UA76259C2 - Aryloxyphenyl and arylsulfanylphenyl derivatives as glycine transport inhibitors, a pharmaceutical composition based thereon and a method for the treatment of diseases - Google Patents

Abstract

The invention provides compounds of the formula (I) wherein the substituents are as defined in the application. The compounds are valuable glycine transport inhibitors.

Description

Description of the invention

This invention relates to novel compounds that are glycine transporter inhibitors and are essentially effective in the treatment of CNS disorders.

Glutamic acid is the main excitatory amino acid in the mammalian central nervous system (CNS) and acts through two classes of receptors, ionotropic and metabotropic receptors, respectively. Ionotropic glutamate receptors are divided into three subtypes based on the affinity of agonists for these receptors, namely, M-methyl-O-aspartate (MMOA), (K,5)-2-amino-3-(3-hydroxy-5- methylisoxazol-4-yl)propanoic 70 acid (AMPA) and kainic acid (or kainate).

MMOA receptors contain binding sites for modulatory compounds such as glycine and polyamines.

The binding of glycine to its receptor enhances the activation of the MMOA receptor. Such activation of the MMOA receptor may be a potential target for the treatment of schizophrenia and other diseases associated with dysfunction of the MMOA receptor. Activation can be achieved with a glycine transporter inhibitor. 12 Molecular cloning revealed the existence of two types of glycine transporters, SIUT-1 Her SIuT-2, and

SIUT-1 can be further subdivided into SIUT-Ta, SIUT-16 and SIUT-1c.

The MMOA receptor is blocked by compounds such as phencyclidine, which induce a psychotic state resembling schizophrenia. Similarly, MMA antagonists such as ketamine produce negative and cognitive symptoms similar to schizophrenia. This indicates that the dysfunction of the MMOA receptor is involved in the pathophysiology of schizophrenia.

A number of diseases are associated with the MMOA receptor, such as pain (Uakzi Raip 1989, 37,111-123), elasticity, myoclonus and epilepsy (Tgyopu ei ai. Mometepi Oizogdege 1988, 3, 77-87), as well as the ability to learn and remember 'yat (Kivop ei a). Meygovzsi Viorepam. Kew. 1995, 19, 533-552).

Antagonists or inhibitors of the glycine transporter are believed to be very useful in the treatment of schizophrenia (Chamii UUO 97/20533). with

Antagonists or inhibitors of glycine transport can be used to treat both positive and Ge) negative symptoms of schizophrenia and other psychoses and to improve cognitive function in conditions in which cognitive processes are reduced, ie, Alzheimer's disease, dementia associated with multiple infarcts, AIDS-related dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, or diseases in which the brain is damaged internally or externally, such as a head injury or stroke. at

Similarly, antagonists of the glycine transporter can have a beneficial effect on seizure disorders such as epilepsy, muscle stiffness or myoclonus.

Clinical trials with glycine Mami eiaIAt.) have been reported. Rzuspiayu 1994,151,1234-1236 and sch

She eidegtap her ai. Vioi Rzuspiaiu 1996, 39,213-215). Treatment with high doses of glycine has been reported to alleviate schizophrenic symptoms. There is a need for more effective compounds for the treatment of MMOA-related diseases. -

This invention provides compounds that are potent inhibitors of the glycine transporter and, therefore, can be used in the treatment of diseases associated with MMOA dysfunction.

This invention relates to compounds of the general formula | « - with vh: y g Y Y te cha DE), "I dl u piky Kin i " 4 Aa dev (VV, ko Ah y ; zgo : No ; i sto 20 SHA a: Y NI oo Y s : LE | And t; rya, ;

Гебе и - и во where У represents M, С or СН;

X represents O or 5; t is 1 or 2; p is 0,1,2, C or 4; d is 0, 1 or 2; 65 with represents 0,1,2 or 3; r is 0.1 or 2;

O represents C, R-OK? or 5-0, where is KE? is hydrogen or C 1-6-alkyl; A is OK b where B5 is hydrogen, C 4.6-alkyl, aryl or aryl-C. β-alkyl, where aryl can be replaced by halogen, CEz, OSE",

SM, MO" or C. γ-alkyl; AK is phenyl or heteroaryl; each B" individually represents C.sub.6-alkyl, C.sub.3-sub.cycloalkyl or C.sub.3-sub.cycloalkyl-C.sub.4-sub.alkyl; the dashed line represents an optional bond; each EC" which may be the same or different, independently selected from the group consisting of

C. Cd-alkyl, or two B" attached to the same carbon atom, can form a 3-membered spiro-adjoined cycloalkyl; then each K?, which can be the same or different, is independently selected from the group that consists of halogen, cyano, nitro, C. v-alk(en/yn)yl, C. v-alk(en/yn)yloxy, C. v-alkK(en/yn)ylsulfanyl, hydroxy, hydroxy-C 4 β-alk(en/yn)yl, halogen-C. β-alk(en/yn)yl, halogen-C. β-alk(en/yn)yloxy, C3 β-cycloalk(en)yl,

C3.8-Cycloalk(en)yl-C..v-alu(en/yn)yl, acyl, C..v-aluk(en/yn)yloxycarbonyl, C.v-alu(en/yn)ylsulfonyl or 75 -MVUV'O, where Z and v'U independently represent hydrogen, C 46-alk(en/yn)yl, C a-cycloalu(en)yl,

C. v-cycloalk(en)yl-C 1 v-aluk(en/yn)yl or aryl, or BO and k'b together form a 3-7-membered ring, which optionally contains one more heteroatom; each KZ by which AK is replaced can be the same or different, independently selected from the group consisting of halogen, cyano, nitro, C 4.v-alk(en/yn)yl, C. v-alu(en/yn) yloxy, C. v-alkK(en/yn)ylsulfanil, thydroxy, hydroxy-C.4 v-alk(en/yn)yl, halogen-C. v-alk(en/yn)yl, halogen-C. β-alk(en/yn)yloxy,

C3 c-cycloalk(en)yl, C3 vd-cycloalk(en)yl-C.4 c-alk(en/yn)yl, Si c-alk(en/yn)ylsulfonyl, aryl, aryl-C. в-alk(en/yn)yloxy, aryl-C. v-alk(en/yn)yl, Si v-alk(en/yn)yloxycarbonyl, acyl, -MNSO-C. v-aluk(en/in)ilu, "-"SOMA"V"?, where KK"! and VK"? independently represent hydrogen, C 46-alyu(en/yn)yl,

