness, sleepiness (somnolescence) or Yves antagonists

ov - _ complete dopamine-Dy receptors haloperidol Jie (cemotional blunting, anxiety, dysphoria, tardive dyskinesia) and because of these many antagonistic effects; complete antagonists and auxiliaries have found very limited use In the treatment of anxiety disorders, depression and anxiety, not only does the partial aid of dopamine-D;0 appear to exhibit a flexible modulation and a favorable side-effect property, it also has a pronounced anxiolytic property in relevant animal models (128-132:26). 2, 2001. Drugs of the Future (Drugs of the Future) Dopamine-D partial adjuvants, according to the present invention, are compounds that, when tested in a concentration response range, achieved efficacy in an experiment based on cell CAMP function (as stated). (after).Partial adjuvants to (000810106-1) will act as an adjuvant in 0 cases in which the endogenous synaptic tone of dopamine is low or in the presence of a complete antagonist of the -00080106 receptor; it will act as an antagonist in cases Le dopamine intrinsic synaptic tension is high or in the presence of a complete cofactor for the dopamine-D receptor, . Like complete agonists, partial agonists of the dopamine-D receptor are generally effective in systems that have been rendered desensitized, as they induce a corresponding shift in rats with 0 hits on the 6-hydroxy-dopamine (6-OHDA) side of the substance. black for the embedded part. In known young American monkeys treated with MPTP, long-acting dpe movements produce symptoms of the locomotor system (2001, 26:128-132) (2001, Drugs of the Future), however, unlike full aids, partial aids to dopamine-D is less effective mainly in systems that have not been rendered sensitized: it hardly reverses the hypokinesia caused by reserpine |0 in rats.

M - For the treatment of disorders of the central nervous system (ONS disorders) in which the xy Lib dopaminergic activity is involved, it is recommended to use a pharmaceutical preparation that includes. Has partial cofactor activity at the dopamine-D receptor; has implicit functional activity with serotonin reuptake inhibition in Alla disorder involving AUS dopamine© has a pharmaceutical product with partial cofactor activity dopamine-D; has high intrinsic functional potency with serotonin reuptake inhibition according to the patent. Disorders characterized by dynamic fluctuations in dopamine neurotransmission such as AL depression, polarity 0 | (M1016891 bipolar and addiction ddiction of the flexible tuning of the dopamine system by partial adjuvants of the dopamine-D receptor, present in the pharmaceutical preparation. The combination of efficacy of stabilizing dopaminergic neurotransmission with efficacy of inhibition of serotonin reuptake will enhance serotonin reuptake inhibition Antidepressant and anxiolytic efficacy The compounds can be used to treat disorders or diseases of the central nervous system caused by 1 disorders of the dopaminergic or serotonergic systems such as aggression, anxiety disorders automatic selfishness, vertigo, depression, disturbances of cognition or memory, Parkinson's disease, especially schizophrenia PBA dll, and psychological disorders. the other

(f) pharmaceutically acceptable salts may be obtained using standard procedures well known in the art; For example; By mixing a compound of the present invention with a suitable acid such as an inorganic acid such as hydrochloric acid with an organic acid. Pharmaceutical preparations:

0 The compounds of the invention can be converted into forms suitable for administration by the usual processes using Jie auxiliary materials, liquid or solid carrier material. The pharmaceutical compositions of the invention can be administered enterally, orally, or parenterally (intramuscularly or intravenously); Or rectally, or locally for pain 1. And it can be given

00 in the form of solutions, powders, tablets + or Wy capsules, including microcapsules, or ointments (creams or gels). (gel or suppositories. The appropriate excipients for these formulations are the liquid or solid materials familiar from pharmacology: Jia fillers; ida ly solvents solvents 5 “ extenders; and emulsifiers 1 lubricants and flavorings; colorings and/or pH regulators. Among the commonly used auxiliary materials (Say) is magnesium carbonate.

lactose 5 « titanium dioxide 3 » and mannitol and other sugars; tales; milk protein; - and gelatin; starch, cellulose and its derivatives; and vegetable and animal oils Fie cod liver oil; sunflower oil (0) and peanut oil (Cu) 5 polyethylene glycol

Yves

And 1 - Jia solvents, sterile water and mono- or polyhydric alcohols such as glycerol. In general, compounds 1 of the present invention are given in the form of pharmaceutical formulations that zal is considered important and new to the invention due to the presence of the compounds; No specific compounds detected here. oo The types of pharmaceutical formulations that may be used include, but are not limited to: 0 tablets and chewable tablets; capsules; solutions, solutions for injection, and suppositories; pendants; and other types disclosed herein or will be apparent to an individual skilled in the field from the full description or from general information in the field. in invention models; A pharmaceutical set or set is provided comprising one or more containers filled with one or more of the components of the pharmaceutical composition of the invention. can; With this container(s) attach written materials such as 'Instructions for Use' or note in an authorized form from a government agency regulating the manufacture, use, or sale of pharmaceutical products; This note reflects the approval of this authority for the manufacture, use or sale for administration to humans or animals. Pharmaceutical methods: vo measure affinity towards dopamine-D receptors; in vitro: then determine the affinity of compounds towards dopamine-D receptors, using the receptor binding assay described by Creese, R.

Schneider and 5.11. Snyder: 1. With the title: “[*H]-Spiroperidol labels dopamine receptors in rat pituitary and brain” in Eur.J.Pharmacol., 46, 377 - 381, 1977, Yves.

Measuring affinity toward sites of 'lee serotonin reuptake inhibition' The affinity of the compounds toward the :106-0'M00 receptors was determined using the receptor binding test described by E.

Habert er al., “Characterisation of [*H]-paroxetine binding to rat cortical membranes” in Eur.J.Pharmacol., 118,107 — 114, 1985 | Induced by forskolin: The functional activity of Dy-dopamine receptors including the implicit (©) activity of the compounds of the invention was measured in vitro by measuring their ability to inhibit the accumulation of [PH]-cAMP that forskolin induces. 11 Then, the human dopamine receptor, Day, was cloned in the add 0110-1 blastoma cell line. Then, obtaining lle from Dr.