C. v-cycloalk(en)yl, Cz.v-cycloalk(en)yl-C. β-aluk(en/yn)yl or aryl, or B" Her "2 together with the nitrogen to which they are attached form a 3-7-membered ring, which optionally contains one more heteroatom; He) or ME'ZV", where VK"Z and B" independently represent hydrogen, C 4.6-alk(en/yn)yl, C a-cycloalk(en)yl,

C. v-cycloalk(en)yl-C 1 v-alk(en/yn)yl or aryl; or ZB", together with the nitrogen to which they are attached, form a 3-7-membered ring, which optionally contains one more heteroatom; He»! or two adjacent BZ substituents together form a ring condensed with an AK ring selected from the group , consisting of yu p

THE SECRET you S, this TSI Kn y schi for What and sov i ch g, ki Zh dnk y "ani. still shov in NI Z I DY 40 shi i I - s where MU represents O or 5, and K and K " represent hydrogen or C..C.-alkyl; "with or two adjacent KZ substituents together form a heteroaryl containing one or two heteroatoms condensed with AK; or their acid addition salts.

In the case when p, 4, g or c are equal to 0, the substituents are hydrogen atoms. If U represents C, then there is a dashed line. The dashed line is not present if Y represents M or

Ge") dream

The invention offers the above compounds of formula I for use as a medicinal product. o The invention offers a pharmaceutical composition containing the above-mentioned compound of the formula! or its 1 50 pharmaceutically acceptable acid addition salt and at least one pharmaceutically acceptable carrier or diluent. The invention offers the use of the above-mentioned compound of the formula | or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of diseases selected from the group consisting of schizophrenia, including both positive and negative symptoms of schizophrenia, and other psychoses, 959 | when improving cognitive function in conditions in which cognitive processes are reduced, i.e. diseases

HF) Alzheimer's, dementia due to multiple infarcts, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases in which the brain is damaged internally or externally, such as head trauma or stroke, and seizure disorders such as epilepsy, muscle spasticity or myoclonus. 60 The invention provides a method of treating diseases selected from the group consisting of schizophrenia, including both positive and negative symptoms of schizophrenia, and other psychoses, and in improving cognitive function in conditions in which cognitive processes are reduced, i.e., Alzheimer's disease, dementia due to multiple heart attacks, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases in which the brain is damaged by internal or external influences, such as head trauma or stroke, and seizure disorders such as epilepsy, muscle elasticity or myoclonus in a living organism of an animal, including a person, which includes the introduction of a therapeutically effective amount of the above-mentioned compound of formula I or its pharmaceutically acceptable acid addition salt.

Detailed description of the invention

A preferred embodiment of the invention are compounds where U is M.

A preferred embodiment of the invention are compounds where X is 5.

A preferred embodiment of the invention are compounds where CO) is C

A preferred embodiment of the invention are compounds where A is OH.

A preferred embodiment of the invention are compounds where p is 1 or 2. 70 A preferred embodiment of the invention are compounds where t is 1.

A preferred embodiment of the invention are compounds where 4 is 0.

A preferred embodiment of the invention are compounds where r represents 0 or 1.

A preferred embodiment of the invention are compounds where 5 is 1 or 2.

A preferred embodiment of the invention are compounds where AK is phenyl, thiophene, pyridyl, pyrimidyl, thiazolyl, imidazolyl or benzothiazolyl.

A preferred embodiment of the above is a compound where B is CH.

A preferred embodiment of the invention are compounds where AK is phenyl, and r and 4 are 0, p is 1 or 2, c is 1 or 2, r is 0 or 1, t is 1, K is CHniu , (A is OH, CO) is C, Y is M and X is 5.

An even more preferred embodiment of the above are compounds wherein B is independently selected from halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkyl.

An even more preferred embodiment of the above is a compound wherein C is selected from the group consisting of C1, E, C1, tert-butyl, 2-propyl or methyl.

Particularly preferred embodiments of the invention are those where the compound of the invention is any of the following: o (17-)-44-(2--4-methoxyphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylacetic acid, (17-)-14-(2-(4-chlorophenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylacetic acid, (1-)-44-(2-(4-tert-butylphenylsulfanyl)phenyl)trans -2,5-dimethylpiperazine-1-ylacetic acid, (17-)-14-(2-(4-fluorophenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylacetic acid, Me (1-)-44- (2-(4-tert-butylphenylsulfanyl)phenyl)|-2-methylpiperazine-1-ylacetic acid, y (1/-)-14-(2-(4-iso-propylphenylsulfanyl)phenyl|-2-methylpiperazine-1 -ylacetic acid, (1--)-2-14-(2-(4-tert-butylphenylsulfanyl)phenyl-trans-2,5-dimethylpiperazine-1-ylylpropionic acid, c t14-(5-chloro-2-(4- methoxyphenylsulfanyl)phenyl|-2(K)-methylpiperazine-1-ylacetic acid, Ge 14-(2-(4-methoxyphenylsulfanyl)phenyl|-2(K),5(5)-dimethylpiperazine-1-ylacetic acid,

Zo T14-(5-chloro-2-(4-methoxyphenylsulfanyl)phenyl|-2,2-dimethylpiperazin-1-yl)acetic acid, y- (17-)-44-(5-chloro-2-(4 --rifluoromethylphenylsulfanyl)phenyl|-2-methylpiperazine-1-ylacetic acid, t14-(5-chloro-2-(3-methoxyphenylsulfanyl)phenyl|-2(K)-methylpiperazine-1-ylacetic acid, (1-)- 14-(2-(4-phenylphenyloxy)phenyl|-2-methylpiperazine-1-ylacetic acid, « (17-)-44-(2--4-methylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1- Iluacetic acid, (1/-)-14-(2-(4-iso-propylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-iluacetic acid, C c (/-)-14-(2-(2 ,4-dimethylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylacetic acid, "» (4-/-)-2-14-(2-(4-tert-butylphenylsulfanyl)phenyl|-3-methylpiperazine- 1-Ilyupropionic acid, " 14-(2-(4-isopropylphenylsulfanyl)phenyl|-piperazine-1-illuacetic acid, (4-)-2-4A4-I2-(4-methoxyphenylsulfacyl)phenyl|-3-methylpiperazine-1 -iliupropionic acid, or their pharmaceutically acceptable acid addition salts - Definition of substituents b Halogen means fluorine, chlorine, bromine or iodine.

The expression "C.sub.6-aluk(en/yn)yl" means a C.sub.6-alkyl, C.sub.6-alkenyl or C.sub.6-alkynyl group. The term "C3-8-cycloalk(en)yl" means a C3-8-cycloalkyl or cycloalkenyl group. c 20 The term "C 1-6 alkyl" refers to a branched or unbranched alkyl group containing from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl , 2-methyl-2-propyl sr and 2-methyl-1-propyl.

Similarly, the terms "C0-6-alkenyl" and "C0-6-alkynyl", respectively, refer to groups containing from two to six carbon atoms, including one double bond and one triple bond, including but not limited to but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

F! The term "C3-C-cycloalkyl" refers to a monocyclic or bicyclic carbocycle containing from three to eight C atoms, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like. where The term "C3.8-cycloalkenyl" denotes a monocyclic or bicyclic carbocycle having from three to eight C atoms and including one double bond. 6o The terms "C3 d-cycloalk(en)yl-C.4 c-alk(en/yn)yl", "C3 i-cycloaluk(en)yl" and "C. c-aluk(en/yn)yl" are as defined above.

The terms "Si in-alk(en/yn)yloxy", "Si in-alk(en/yn)ylsulfanyl", "hydroxy-C. in-alk(en/yn)yl", halogen-C 4 in-alk (en/yn)yl", "halogen-C.4 in-alk(en/yn)yloxy", "Si in-aluene/yn)ylsulfonyl", etc. denote such groups where C. in-alu(en/in )yl is as defined above, for As used herein, "C..i.-alk(en/yn)yloxycarbonyl" refers to groups of the formula

"Si in-alk(en/yn)yl-O-CO-", in which the C. in-alk(en/yn)yl groups are as defined above.

The term "acyl" as used herein refers to formyl, C 4,6-aluk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C. β-alk(en/yn)ylcarbonyl, C3 β-cycloalk(en)ylcarbonyl or "C3.8-Cycloaluk(en)yl-C 4,6-alkK(en/yn)ylcarbonyl group.

As used herein, the term "3-7-membered ring optionally containing another heteroatom" refers to ring systems such as 1-morpholinyl, 1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1- homopiperazinyl, 1-imidazolyl, 1-pyrrolyl or 1-pyrazolyl, all of which may be further substituted with C 1 -alkyl.

The term "heteroaryl" can represent 5-membered monocyclic rings such as 3H-1,2,3-oxathiazole, 70 1,3,2-oxathiazole, 1,93,2-dioxazole, 3H-1,2,3-dithiazole , 1,3,2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thidiazole, 1H-1,2,3-thiazole, isoxazole, oxazole, isothiazole, thiazole, 1H-imidazole, 1H-pyrazole , 1H-pyrrole, furan or thiophene, and b-membered monocyclic rings such as 1,2,3-oxathiazine, 1,2,4-oxathiazine, 1,2,5-oxathiazine, 1,4,2-oxathiazine, 1,4,3-oxathiazine, 1,2,3-dioxazine, 1,2,4-dioxazine, 4H-1,3,2-dioxazine, /1,4,2-dioxazine, 2H-1,5,2 -dioxazine, 1,2,3-dithiazine, 1,2,4-dithiazine, 4H-1,3,2-dithiazine, 1,4,2-dithiazine, /2H-1,5,2-dithiazine, 2H- 1,2,3-oxadiazine, 2H-1,2,4-oxadiazine, 2H-1,2,5-oxadiazine, 2H-1,2,6-oxadiazine, 2H-1,3,4-oxadiazine, 2H- 1,2,3-thiadiazine, 2H-1,2,4-thiadiazine, 2H-1,2,5-thiadiazine, 2H-1,2,6-thiadiazine, 2H-1,3,4-thiadiazine, 1, 2,3-triazine, 1,2,4-triazine, 2H-1,2-oxazine, 2H-1,3-oxazine, 2H-1,4-oxazine, 2H-1,2-thiazine, 2H-1, 3-thiazine, 2H-1,4-thiazine, pyrazine, pyridazine, pyrimidine, 4H-1,3-oxathiine, 1 ,4-oxathiene, 4H-1,3-dioxin, 1,4-dioxin, 4H-1,3-dithiyne, 1,4-dithiyne, pyridine, 2H-pyran or 2H-thiyne.

The term "aryl" refers to carbocyclic aromatic systems such as phenyl and naphthyl.

The acid addition salts according to the present invention are mainly pharmaceutically acceptable salts of the compounds according to the invention, obtained by interaction with non-toxic acids. Examples of such organic salts are maleic, fumaric, benzoic, ascorbic, amber, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, milky, apple, almond, cinnamon, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophyllineacetic acids, and (8) formed with 8-halotheophyllines, for example, 8-bromotheophylline. Typical examples of such inorganic salts are salts of hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.

In addition, the compounds of this invention may exist in unsolvated and solvated forms, either obtained using pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms are generally equivalent to unsolvated forms for purposes of the present invention. at

Certain compounds of this invention have chiral centers, and such compounds exist as isomers (ie, c enantiomers or diastereomers). The invention covers all such isomers and any mixtures thereof, including racemic mixtures. ise)

The racemic forms can be resolved into optical antipodes by known methods, for example, by di-dissolving their diastereomeric salts with an optically active acid and subsequent liberation of the optically active amine compound by treatment with a base. Chromatography on an optically active matrix is another way of dividing racemates into optical antipodes. Racemic compounds according to this invention can also be divided into optical antipodes, for example, by fractional crystallization of α- or 1-salts (tartrates, mandelates or camphorsulfonates). The compounds of this invention can be divided by the formation of diastereomeric s derivatives. . Can be used additional methods of distribution of optical isomers, known to specialists in this field and? techniques Such methods are discussed |). Chadyez, A. Soes apa 5. MUpPep in "Epapitegv, Kasetai (jevz, apa

Kezoiishiopvg", duopp UMieu apa Bopvs, Mem Hogk (1981).