Grandy, Vollum Institute, Portland, Oregon, USA. CHOWA was then grown in culture medium containing Dulbecco's modified Eagle's medium (DMEM) supplemented with +7) heat deactivated fetal calf serum; And ? mM glutamine; and 1 mM gopyruvate .5.0.9 ve units/mL penicillin ¢ and © ov µg/mL streptomycin ¢ and 01 µg/mL at a Yv in 9 air and 00277 . For incubation with the tested compounds, pooled cultures were used in 74-well plates. Every Alla or substance is routinely tested; times. Cells were loaded with [PH-adenine:© in 15 mL of medium/well. After two hours, the cultures were washed with 8.5 ml 53 containing 1 mmol of phosphor-diesterase inhibitor Yyes.

11 - - labeled sobutylmethylxanthine (IBMX) and incubated for 0 min with 5 ml PBS containing 1 mM IMBX and forskolin with or without the tested compound. After aspiration the reaction was stopped with 1 ml trichloroacetic acid © (w/v). The presence of -[311] ATP and 24”-[11]_ formed in the cell extract was tested as mentioned by: Solomon Y, Landos C, Rodbell M, 1974, A highly selective adenylyl cyclase assay, ° ‎Anal Biochem 58 :541-548 and Weiss S, Sebben M, Bockaert JJ, 1985, Corticotropin- peptide regulation of intracellular cyclic AMP production in cortical neurons in primary culture, J Neurochem 45:869-874. 8 mL of extract over Dowex 30 acl (50WX-4) dried £20 s (aluminumoxide 0 mesh), eluted with water and + M, imidazole (pH = 2.5 The eluent was mixed with 1 mL Inst-gel and the radioactivity was counted by a liquid scintillation counter.The shift of 877-[211] and PHJ]-CAMP was expressed as a percentage of the radioactivity in the picking cAMP compared to the combined radioactivity in the cAMP and ATP extracts; the baseline activity was subtracted to correct for the activity A vo The tested compounds were obtained as crude 01 mM solutions in DMSO (0) and diluted to final concentrations in 7. Compounds are typically used at concentrations ranging from 10 “' mol to neg molar. From count data; times per sample averaged as an estimate of the effects induced by the drug and involved in the receptor at the accumulation of a given second messenger; expressed as a percentage of Comparison values (accumulation of forskolin-induced CAMP minus 0 baseline activity) by using INPLOT or Excel-Yvyéa non-linear curve drawing software.

As add-in 2018; Then the average values were plotted against the concentration of the drug and a segmental curve (logistic curve with ; variables) was generated. The maximum excitatory conversion induced by forskolin was taken as a maximum value and the maximum inhibition (usually at drug concentrations of 701 M or 11 M) as a minimum and these values were fixed during the plotting process. Thus, the compound concentrations causing 7500 max inhibition obtained from the accumulation of (ECso) forskolin-induced cAMP were averaged across several experiments and expressed as mean pECsp + SEM. Adjuvant efficacy was evaluated by co-incubation of cells with a fixed concentration of adjuvant and defined concentrations of adjuvant. The procedures for plotting the curves are identical to those used to determine the ECsp values. Thus the values of the ICs can be obtained; That is, the concentration that occurs 7500 of the maximum Lin anti-0 can be obtained by this compound. The values of f and 10 are corrected using the Cheng-Prussoff equation and corrected for the ECso ps concentration obtained in the same experiment. Thus, (ECsp / [Co] + Kp = 1 / 1 ) . The corresponding RM value is -Lo (MCA). Plotting the concentration-response curves allows estimating values of 1700 m and the maximum effect that can be obtained (implicit activity or activity (p). The complete receptor cofactor has p = 1 and the complete receptor anticoupler has p = 0 or the receptor partial cofactor has an intermediate value of the implicit activity. System Dosing: The affinity of the compounds of the invention towards dopamine-D receptors and sites of serotonin reuptake inhibition has been determined as previously explained. Estimates the lowest effective theoretical dose when it equals concentration

_— $ \ _ complex twice the measured Ki value; It is likely that 7001 receptors were occupied by the compound. By converting this concentration to mg of the compound per kg of patient weight; We obtain the lowest theoretical effective dose; Assuming optimal bioavailability. As for pharmaceutical compounds and other considerations, they can change the dose actually given, by increasing or decreasing it. The appropriate dose for administration is 601 to fama 0001 kg; Preferably 1.1 to 100 mg/kg of patient weight. Cure: The term "cure" as used herein means any treatment of any condition or disease of mammals; od is preferred and includes the following: (1) preventing the disease or condition from occurring in a person who may have been exposed to the disease but not yet diagnosed; (Y) inhibiting the disease or condition; i.e. preventing 0 from developing (©) Alleviation of a disease or condition; i.e. causing its regression (£) Alleviation of the condition resulting from the disease i.e. stopping the symptoms of the disease. The preparation of compounds of formula (1) will now be described in more detail in the following examples: Examples: 1 Substitution of the 1] atom or the N-H moiety of the phenylpiperazine moiety for compounds of formula ([); amines 1-11 to 7-11 can be substituted by Q by the general chemical method A which practically results in the compounds of the invention listed in Table (1) Subsequent. 4;?1?

oo — \ — Method A: The compounds were prepared by the synthesis described in Scheme A. An amine has been reacted with a Q-X)=X leaving group such as “Cl” or “Br 1) in eg acetonitrile or butyronitrile with 121-201 acting as a base; In some cases KI or Nal is added. 150011 can be used instead of © in 2f-210. R1 R1 / / N pe R2 0 R2 0 Na Q-X XL 0 Ra Tsip N X = leaving group N LL dl with ki and with “R4 care” seated H Q Scheme A1 Example No. (1) H N 1 Cri Gh : 0 N + Seth : N compound 5 CJ 7 © CLL on Msa H LHHCI Q5-Br 01 Diagram Yi Diagram Yi Step 1: A suspension of piperazine hydrochloride 1-HHCL (0.1 g) was heated; 01 mmol) bromides (1.0 g; YO mmol) and KL (V,Y0) g) and 01 mM DIPEA (Da (+,T) (Use be careful

in © ml acetonitrile on an oil bath at gla Yl in a nitrogen atmosphere for 100 hours. After it has been cooled to room temperature; The suspension was filtered by suction; And it was concentrated in the medium of the g. Then, the purification was carried out using a column chromatography on (dda (Al) sal) silica gel sequentially: 41 with a ratio of 2/75/970) to produce two parts of the compound (JS) (of which Y,4 0 g) where they were recrystallized together from VO ml acetonitrile; To yield EEA g of compound 5 in the form of a solid with a hal ratio of 0. Its melting point: 15.5 a . Table No.: (1) Examples of the compounds of the invention: Salt, the amine method, compound 2, leaving 0, the servants, Pe, A, A, A, Na, EES, then | “ | No | Baa, 1 Pe EET | Qa What is the purpose of EE Pe A 4;?

-oy-

[oe i] = s

. Salt compound amine method

Left Q 5

[mom] grate | Nala" ra a Tee rene | and | for ae [omen] 6 that | 1 | 1 | Aya

I left until SAL L

Lo | | [ea | Ba Ama

oa Lahk Les | for rena]

| | a | ta | Aja 1 | Jes [ene | »| Baya [ee seme | “Aaa what a sun a a la | ha ja [re hr | « A L NA AA RS ‎fees] and | | | A |v | 5 1 Ta Jom [homer ya [ee [ems [ ver | aa a [eas] eer b | |v Lo | 1 [vee] na a l oe |v [oe Lua foes l ta mai [eee] #4 | and | 4h aa m fee 00 and | 1 d | lw

*) See chart 717-111b

The piperazines used in these methods are denoted by the symbols IH to IX-H ci N F N N oy l ml 02 Cr =o TX =o TL =o Cr =o 0 0 0 0 0 Q ' ا' 0 0 Ne Ne Ne L AN C J No no aaa i . / a: / “Cx = o m Ra m Tr m x 0 0 0 0 1 : 0 0 for Ne Ne L BY C Vil Vill IX except for the synthesis of compounds described piperazines 111, 11-11 and V-H in the international application AV/TIARY Synthesis of the amine JH al 1 iC 1 ° a 1 cl liberated Tx ha x = o gel m x 0 0 0 NO, NH, N 0 . N H Scheme No. Y How the starting material was synthesized is described in (German Patent 479614). Scheme 7- HA 3 glad 0 10 g VE (mol) of the starting material is suspended in 100 mL MeOH. Then a small amount of Raney nickel (a spongy nickel used as a catalyst) was added, after which hydrogenation began (at atmospheric pressure and room temperature) 0. After YE an hour, absorption of v,Y Cr ( Quantity Yves

and 1 - theoretical 4.4 liters) of hydrogen . and to the reaction mixture; 101 ml THF and another trace amount of Raney nickel were added. After one hour the reaction mixture was filtered “over hyflo” and the remainder was washed with THF and the filtrate was concentrated in vacuo; To give YO, gm (948/) of the corresponding aniline. chart 7; Step ?: YET was suspended as 10.7 g (mmol) of aniline from the previous step (YOM (g d 4 mmol) of bis (2-chloroethyl)amine in ©Y© ml chlorobenzene . I want to flip; Yo ml was extracted from the solvent by distillation with the help of a Dean-stark apparatus. After removing the Dean-stark device; The reaction was connected to the return for 48; hour. After cooling the reaction mixture, Ve, to room temperature. The mixture was filtered and the remainder was washed twice with EO. Then pipette the addition of 406 mL MeOH ; The mixture was then heated until almost all of the remainder had been dissolved. after that 0010 mL of silica was added; Then the whole mixture was concentrated in vacuo. The remainder was then placed over a flash chromatography column using DMA 175 as eluent filter. After removal of the solvent a residual fraction was isolated and suspended in about 100 mL of acetonitrile Vo and stirred for ; 0 hours after filtration and drying, VY yielded the required 11-17 g of piperazines in free base form. Yves

—- XY. - 11-17: Takhleeq Al-Amin

Br i 7 i Clo Ph oH ~~ 0” Ph >

Br Br A 1

N

H

N._Ph N > replace i CL “Ph iv CL,

NvN

LN LN IV-H

H H

§ Scheme No. 1: Scheme 4; Step 0 00.9 g (AY,Y) mmol) dibromophenol and 01 g potassium carbonate were suspended in +£ mL acetone ; Then 15.7 ml benzylbromide was added. The reaction mixture was returned for YE 1 h. After the mixture reached a temperature (adyl) and then concentrated in vacuo. Then water and :011:01 were added. The organic layer was filtered using a water-repellent filter; The dry filtrate was then concentrated in vacuo and then dissolved again in Yoo 0 ml acetonitrile. and then; 11 ml piperidine was added and the temperature was increased to 0°C for one hour. The reaction mixture was concentrated in vacuo and CHyCly was added. Then, the latter was washed using: 1 moratorium of HCI 9 times) and 71 molars of NaOH and water a second time. The organic layer was filtered using a celal expeller filter and then the filtrate was concentrated in a vacuum buy to give 797.7 g (799) of the corresponding benzylated phenols.