Optically active compounds can also be obtained from optically active starting substances. -I Pharmaceutical compositions

The pharmaceutical compositions of the invention can be prepared by standard methods known in the art. For example, tablets can be prepared by mixing the active ingredient with conventional adjuvants and/or diluents and then pressing the mixture on a conventional tabletting machine. Examples of adjuvants or diluents include: corn starch, potato starch, talc, magnesium stearate, 1 gelatin, lactose, gums and the like. For such a purpose as coloring, flavoring, preservation, etc., they can

Ge) be used any other adjuvants or additives that ensure compatibility with the active ingredients.

Solutions for injections can be obtained by dissolving the active ingredient and possible additives in part of the solvent for injection, preferably in sterile water, bringing the solution to the desired volume, sterilizing the solution and filling the appropriate ampoules or bottles with it. Any suitable additives commonly used in practice may be added, such as isotonicity agents, preservatives, antioxidants, etc. (F) The pharmaceutical compositions of this invention or made in accordance with this invention can be administered by any conventional route, for example, orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. Methods well known in the art can be used to prepare these compositions, and any pharmaceutically acceptable carriers, diluents, excipients or other additives commonly used in the art can be used.

It is convenient to administer the compounds of the invention in a standard dosage form containing the specified compounds in an amount of approximately 0.01 to 100 ug. The total daily dose is usually in the range of about 0.05-500 Ω and most preferably from about 0.1 to 5 Ω of the active compound of the invention. 65 The compounds of the invention are prepared by the following general methods.

Alkylation of an amine of the formula II by an alkylating agent of the formula PI ny OO yk What A and t " h Y I I U. ko E p - E s | IV k What and r. I though g I to t Y Mi: A: a (85, where I is a convenient leaving group such as halogen or tosylate Substituents AK, K 1-87, mM, o, X,

A, t, p, 9, g and 5 are as defined above. The reaction is usually carried out in a suitable solvent such as ethanol, M,M-dimethylformamide or acetonitrile containing an inorganic base such as potassium or cesium carbonate or an organic base such as M-ethyldisopropylamine at an elevated temperature of 40-1202b. The compound of the formula I, where OO is carbon, and A is OK 6 where B5 is hydrogen, can be obtained from the corresponding esters СООВ5, where K9 is an insoluble polymer or C 4 6-alkyl, aryl or o aryl-C , /-alkyl. The transformation can be carried out under alkaline conditions, for example, using aqueous sodium hydroxide in an alcohol solvent, or under acidic conditions, when KE? is a tert-butyl group or an insoluble polymer. Gee!

Compounds of the formula II can be obtained by any of the following reactions: a) chemical transformation of the compound of the formula II about sshsh. сч з Ш оОЙх s r zo - still yashy STILL I Z -y and sh-! B - What is in " ko ZHI c), x EI and What is " . by further (2) reaction with the compound HX-AB-(2Z)", where AB, X, B and C are as defined above; with p) chemical synthesis, depicted in the scheme with 50 and Che)

Ф) име) 60 b5 in KZ r VE b Liu bore ate that

OD ik well You, : g I shi , A: in; х и и и ю и х дяк ив: I - и 7 zu ; And I: from Zhv-rvh syu ov

And where AB, B", B2, VZ, в, т, р, 4 and X are as defined above, and 5 in the circle is a solid carrier; c) by the chemical synthesis depicted in scheme II, where X represents 0, and U represents M. p

Ve (se) ozhekorom (VAV THEY i (y (2 i--e i VV ch a same in 2 s 5 Ot nt shi av ZSH

F: She Ye i s 50 ots AI dvy 0000 Ya o t v pan Ach; sh-k i (y, Uidv 65 a) by the chemical reaction of the compound of the formula M in which I and any K, K, X, z ii d are as defined above, and Z represents an atom of bromine or iodine, with the compound of the formula MI zo Z te and vah: aa oyu (Se) in which B, those p are as defined above; f) dehydration of the compound of formula MI with optional simultaneous removal of protection "

B sonata in E C c and B 4 Mk J

Uk (V, i zn; U 20 An SHI I ME ac.

Ge De CHI K Ko y ' J I Me mish el che, zv volya i; where B", B2, BZ, X, t, p, 4 and 5 are as defined above, and K represents either a hydrogen atom or a BOC group; 6о 7) hydrogenation of the double bond in the Compound of the formula MI b5 с A: "Y "Y pi in which B", B, 23, X, t, r, 4 and z are as defined above; 9) deoxygenation and deprotection of the compound of the formula MI! re;

Zh v o) 7 Anya yu (he eats y

AC manifest s, (Se) their p, with 7 what and where Es, ,I | h-

AL. vu, " c c sk rve in which B", 82, 23, X, t, p, 4 and 5 are as defined above and K represents either a hydrogen atom or a BOC group. and Dianitrogenation followed by reaction with compound НЗ-Аг-(В 3) in accordance with method a) is performed by addition

He») of the diazonium salt of the corresponding aniline to a solution of the sodium salt of thiophenol in water containing a suspension of copper.

The starting material of formula IM is prepared as follows. Conduct a reaction of a derivative of fluoronitrobenzene di with a derivative of piperazine in a solvent such as DMF, MMP or another dipolar aprotic solvent that 4! 20 contains an organic base such as triethylamine to obtain an orthonitrophenylpiperazine derivative. The nitro group is then reduced using standard techniques known to those skilled in the art to obtain the starting substance of formula IM.

For 2,5-dimethylpiperazine derivatives, M-benzyl-2(K),5(5)-dimethylpiperazine was obtained according to methods known from the literature. Spent 2000, 43, 236-249). M-benzyl-2(5),5(K)-dimethylpiperazine 29 was obtained according to patent application MUO 00/71535.

GF) The sequence of reactions in method B) is carried out in accordance with the methods described in the patent application UMO kyu 01/49681. Diamines are either commercially available or synthesized by methods known to chemists skilled in the art. Complex compounds of iron similar to hexafluorophosphate /-«-9-1,2-dichlorobenzene-« ?-cyclopentadienylsalize () and substituted analogs are synthesized according to methods known from the literature | 9). Oh Spent 1996, 61,1297-1305), or synthesized by methods known to chemists-specialists in this field.