- “1 step?: of the chart used in this experiment three hours before it was used. Toluene has been degassed

BINAP of (Use m£,A0) and 2.07 g Pda(dba)s mmol) of 1 (0.48 g put 6 mL) and then the mixture was stirred and heated to 10 C for +0.0 hours foe in, after which the mixture was allowed to cool to room temperature, after which 0 mmol) of the compound containing benzyl 40 (product A Y) g YY Je was added to the mixture tal) (0.07 mmol) of the 00, (; and 9.7 g toluene ml © 0 dissolved in 1) of step 1 and heated. sodium 16:1.0010<106 mmol) of #01,9.01 (#01) and dimethylpiperazine 1 hour; after which it was left to reach room temperature. Yo the resulting mixture at 1100 °C for a period of vacuum. buy It was concentrated in over hyflo, then CHCl was filtered, and the mixture was dried using 0 as a 1,170 DMA material (Si02) and the remainder was placed on a flash chromatography sequential filter. ARENA: Step 3 of schema This step was performed in a manner similar to the procedure described in the previous step 0: Output: Buchwald in the benzylamine reaction and in this case 4 (0) was used (scheme AA

d“ diagram of step; : 1 mL (4A mmol) of chloride 1 was added; Drip into Ve mL of completely cooled pure ethanol and stir for 11 minutes. and the last solution was added to a solution of 1 g YAY (mmol) of the dibenzyl product obtained from the step; in Yor 0 ml methanol. Then 1.0 g (oy) +) C/Pd was added after which the reaction mixture was hydrogenated for YE 1 hour. The mixture was filtered “over hyflo” and the filtrate was concentrated in vacuo. The remainder containing the 1101 salt of the amino phenol was used in step 0. Scheme ff Step 0 : mM YAY (Use obtained in step 4 2 and ?# mL DIPEA) was added (TAA) 0 mmol); and 70.9 g VY (mmol) CDI ; to 150 ml THE; Then the mixture was returned for 1 hour in a nitrogen atmosphere. After cooling to room temperature; The mixture was concentrated in vacuo; and to :011:01 remaining; 70 NaHCO ; The whole mixture was stirred for one hour. and extracted using (YY)CHCl times); The water fraction was concentrated and extracted again (0 CH,Cly * times). The combined organic fractions were concentrated in 1 vacuo; And the remainder contained a fairly large amount of 100108201 . All were dissolved in 171 ml “acetonitrile” and then the solution was left to reach room temperature. The precipitate that was formed was filtered to give almost pure piperazines 17. 11 4

Y Y _ — Synthesis of amine Synthesis of amine V-H : / / H N N 1 i CL i Co edited CL — H 0 N ii N N b 0 0 N I-H N H V-H .

HCH boc Scheme no. 0 Scheme © Steps 1, 0, and: amine synthesis 7-1 is described in ISBN 97/774847 . Steps 1 and ? And in a similar way to the steps or ? and AY chart 4 . Synthesis of Amine 71-11: cl / / cl 1 Cl N N CL i CL i Cr N ii N N 0 0 N I-H ! § VI-HHCI 00 Scheme No. 1 0 Scheme 1 Step: 1 While stirring; YA g (10 mol) of piperazines 11-11 was suspended in 5,147 mL (mmol blood g) DIPEA and the mixture was cooled to -afr and a solution of 04 aE was added .5 (mmol; 1.57 equiv.) of Boc-anhydride in yo mL O 0 11:0 « by continuous drip

- Y¢- (for 2 hours); Fe - (for 1 hour); Then at Ee a minute. Stirring continued at 0 for an hour). Then VT was added and the reaction mixture was left to reach room temperature (for a duration); after that the mixture was extracted using WA 0:0 11. The MeOH water and some combined organic silica fractions were filtered using a water-repellent filter; the mixture was mixed The dry filtrate was mixed with #0 mL HH and then all was concentrated in vacuo. The remainder was then placed over a chromatographic column as a filtrate. The fraction of Y/4A (with a ratio of MeOH/CH, Clp (Si02)

CHCl Column containing product; The product was washed away from the column material using the required. 11 306 = N of (£1Y) to give 0.00 ¥ (Y/4A) MeOH:7 (Chart 1 step equivalent) of TT ) with 8.8 g Lis 17 Boe - N of (Use ©,; g) suspended (17.7 mL 0 -) and while stirring, the reaction mixture was cooled to 0 mL acetone. in » potassium carbonate ; drop. methyl iodide eq.) of 1.1 mmol; VE) ml 0897 then 0 M was added

VE min; The reaction mixture was allowed to reach room temperature and the stirring was continued for 15 and after CHCl, 1 h. and then; The reaction mixture was concentrated in vacuo; the remainder was mixed with water and the CHCl organic layers were filtered off and the aqueous layer was separated and extracted twice using 1 (184) g £.0 hand mounted with a water-repellent filter; The filtrate was concentrated in the corresponding vacuo. methyl containing IT 306 —N = N from iY scheme 1 step (8.8 mEq); V+ 8) acetyl chloride during flipping at -10”m; © mL was added (Use 17.7 mM) and the last solution was added to £0 g ethanol mL Yo dropwise to -0

— Mg Y — Boo -N - 1 methyl content isolated in YB shi The resulting mixture was stirred for ¥ hours at 0,200 and then the reaction mixture was left to come to room temperature; The stirring continued for 16 hours. and then; The mixture was concentrated in incubator medium and the remainder was stirred in diisopropyl©: and stirred for 2 hours. The precipitate was isolated by filtration to yield 3.7 © g (73Y) of piperazine VI-H.HCI. Synthesis of Amine 711-11: F Br F N ~-Fh i TLS, mia Br i b F Br OH > 0” ph ' I > 5 Br Br Ne boc boc For F N F 0 iv CL vi TL v N vi VII-H.HCI 00 5 H boc Scheme No. 7 and Scheme ov Step 1: 0 Then perform this step in a manner similar to step 1 in the diagram ;. After purification using a chromatograph; Joe's oil contains the benzylated AA product. The oil has hardened after settling. z

Scheme ov Step 7: This step was performed in a manner similar to Step 4 in Scheme 4. Boc-piperazine was used in this Buchwald reaction. After purification by chromatography yield 146 was brown oil.

° Scheme J step ?: This step was performed in a manner similar to the procedure described in the previous step 1 (scheme Ay. v) In this case benzylamine was used in the Bunchwald reaction. The yield was obtained after purification with Chromatograph: (BVT) brown oil photograph. Scheme 7 step:

dibenzylated mmol) of the product containing two VE groups (11.11 g 0; 011 ml ethanol that was isolated in the previous step (Scheme 71) is suspended in a mixture of During the stirring, 8.8 g of acetic acid was added to 11 ml of water and VY was added, and after one day and also after three days had passed, the hydrogenation took place for a period of ay. C/P(OH), and a small additional amount of 0/00(017(2) was added over hyflo. The reaction mixture was filtered.

1 Concentrate the filtrate in vacuo. All was treated with toluene and concentrated in vacuo; This procedure was repeated; to leave a black drink 7.9 g (7848); Contains amino phenol.

B_ 7 Y _ Scheme V © step: This step (closing the loop using CDI) was performed in a similar way to the © step in the scheme;. After obtaining the crude product, it was subjected to a chromatograph (flash column; D510; in which filtering is carried out sequentially using MeOH/DCM with a ratio (Y/Y) to give 1.6 g of foamy material ° impure Ly color. Then it was subjected to a second chromatograph (flash column “S10, 0) in which the sequential filtering was carried out using petroleum ether / EtOAc in a ratio of 1/1 to give 7.7 g (EY) of a pure brown foam “alll” containing benzoxazolinone piperazine protected by 1-306. Scheme Vv step 6 Step VV: This methyl group introduction step was performed in a manner similar to the procedure described in Y step 1 (scheme 7). Output aA: 7 as brown foam J Vv graph step VV 7: This deprotection step was performed in a manner similar to the procedure described in Step ?(Scheme 1). Yield: 794 is a light pink solid of purity 974 containing 711-11.110©1 product.yo synthesis Ameen 111-11: / H H J i Coe A N i N 1 = Mb D Crm = Mi 0 0 NH, Br 5 [ BN Aal Chart No. A Yves

— Y A —_

1:3 ghd A chart

Then the description of the synthesis of the starting material in the patent & European 7.17

4.91 g (7.7” ml (Use) of VO aniline ml HBr / water at a concentration of 7448 was suspended while the

Cool it down to -#um. Then 7.77 g (77 mmol) of sodium nitrite was dissolved; ml© water; Adding this solution to the previous suspension by continuous drip for 1 minute. Stirring continued

Zero degree of the stomach for 15 minutes.

and after eld the reaction mixture was added; lump sum; to a solution with a temperature of zero isha

is 7.47 g (11.9 mmol) CUBr in 00 mL /EA > Sele [HBr] and after

the passage of Ye minutes; Then the reaction mixture was heated to 5 a A for one hour; Then the mixture was left to reach the temperature of ad all and the stirring continued for 14 hours. calg added

clay diethyl ether to the mixture; and after shaking the mixture; The Cua organic layer was isolated and washed

with water. and then concentrate the organic layer; together with some silica ¢ in vacuo; And then put the rest

358) a scintillation column chromatograph (SI0;) using petroleum ether | ERO (at a ratio of 1/1);

It was then applied to pure Et,O as a filtration material. After concentration in Mafra2 medium, 1 yielded the complex product consisting of YY parts g (EY) of the desired corresponding bromo product.

: 1 step (A diagram

This step was done in a similar way to the step ? In diagram 1, the result is 797 bromo

Views containing methyl .

Yves

_ Y q — Scheme A step ?: In the following order: TAY was added 4.07 g (8.9 ? mmol) of methyl bromo compound mol) of 1.3 dimethyl piperazine g (81.9 mmol) of 0:00 and 0.47 g (39.¥ mmol) of X-Phos (see J. Am. Millah Huang H (Chem. Soc.,125(2003)6653 and 00,+g (71© m(se) from Pdy(dba)s to YYo ml toluene Degassing it before using it for a period of hours, il stirring and in an atmosphere of nitrogen the temperature was increased to 01 30d a 001 hours then the mixture was left to reach room temperature the mixture was diluted using W0110 and after that was filtered and concentrated in vacuo.The remainder was placed over a scintillation chromatograph column (Si02) using DMA Le YOY,and the resulting complex product was concentrated in vacuo;VY g (13) From 05 Pure Required 711111. Synthesis of Amine OX-H : { {_

Clo Co (Lo 0 starts 0 must ' CO C) 0 IH N for IX-H.2HCI

H boc q Diagram No

Yves

- VY. - . Ys Y and 1 diagram 9 steps and 7 and ? By method 1 and steps 4 were performed v/v [A]Y in the international application FH synthesis was described.

J in chart Yel and 1 are similar to steps Q26 : Here are the different pictures from 1 0 to 0

Ce Ce 6 CN N oN 1 3 CN N a N 5

NOS RN Mia Mia " Ba 0 8 9 L 6 oN 3 7 r 5 5 0 | F 5 2 Cl 0

Ce Ce 1 0 0

N 11 12 N 15 mg of A AG Ai Ai Ai Sa Ba N Ten 0 R CF, chew s Za ON

UT 0 © Ha A 1 1 C 0 2 N 1 21 CN 5 22 D H 23 F 3 CN 5 25 CN 2 R C 5 6 3 1 sol

So

Yye¢s

In these formulas “0” the point denotes the junctions that connect compounds of formula (1) to the phenylpiperazine moiety. Synthesis 01 to 011; 018 to 019; and 024 to 026: A AO, Aa oh every 8 hr” + BS 0-3 S1=H,82=CN S1=H,82=Cl S1=H,82=F S1=H,82=CF, §1=OCH ,, 522 CN Chart 1 to 50 (18 to 19 and 71 YE) All phenols used as starting materials (except 81 = -7) (CN-5 = 82 “OCH”; see chart 11-1 14-18 77-74; b) as well as alcohols are commercially available. -fluorophenol fill 1/7.47 mmol) and pphs 0 (7.4 g 010 mm (Use and VY,Y0) 4-bromo-1-butanol ml; 177.4 mmol) in YVO ml toluene at zero percentile in a nitrogen atmosphere; a solution of DIAD (ve 7 ml + Yoo mmol) in Te ml toluene was added ¢ Drip (temperature was maintained between 0 and ©”C during the reaction). The reaction mixture was stirred for 10 sad hrs at room temperature. The solution was evaporated under reduced pressure and 300 mL BLO / petroleum ether vo - in a ratio of 1:1 was added to the residue. The precipitate formed during stirring was filtered for +7 min at room temperature; It was washed twice with petroleum ether / Et,O in the ratio (de © 0) ¥ :1 Yves.