The starting substance in method c) is obtained by combining orthobromophenol with the corresponding arylboronic acid or complex boronate ether according to the method known from the literature (Emapz ei ai., Tei. I ei, 1998, 39, 65 2947-2940). The resulting biaryl ether bromide is then coupled, using a palladium catalyst, with a protected piperazine, where the protecting group can usually, but not exclusively, be

tert-butyloxycarbonyl (BOC) or benzyloxycarbonyl (CB2) derivative, and the protecting group (PO) is then removed by acid cleavage, for example, using hydrogen chloride in an alcoholic solvent to remove the BOC group or catalytic hydrogenolysis in the case of CB7 removed to yield intermediates of the formula II, where X represents O and U represents M. General methods of removing the corresponding protective groups are described in the manual (Rgobyesiime Sgotsrz ip Ogdapis Zupipeviv T.MU.Sgeepe apa R.s.M. MUtsiv, UMpPeu Ipiegesiepse, (1991) IBVM 04716230161.

The reaction of the compound of the formula M with the diamine of the formula MI in method 4) was carried out according to the method similarly described in (Mizpiuata ei ai. Teigapedgop I ek. 1998, 39, 617-620). The starting substance of formula MI was obtained by the same method as described in IZsporheg ei a). Teigapedgop 2001, 57, 3069-3073).

The reaction of dehydration of the compound of the formula MII with optional simultaneous deprotection in the method is) was carried out according to the method similarly described in I|Raiteg eii ai. 9). Honey. Spent 1997, 40, 1982-1989). The starting substance of the MI formula! was obtained from the compound of the formula MII, in which K is a BOC group, by deprotection with hydrochloric acid in methanol. Compounds of the formula MYI can be obtained as described in IRaiteg ei ai).. /5 Med. Spent 1997, 40, 1982-1989).

Recovery of the double bond according to the method І) is generally carried out by catalytic hydrogenation at low pressure ("Zatm.") in the Parr apparatus or using reducing agents such as diborane or derivatives of borodonium, obtained by starting with MavVvVnNu; in trifluoroacetic acid in inert solvents such as tetrahydrofuran (THF), dioxane, or diethyl ether.

Deoxygenation of intermediate compounds of tertiary alcohols of the formula Mi! in method 9), where K is VOC, was carried out according to Barton's modification of the recovery method, similarly described in (Napzep ei ai. zZupipeviv 1999, 1925-1930). Intermediate tertiary alcohols were obtained from appropriately substituted 1-bromo-phenylsulfanylbenzenes or their corresponding simple ethers by metal-halogen exchange followed by the addition of a suitable electrophile of formula IX according to a method similarly described in |Raiteg ei ai..sch

May Spent 1997, 40, 1982-1989). Correspondingly substituted 1-bromophenylsulfanylbenzenes were obtained by a method similar to that described in the literature: reaction of correspondingly substituted thiophenols with correspondingly substituted i) aryl iodides according to |Zsporieg apa ZspIarrasi! Teigapedhop 2001, 57 3069-3073, Vayez ei ai., Ogo. Heck. 2002, 4,2803-2806 and Kmzhopa ei aY. Oho. Gay. 2002, 4 (in press)). The corresponding substituted 1-bromophenoxybenzenes can be obtained as described in IVisK and a). Wow Gay. 2002, 4,1623-1626). Removal of the VOS group was carried out according to Ge! by standard methods known to those skilled in the art. oyu (83, y szhshk s shi U -

She and t - ;"

AND

- And Examples

General methods

Me, LC-MS analysis data were obtained on a RE bZsieh АРИ 150ЭХ device equipped with an IopbZrgau ion co-spray source and a Zpitaydyga I S-BA/5I S-10A LC system. Column: З30Х4, bmm UUafeg butteyu C18 with 5o particle size З, 2μm. Solvent system: A is water/trifluoroacetic acid (100:0.05) and B is water/acetonitrile/trifluoroacetic acid (5:95:0.03). Method: elution with a linear gradient from 9095 A to

Ge) 10095 V in 4 minutes and with a volume flow rate of 2 ml/min. Purity was determined by integration of UV (254 nm) and EI 50 trace.

Retention time (RT) was expressed in minutes.

Preparative LC-MS purification was performed on the same device. Column: 50 Ох20 mm UMO 005-А with the size of two bmcm particles; method: elution with a linear gradient from 8095 A to 10095 V in 7 minutes with a volumetric flow rate of 22.7 ml/min. Fractional collection was carried out with the help of MSS-detection of a branched stream.

F, H-NMR spectrum was recorded at 500.13 MHz on a Vgykeg Amapse OBH5O0 device or at 250.13 MHz on a VgyKeg AS 250 device. Deuterated methylene chloride (99.89603), chloroform (99.89603) or dimethyl sulfoxide (99 ,8950)). TM5 was used as an internal standard. The values of chemical shifts were expressed in parts per million (ppm). The following abbreviations were used to denote the multiplicity of NMR signals: c o - singlet, d - doublet, t - triplet, k - quartet, qv - quintet, d - heptet, dd - doublet of doublets, dt - doublet of triplets, dkw - doublet of quartets, tt - triplet of triplets, m - multiplet and w - wide singlet.

The following materials were used for ion-exchange chromatography: a ZSh column (1g) from Magiap Meda Vopa 65 Bish, Mo220776 according to the Spgotrask catalog. Before use, the ZSC column was pre-conditioned with a 1090 solution of acetic acid in methanol (Zml). For decomplexation by irradiation, a source of ultraviolet radiation (300 W) manufactured by Rpiirrv was used. Wang's resin (1.0 Zmmol/g, Karr-Roiutege, Toeripdep, Germany) was used as the initial polymer carrier for solid-phase synthesis.

Preparation of intermediate compounds of the formula IM 2-(3-methylpiperazin-1-yl)uphenylamine 2-Fluoronitrobenzene (7.1 g, 30 mmol) was dissolved in DMF (100 Oml), which contains triethylamine (10 g, 10 Omol), and placed in a nitrogen atmosphere. 2-methylpiperazine (5.0 g, 10 mmol) was added to the reaction mixture. The reaction mixture was heated to 8092C for 16 hours. The reaction mixture was allowed to cool to room temperature before the amount of solvent was reduced to half the volume under vacuum. Ethyl acetate (2000ml) and ice water (250ml) were added to the solution and the product was extracted with diethyl ether (2x200ml). The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate (2 x 200 ml). The organic phases were combined, washed with a saturated salt solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated in a vacuum.

The product (10.5 g) was dissolved in ethanol (250 ml). Palladium on activated carbon (1090 mass/mass, 2.2 g) was added as a catalyst to the solution and the solution was hydrogenated in a Steam apparatus at 3 bar for 3 hours. The solution was filtered and 7/5 evaporated to give the aniline product. Output (8.0g, 8390).

The following intermediate compounds were obtained in a similar way: 2-(3,5-dimethylpiperazin-1-yl)uphenylamine 2-(3,3-dimethylpiperazin-1-yl)uphenylamine 4-methoxy-2-(33-methylpiperazin-1-yl) uphenylamine 2-(2(5),5(K)-dimethylpiperazin-1-yl)phenylamine. 2(Kk),5(5)-Dimethyl-1-M-benzylpiperazine (6b, 0g, 29mmol) was dissolved in dimethylformamide (100ml) and triethylamine (b, 4ml, 44mmol) and the mixture was placed under a nitrogen atmosphere. 2-fluoronitrobenzene (333.5 ml, Zimmol) was added to the solution. The reaction mixture was heated at 1002 for 72 hours. The solution was evaporated in vacuo and re-dissolved in ethyl acetate (1000 ml). Then the solution was washed with a saturated sodium bicarbonate solution (10 Oml) and a saturated salt solution (10 Oml). The isolated organic phase was dried over magnesium sulfate, filtered, and the filtrate was evaporated under vacuum. The crude product was then purified by flash chromatography with i) elution with ethyl acetate/methanol/triethylamine 85:10:5. The product (8.2 g) was dissolved in ethanol (25 Oml).

Palladium on activated carbon (1095 wt/wt, 2.2 g) was added as a catalyst to the solution and the solution was hydrogenated in a Steam apparatus at 3 bar for 3 hours. The solution was filtered and evaporated to give the aniline product. Ge")

Output (5.2g, 87905).

The following intermediate compounds were obtained in a similar way: 2-(2(K),5(5))-dimethylpiperazin-1-yl)uphenylamine si 4-Chloro-2-(3,3-dimethylpiperazin-1-yl)uphenylamine 2, 2-Dimethylpiperazine (9.55 g, in 84 mmol) was dissolved in dimethylformamide (1400 ml). Triethylamine (12.07ml, 83.bmol) was added to the solution and the reaction mixture was placed in a nitrogen atmosphere. The solution was heated to 80°C and 4-chloro-2-fluoronitrobenzene (13.5 g, 7 mmol) was added in the form of a solution in dimethylformamide (35 ml). The reaction mixture was stirred at 402 for 16 hours. The solvent was removed in vacuo and the residue was dissolved in ethanol (250 ml). Ammonium chloride (28g) and zinc powder (17g) were added. The reaction mixture was refluxed at 80°C for 1 hour and then stirred at 402°C for 72 hours. Then the reaction mixture was filtered and the filtrate was evaporated under vacuum. The solid was then washed with ethyl acetate and then with a small amount of methanol. Yield: 16.04 g, 8890. h The following intermediate compounds were obtained in a similar way: » 4-chloro-2-(3-(«К)-methylpiperazin-1-yl)uphenylamine 4-chloro-2-(3-(5) -methylpiperazin-1-yl)uphenylamine.

Preparation of intermediate compounds of formula II by method a) - 1--2--4-chlorophenylsulfan)phenyl|-3-methylpiperazine b 2-(3-Methylpiperazin-1-yl)uphenylamine (0.96 bg, mmol) was dissolved in water (30 ml ), containing concentrated sulfuric acid (0.28ml, 5.2mmol), the solution was cooled to 09 and sodium nitrite (0.36bg, 5.2mMmol) was added. where The reaction mixture was stirred for 30 minutes before the pH of the reaction mixture was adjusted to pH 7 with 20 sodium acetate. The diazonium salt solution was then added dropwise to a solution of 4-chlorothiophenol in 2M Mahon (4ml) containing a suspension of copper (0.3g, zmmol). After addition, the mixture was heated to 602 for 30 minutes before allowing the mixture to cool to room temperature and ethyl acetate (10 mL) was added. The mixture was filtered and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2x10ml). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by 595 flash chromatography using silica gel eluting with a mixture of ethyl acetate/methanol/ammonia, 96:31.

GF) The pure product was isolated as a colorless oil. Yield (0.18g, 1195) IN nNMR (SOSIZ, 500MHzC) 1.12 (d, 7 ZN), 2.6-2.72 (w. m, 2H), 3.0-3.15 (m, 5H), 6.9 (m, 2H), 7.08 (d, 1H), 7.15 (m, 1H), 7.25-7.35 (m, 4H); MS (MN) 319.1.

The following compounds were obtained in a similar way: in 1-(2--4-chlorophenylsulfanyl)phenyl)|-3,5-dimethylpiperazine (17-)-44-(2--4-methoxyphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine (17-)-44-(2-(4-chlorophenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine (1-)-44-(2-(4-tert-butylphenylsulfanyl)phenyl)grans-2,5-dimethylpiperazine (17-)-14-(2-(4-fluorophenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine (1-)-44-(2-(4-tert-butylphenylsulfanyl)phenyl)|-2-methylpiperazine 65 ( 1-)-14-(2-(4-isopropylphenylsulfanyl)phenyl|-2-methylpiperazine

4-(5-Chloro-2-(4-methoxyphenylsulfanyl)phenyl|-2(K)-methylpiperazine 4-(2-(4-Methoxyphenylsulfanyl)phenyl|-2(K),5(5)-dimethylpiperazine.

Preparation of intermediate compounds II according to method B, where A is an insoluble polymer

Preparation of complex compounds of iron

Hexafluorophosphate "-9-1,2-dichlorobenzene-" ?-cyclopentadienylalase (I!)