The filtrate was evaporated under reduced pressure; The product was subjected to a chromatography using petroleum ether / DCM in a ratio of 1:1. ; as a filter bypass to give 18.79 g (797) of ether Q9-Br as colorless oil. Synthesis of phenols with 51 = OCH; —Y and 52 - #-:CN 0 oH | NC OX OH OMe OMe o Chart CYTE 11-18 1-1 Chart 11-1 14bag;11-76; cu step 1: returned a mixture of 011.6 can YY, 4( 3-hydroxy-4-methoxybenzaldehyde mmol) and YAY) hydroxyl-amine monohydrochloride g; 6:77 mmol) in 166 ml of formic acid 01 for one hour. A Cool the reaction mixture to room temperature and add 1 ice cube. The precipitate was filtered and the rest was washed with ice water. The solid was also dried by co-evaporation with acetonitrile to yield 1.84 g (0 1 lb) of a solid; containing 2-methoxy-5-cyano-phenol. Yves

: 012-17 N=C nT Synthesis

CrQ12-

Q13- 0,2 | 1

N=C NH, re a N=C Nh" +47 name of the least arg. _ \ OH

N=C Or N + ii NEC Nh ! Wa , PPh, , imidazole J 015- 0161 0917-1 Scheme 117-17 Scheme 117-11 Step 1: © For n=2 and 3-cyanoaniline : mixture returned ke 3 for (Y,40) 3-cyanoaniline g; (YO mmol) NaLy (V,0) g 000 mmol); and DIPEA (¥,£ ml; YO mmol) and Yo (Je ¥,Y0) 3-bromo-1-propanol mmol) in 0 mL butyronitrile ¢ for 4 h. The solvent was evaporated under reduced pressure. HO and CHCl, were added to the residue and the organic layer (W50H<) was dried after separation. Cdl g 01 Removal of drying agent by filtration; Solvent removal by Caan evaporation at low pressure. The remainder was subjected to a (SiOz) chromatograph using NH3/CH3;0H/CH,Cl, in a ratio of 2/7 as eluent to give 7.40 g (774854) of product containing Ne alkyl 013-011 in the form of oil. Yes

ace

Chart 7-117 Step 7:

to a pre-stirred solution of the moll-nealkylated product from Step 1 (¥,¥

188 aa mmol) and a 1,777 formaldehyde solution (mL; 1848 mmol)

and NaCNBH; (,7 g; 071.4 mmol) in 1 mL “CH3ON” added 1.8 mL of glacial acetic 80:1© by continuous drop for yo min. The reaction mixture was stirred for two hours at

room temperature. Another 1.0 ml of glacial acetic acid was added drip and continued

Stir for vo min at room temperature. EO was added to the reaction mixture

The ether fraction was washed twice with 1 morat NaOH. The composite organic fractions were dried

(B 21050). The drying agent was removed by filtration and the remainder removed for a chromatograph (0:5) of which 1 NHy/CH;OH/CH,Cly in a ratio of +,0/Y,0/4Y was eluted to give VA g (4, 15

Of alcohol containing 17- methyl 016-011 in the form of thick oil.

Chart 11-17 Step:

pphs (1, g; 11.45 mM +,AY) imidazole 5 (Use g; 11.9 mmol) dissolved; in

0 mL 11.9 aa YY (CHoCloLy mmol) and the resulting suspension was stirred for yo min at vo room temperature. and alcohol solution 016-011 (from step 1) was added (8, g LEY

mL (Use in A ml CHCl; dropwise, then the reaction mixture was stirred for 1 hour at 100 °C

room temperature. 11.0 has been added. The part was dried: 11:01 (,118250) after its separation. And done

Removal of the drying agent by filtration and removal of the residue for a chromatogram (:5:0) of which CHCl, as a

Eliminating to yield 7.18 g (77.4/) of 1-016 100:0 as thick oil.

— A Y — There is another study to obtain: Q14 gl “I Ph M —— rN i \ or Ph fn NEC ONS SE A, pT ii 7 wv | KF 2H,0 TEBACI vi gravel NEC NSS NEC Tr 7 0 oo Y | © 2HCI BIG HC! / THF 0 © vil eral .> compound 33.HCI ° 4 0 viii CL compound 34.HCI 5 \ rT Scheme -11 Aug Scheme 11-71 Aug; Step: 1 © to a preceding solution Stirring of 1 ( 4-bromo-1-butanol g; YALE mmol) 5 imidazole 7 g ALY mmol) in Ve ml DMF; tert-butyldiphenylsilylchloride was added ) 4 ml 4 mmol b) Then the reaction mixture was stirred for 1 hour at room temperature, the DMF was removed by evaporation under low pressure, and then H0 and 0:011 were added, and then dried L 02 fraction (01,250 H01 Cbg. The drying agent was removed by 0 filtration. The drying agent was removed by filtration and the remainder removed for a chromatography (0:5 d) of which a was used.

petroleum ether / CHCl in a ratio of:1; as an eluentre to yield 17.7 g (796,Y) of

silylated alcohol in the form of oil.

Scheme 711-71b step?:

then returning a mixture of 61 9) 3-cyanoaniline g; YAY mmol) and silylated

alcohol 0 (from step can 10) 1) 78.75 mmol) and DIPEA (1.16 fill 38:77 mmol)

mol) and aa (VY, ©) NaL 7.77 mmol) in 509 mL butyronitrile for 14 hours. And done

Evaporation of the solvent under reduced pressure. 11:0 and :611:01 were added to the remainder and the layer was dried

Organic (N2pSO4) after its separation. The drying agent was removed by filtration and the remainder removed

For a chromatograph (D 5:0) of which 011:02 was used as an eluentrefining material to yield 0 (7 g) VY (EVV) of alkylated aniline as oil.

Scheme 711-11 ab; step? :

A mixture of alkylated aniline (from step V) was stirred (Y g; 7.74 mmol);

acetyl chloride )1+ ml; 7.74 mmol); and DIPEA (.40 mL; 0.7 mmol) in

0 mL CHCl, at room temperature for one hour. Then the solvent was evaporated under low Ve pressure and then the remainder was subjected to a SiOz chromatography using MeOH/CH,Cl, as filter material.

sequentially to give AA g (JAY) of acylated aniline in the form of a thick oil.