Ferrocene (167g), anhydrous aluminum trichloride (238g) and powdered aluminum (24g) were suspended in 1,2-dichlorobenzene (50Oml) and heated to 9092C in a nitrogen atmosphere for 5 hours with vigorous stirring. The mixture was cooled to room temperature and water (1000 ml) was carefully added in small 70 portions while simultaneously cooling in an ice bath. Diethyl ether (50 mL) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with diethyl ether (300 ml).

The aqueous phase was filtered and aqueous ammonium hexafluorophosphate (b0 g in 5 Oml of water) was added in small portions while stirring. The product was allowed to precipitate at room temperature. After 3 hours, the precipitate was filtered off, washed extensively with water and dried under vacuum (5022), yielding 81 g (21905) of the title compound in 75 as a light yellow powder. "H NMR (DMSO-dbv): 5.29 (s, 5H), 6.48 (m, 2H), 7.07 (m, 2H).

Preparation of amines bound to polystyrene 4-((Piperazine-1-ylcarbonyloxymethyl|phenoxymethylpolystyrene 4-K4-Nitrophenoxy)carbonyloxymethyl|phenoxymethylpolystyrene (267g, 235mMmol) was suspended in anhydrous M,M-dimethylformamide (2L). M-methylmorpholine ( 238.0 g, 2.35 mol) and piperazine (102.0 g, 1.17 mol) and the mixture was stirred at room temperature for 16 hours. The resin was filtered and washed with M,M-dimethylformamide (2 x 1 L), tetrahydrofuran (2 x 1 L), water (1 x 500 ml ), methanol (2 x 1 L), tetrahydrofuran (2 x 1 L) and methanol (1 x 1 L). Finally, the resin was washed with dichloromethane (3 x 500 ml) and dried in vacuo (252C, 36 hours) to give an almost colorless resin (240.0 g).

In a similar way, the following diamines bound to polystyrene were obtained: c 29 4-(2,5-dimethylpiperazin-1-yl)ucarbonyloxymethylIfenoxymethylpolystyrene ge) 4-(3-methylpiperazin-1-yl)ucarbonyloxymethyl|phenoxymethylpolystyrene.

Preparation of resin-bound hexafluorophosphates "-aryl-" 2-cyclopentadienylalase(II)

Hexafluorophosphate Fo 4-(4-(is-9(2-chlorophenyl)-"?-cyclopentadienylaliso(II)|piperazin-1-yl)carbonyloxymethyl)phenoxymethylpolystyrene 4-((Piperazin-1-yl)ucarbonyloxymethyl)phenoxymethylpolystyrene ( 115.1g, 9U2mmol) was suspended in anhydrous SU tetrahydrofuran (1.6l) and added hexafluorophosphate "9-1,2-dichlorobenzene-"?-cyclopentadienylsaliase(I!) with (76.0g, 144mmol) followed by the addition of potassium carbonate ( 50.9g, Zbvmmol). The reaction mixture was stirred at 602C for 16 hours. After cooling to room temperature, the resin was filtered and washed with - tetrahydrofuran (2x500ml), water (2x250ml), tetrahydrofuran (2x500ml), water (2x250ml), methanol (2x250ml), dichloromethane (2x250ml) and methanol (2x250ml). Finally, the resin was washed with dichloromethane (3x500ml) and dried under vacuum (252C, 36 hours) to give a dark orange resin (142Hg). "

In a similar way, the following complex iron compounds bound to polystyrene were obtained: 70 hexafluorophosphate 8 s 4-(4-(ε-9(2-chlorophenyl)-"2-cyclopentadienylzapizo(1I))1-2,5-dimethylpterazine-1 -yl)ucarbonyloxymethyl)phenoxymeth;" polystyrene hexafluorophosphate 4-(14-Ie 5(2-chlorophenyl)- ?-cyclopentadienyliso(1I)|-3-methylpiperazin-1-yl)/carbonyloxymethyl)phenoxymethylpolystyrene. -i Preparation of ortho(arylsulfanyl)phenylpiperazines bu (49-)-1-(2-(4-Methylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine:

Sodium hydride (7.4 mmol, 6095 in mineral oil) was carefully added to a solution of 4-methylthiophenol (1.4 g, 9.8 mmol) in a 1:1 mixture of tetrahydrofuran/dimethylformamide (5 mL) at room temperature (Caution: 50 ml separation hydrogen). The mixture was stirred for another 30 minutes after the hydrogen evolution stopped. Then hexafluorophosphate with 4-(4-Ie5(2-chlorophenyl)-"?-cyclopentadienyliso(I)|)grans-2,5-dimethylpiperazin-1-yl)carbonyloxymethyl)phenoxymethylpolystyrene (3.5g, 2.45mmol) was added ) and the mixture was stirred at 552C for 6 hours. After cooling to room temperature, the resin was filtered and washed with tetrahydrofuran (2x50ml), a mixture of tetrahydrofuran/water (1:1) (2x5O0ml), M,M-dimethylformamide (2x50ml), water (2x5Oml), methanol (3x5Oml),

HF) with tetrahydrofuran (3x5Oml) and then with methanol and tetrahydrofuran (5Oml each, 5 cycles). Finally, resin

HF was washed with dichloromethane (3x5Oml) and dried in a vacuum (252C, 12 hours), obtaining a dark orange resin.

The resin obtained in this way and a 0.5 M solution of 1,10-phenanthroline in a 3:11 pyridine/water mixture (20 ml) were placed in a transparent reaction tube. The suspension was stirred by rotation under visible light irradiation for 12 hours. The resin was filtered and washed with methanol (2x25ml), water (2x25ml) and tetrahydrofuran (3x25ml) until the washing solutions became colorless (approximately 5 cycles), and the irradiation procedure was repeated until the decomplexation of the complex was completely completed (approximately 5 cycles). After complete decomplexation, the resin was washed with dichloromethane (3x25 ml) and dried in a vacuum (252С, 12 hours), obtaining a light brown resin. 3.7 g (24 mmol) of the resin thus obtained was suspended in a 1:11 mixture of trifluoroacetic acid and dichloromethane (2 ml) and stirred at room temperature for 2.5 hours. The resin was filtered and washed with dichloromethane (5x0.5 ml). After evaporation of volatile solvents from the filtrate in a vacuum, an orange oil was obtained. The crude product was purified by preparative LC-MS and then by ion exchange chromatography.