Chart “VY - 11 steps; :

mixture returned acylated aniline (from step 0 AA) 1 g; VAY mmol); And

KF.2H,0 (71 g; 7.80 mmol) and +,YV) benzyltriethylammoniumchloride g

11 4

— Bg_7 mmol) in YY ml CH3ON ; for € hours. The solvent was evaporated under reduced pressure. Then Wit and CH,Cl; were added to the residue and the organic layer (NazS0q) was dried after separation. The drying agent was removed by filtration and the remainder was removed for a chromatograph (S102) of which NH;/CH;0H/CH,Cl, at a ratio of 0 © , 5/3 Y was used as an eluate to yield 9 g (0) alcohol a 0 image of a thick oil. step 6: 00 then gla mixed piperazines ) 641 g; 0,4 mmol) and iodo obtained from step e 0.74 can .47(mmol) and *,AA) DIPEA ml; 5.11 mmol) and (Y) Nal gm 4 mmol) in 90 mL CHICN; for YE hours. The solvent was evaporated under reduced pressure. 11.0 and .211:01 were added to the residue and the organic layer (N2S0y) was dried after separation. The drying agent was removed by filtration and the remainder removed for a chromatography (:D 5:0) of which CHCl, 0/011:011/H1L1, with a ratio of 76/7.78/95.3, was eluted to yield Yo g (.4; 7) from 101:01 as thick oil. Scheme 111-17b; Step 7: to a pre-stirred solution of alkylated piperazine from step 1 (0.70 g; + 07 mmol) in THF Je Ye « Then, 1 (Ja Yo) titer of HCl was added. And it was returned

— YA — reaction mixture for 7 hours. nothing happened; Thus, © ml of concentrated HCL was added (at a concentration of 78/YN); The reaction mixture was returned for YE 1 h. H.09 THF was removed by vaporization under reduced pressure; Then HCO ; solution was added. and CHCl; Then (NazS04) CH,Cl was dried and vaporized by Cad under low pressure. Then the remainder was subjected to a chromatography (:5:0) in which NHy/CH30H/CHCl, in ratio 70/975, 170/7 was used as eluent. The remaining oil was dissolved in ethtylacetate and 1 equivalent of AcCL (1 M EtOH) was added. Then the precipitate was filtered to produce 0 Yo g (11 7) of the de-acylized product de-10 in the form of a white solid; it contains HCL compound FY its melting point ranges from 174 to 176 m.

PA Step 1-11 Chart 0 Using a simple method to enter the YY compound HCL group from the YE HCL compound, HCI salt was prepared and the Y salt was formed step by step J according to the procedure then described in the diagram methyl

MeOH/ACCL from (LY 30 1) Equivalent 1 Processing Route 020-21: Synthesis B OH _ OH

N=C I nig N=C sth N=C sth [ ) i [ J ii 1 J n=23 K,CO,

Cul yo 1-71 chart Yves

Scheme 71-71 step 1: jodobenzene used as starting material and alcohols; All are commercially available. A mixture returned of 3-iodobenzonitrile) 4 g; 01 mmol) and 4-mercapto-1- 01 “Je 0.1 7 (butanol mmol) 01 “da 0.17 (ethylene glycols mmol) and 1200 Y,YA) 0 g; 01 mmol) and YO) CUL mg; 15 mmol) in 500 ml of 2-propanol in nitrogen atmosphere ; for YE hours. The solvent was evaporated under reduced pressure. 1 aqueous and 3:0 Da was added to the remainder; as the drying of the organic layer (Na2SO4) after its separation. The drying agent was removed by filtration and the remainder removed for a SiOz chromatograph, of which 011.012 NH3/CH30H/ in a ratio of 5 147:1.75 was used as an eluent to yield 0.460 g (7117.1/) of thioalkylated benzene 021-13 01 in oil form. Scheme 71-71 ¢ Step 7: The resulting alcohols were converted to the corresponding lida jodo derivatives for the procedure described in Scheme 11-117 Steps. Compound 011-020 was prepared in a manner similar to that of 011-021. ve Synthesis 2223: sth" r sth! p oH NaOMe/MeOH < c- i 1 ii 1 J n=23 1:4 YY-YY diagram

or the phenols used as starting material and 21601018 are all commercially available. Scheme 77-77 Step: 1 to a previously stirred solution of (AV) NaOMe g; 050 mmol) in 100 mL methanol in nitrogen atmosphere ; 001 «da 3-fluorothiophenol (4,0 mmol) was added dropwise. ° Then the reaction mixture was stirred for 10 minutes at 3° Ad yall and Yoo (Je 1 ) 3-bromo-1-propanol mmol) was added at once; Then, return the reaction mixture for 14 hours. After cooling the reaction; The mixture was concentrated in vacuo and then ddl (11.0) and CHCl , were added to the residue; The organic layer (,218:50) was dried after its separation. Cray filter drying agent and residue removal for chromatography (Si0;) of which: 8:01 0 011.011 at a ratio of 1/99 was used as a lye to yield 18.8 g (99.5/) of The alkylated product in oil form contains 011-022. Scheme (YY-YY step ?: The resulting alcohols were converted to the corresponding jodo derivatives according to the procedure described in Scheme 11-117 step Vo. 023-011 was prepared in a manner similar to the preparation of 022-011 The specific compounds whose preparation methods are described above have been introduced for the purpose of illustrating the invention better and in more detail, and therefore are in no way intended to limit the scope of the invention.

1 — P — Other embodiments of the invention will become clear to those who have experience in the field after they have perused the detailed description given and applied in practice the invention disclosed in this application. Therefore, the detailed description and examples given in the invention must be considered as illustrative ibd Jal and realizing that the true scope and spirit of the invention; Suh refer to them in the oo claim. Abbreviations: acetyl chloride 1,1'-(azodicarbonyl)dipiperidine ADDP carbonyldiimidazol bw See 125(2003)6653 Huang et al., J.

Am.Chem.Soc., dichloroethane dichloromethane diisopropyldiazodicarboxylate DIAD diisopropylethylamine DIPEA (Js) CH2CI2 3 (ml) 1 (ml) DMA - xe Ce |e [ow owes Yves

4-dimethylaminopyridin DMAP

N,N-dimethylformamide SS | so sim | wen methyl(zert.)-butylether MTBE

N-methylpyrrolidon tetrabutylammoniumbromide TBAB tetrabutylammoniumchloride tetrabutylammoniumfluoride TBAF tetrahydrofurane

Huang et al., J. Am.Chem.Soc., 125(2003)6653 See XPHOS Example: formulation of compound 4 used in animal studies: (0.2) for oral administration Solid in a glass tube VE was added to (110 -© mg) of the required amount of compound 1 some glass beads and the solid was ground by vortex stirring for 2 minutes. After adding © in water and 7 (vol/v) methylcellulose (7) mL of solution

YyYes

Y — p_< Poloxamer 188 (Lutrol F68) A suspension of the compound was made by vortexing for 0 minutes. The pH was adjusted at Y by a few drops of a solution of 01 p NaOH. A suspension was made from the remaining particles using an ultrasound bath. For intraperitoneal administration (Hip.) 0 to (+0 = 0 mg) of required amount of VE solid in a glass tube was added

some glass beads and the solid was ground by vortex stirring for two minutes. After adding 1 ml of a solution of 7) methylcellulose and 70 mannitol in water; A suspension of the concentrate was made by vortex stirring for 10 minutes. Finally, the pH was set at 7. Example: Pharmaceutical test results:

0 table?: Affinity and functional potency of the compounds of the invention in vitro: Affinity data for 0008106-12 and All serotonin reuptake inhibition obtained according to the preceding protocols are included in the following table. In vitro functional activity at human dopamine Dp receptor clones measured by radiolabelled cAMP accumulation (self-efficacy Ae) is demonstrated.

1 at the bottom of the table; As for the comparison of the receiver binding data in the laboratory; It was administered to benzoxazolone derivatives bearing a terminal phenyl group as described in the European patent 90017497, where the focus was on amazon O, K, 5AI2, Tazo, Al8, and 2M, as then it was recorded in Table 1 ¢ dada A of European Patent Y 9 7 Nd 9 0

It is clear from the results that these compounds have a dally toward Dy- dopamine receptors; But it does not necessarily inhibit serotonin reuptake inhibition. [ee | HT mew | daw | 7 A | find | aa | I Yves

Claims (1)

— C ¢ B -_ Claims 1 1 - Compounds of the general formula: (1( X i ™N A 0 Rs Rs), ( ~~ N N—T ~~ 7 1) v R, — Rs S=X Cua 7 or 0 ¢ b is Jf H (hf0) J alkyl S CH,CF; J or OH or © - (Ci-Cé) alkyl ° « 1 is the alkyl (Ci-Cs) of H ar halogen ar cyano ; for Ry is H alkyl (Ci-Cs); Ry A is 11 or Lg alkyl (C1-Co) optionally substituted for a halogen atom ; q where: (Rey 1 0 11) indicates its selection expression from the set consisting of: - 1 b VY c oN 8 1 1 3 5 5 5 0" h h LCN 5 y LCN Ce 1 8 - 7 N 8 1 9 - b 10 a c h- OU © for her B Ce 8 11 “N 12 N 13 1 14 3 Bo 6 R-” “C-”” “Or” CT 1 Ce ¢ Ca \ Co B 16 IN 1 5 ROCF, 0B OF, 3 Rmc 00 H UT L H 1 ° § 1 Va W 21 oN l 22 F $ 23 0 CN 6 CN TTT UO M Neen I VY Terminator N-oxidess stereoisomers, tautomers, and YA conjugates Pharmacologically, solubles of the aforementioned compounds that have alpe hydrates s in addition to salts > 4 N-5 stereoisomers and their conjugates tautomers and their conjugates (1) have the formula Ye oxides 7 according to claim No. (1), wherein it contains part (1) the compounds having the formula - 1 for the part chosen from the group consisting of: phenylpiperazine Y Yves - sy Cl “Cr Cl Cr Meg Tb 0 2 LL OQ 1 m Iv Vv “ / 1 / / m Gh gh oe and lbt O: vil Vill IX And where the second part of the part is chosen from the group consisting of: except: “ 4 ON 5 ON 3 ON > 4 5 0 0 “0 0 CN 0 CN 1 © © © 7 © 1 Ha 58 B 5 BF \ UF a Ra 7 © Maha A A, A Cr Ce 1 Lye ye Le Matta Markh A Ce Ce 8 Ce N 16 oN 1 17 oN N 18 CF, \ 19 CF, 3 2 b 1 OT Maha A O As Ma Na A 25 21 CN 22 23 F CN 0 CN . 1 -© Uo Jo 1 20 with 11 JJ z VY and tautomers ¢ and N-oxidess stereoisomers terminated 1" in addition to salts hydrates s and pharmacologically acceptable solutes of compounds having n" formula (1) and their tautomers and isomers stereoisomers and their N-oxides Yo 1 - A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one additional pharmaceutically acceptable Y, a pharmacologically active amount of one compound v the least according to Claim No. (1); or its salt; as an active ingredient. ( ' or its salt; in a form suitable for ingestion. 1 © - compound of claim (1); or its salt; for use as a medicine. 1 + - use of a compound of claim (1); In the preparation of a pharmaceutical composition for the treatment of disorders of the central nervous system Disorders 0115. V 1 - Use according to Claim No. (1), where it is characterized that the aforementioned disorders are aggressiveness, anxiety disorders, autism, vertigo, and vertigo. ; depression; cognitive or memory disorders, Parkinson's disease 22:16050075; Schizophrenia and other psychological disorders. YY¢d A 1 - Use according to Clause (7); Where it is distinguished that the disorder (Saal) disorder is depression. 1 4 - Use according to Claim No. (1) where it is distinguished that the disorders, Y: ©1010 mentioned, are schizophrenia, psychotic disorders, and other 5. 0 1 = use according to Claim No. (76) Where it is distinguished that the aforementioned disorder Y is Parkinson's disease.