LC/MS (t/2) 313.2 (MN); ET-2.17; purity (UV, EI 50): 87.195, 98.795; yield: 47.8 mg (690).

The following arylpiperazines were prepared in a similar manner: (4-)-1-(2-(4-isopropylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine (/-)-1-(2-(2,4-dimethylphenylsulfanyl)phenyl|trans -2,5-dimethylpiperazine (4--)-1-(2-(4-tert-butylphenylsulfanyl)phenylI|trans-2,5-dimethylpiperazine 70 (4/-)-1-(2-(4-methoxyphenylsulfanyl) phenyl|-2-methylpiperazine (4-/-)-1-(2-(4-isopropylphenylsulfanyl)phenyl|piperazine.

Preparation of intermediate compounds of formula I, where A is an insoluble polymer 4-(Chloracetoxymethyl|phenoxymethylpolystyrene)

Wang's resin (10 g, 10.0 mmol) was suspended in dichloromethane (10 mL) and cooled to 02C. 75% diisopropylethylamine (dhuml, 52 mmol) was added. Chloroacetyl chloride was slowly added. The reaction mixture was stirred at room temperature for 30 minutes and then allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 hours. The resin was filtered and washed

M,M-dimethylformamide (3x1000ml), dichloromethane (2x100ml), dimethylformamide (3x100ml), Fg4 dichloromethane (2x100ml) and dried in a vacuum (252C, 16 hours). 20 The following resin was obtained in a similar way: 4-(2-chloropropionyloxymethyl|phenoxymethylpolystyrene,

Preparation of intermediate compounds II by method c) 4--2-Bromophenoxy)biphenyl

A mixture of 2-bromophenol (2.08g, 12mmol), 4-biphenylboronic acid (4.75g, 24mmol), SSHCOAc)" (2.20, "E 259 12mmol) and triethylamine (6.1g, bOmmol) in dioxane (100ml ) were stirred for 48 hours. The crude mixture was evaporated on silica gel and purified by column chromatography eluting with a mixture of ethyl acetate/heptane, 1:9. Output: 0.7Zg (19905). "IN nNMR (SOSIZ, 5 OOMHz) 7.65 (m, 1H), 7.55 (m, 4H), 7.43 (m, 2H), 7.25-7.38 (m, 2H), 7, 00-7.08 (m, 4H); MS (t/z) 325.1. (-/-)-1-(2-(Biphenyl-4-yloxy)phenyl|-3-methylpiperazine Me. 30 Mixture 4 -(2-bromophenoxy)biphenyl (0.73g, 2.25mmol), rac-2-methylpiperazine (0.285g, 0.285mmol), Ragaraz (0.022g, Tmolorb), rac-binaphthyl (0.043g, Zmolobyu) and MaOVy! (0.300g, 3.12mmol) in anhydrous toluene (15ml) under an argon atmosphere was stirred overnight at 902C. After cooling to room temperature, the mixture was filtered and evaporated on silica gel and purified by column chromatography eluting with a mixture of 35% ethyl acetate/heptane, 1 :2. Yield: 0.264 g (34905). "IN NMR (SOSIS, 5OOMHz) 7.55 (m, 2H), 7.49 (m, 2H), 7.38 (m, 2H), chn 7.27 (m, 71Н), 7.10 (m, 71Н), 6.90-7.00 (m, 5Н), 3.30-3.35 (m, 2Н), 2.88 (m, 71Н), 2.62-2.80 (m, ЗН), 2.30-2.40 (m, 1Н), 1.60-2.00 (w, 1Н), 0.99 (d, ЗН); MS ( t/2) 3451.

Preparation of compounds of the invention

Example 1 « 20 1a Hydrochloride (-/-)-14-(2-(4-Methoxyphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylacetic acid 4-2-(4-Methoxyphenylsulfanyl)phenyl| trans-2,5-dimethylpiperazine (0.5g, 1.5mmol) and M-ethyldisopropylamine c (0.315ml, 1.vmmol) were dissolved in acetonitrile (10ml) and placed under a nitrogen atmosphere. Ethyl bromoacetate :c" (019ml, 1 .7 mmol) and the mixture was stirred at ambient temperature for 16 hours. A small amount of silica gel was then added to the mixture and the solvent was evaporated in vacuo. The product absorbed on 45 silica gel was loaded onto a silicon cartridge and eluted with a mixture of dichloromethane/heptane/ethyl acetate - (60:35 :5). The ester was isolated from the corresponding fractions as a light oil (SO0Omg, 4895). The ester was then dissolved in ethanol (1Oml) and 2M Mahon (5ml) was added. The reaction mixture was stirred for 16 hours (2) at room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL). 2 M NOI (15 mL) was added and they were divided. The aqueous phase was re-extracted with ethyl acetate (2x5Oml). The combined 50 organic fractions were dried (M950), filtered and evaporated. The residue was dissolved in a small amount of dichloromethane, precipitated by adding heptane, and the solvent was removed under vacuum. Output (280mg, 10095). "N NMR

He (SOSIZ, 5BOOMHz) 0.87 (d, ЗН), 1.35 (d, ЗН), 3.04 (m, 1Н), 3.12 (m, 2Н), 3.6 (m, ЗН) , 4.11 (d, 1H), 4.31 (d, 1H), 3.81 (c, ЗН), 6.55 (d, 1H), 7.02 (d, 2H), 7.13 ( dd, 1H), 7.2 (m, 1H), 7.42 (d, 2H); LC-MS (t/2) (MH") 387.4;

KtT-2.22; (UF, EI 50) 9895, 9790; 55 and the following compounds were obtained in a similar way: (-/-)-14-(2-(4-chlorophenylsulfanyl)phenyl|trans-2,5-dimethylpiperazin-1-ylacetic acid hydrochloride o "YAN NMR (SOSIZ, 500 MHz) 0, 80 (d, ЗН), 1.28 (d, ЗН), 2.92-3.18 (m, ЗН), 3.64 (m, ЗН), 4.06 (d, 1Н), 4.29 ko (d, 1H), 6.78 (d, 1H), 7.12 (t, 1H), 7.26 (m, 2H), 7.50 (m, 4H); LC-MS (t/2 ) (MH") 391.2; CT-2.43; (UV, EI 50) 9996, 9995; yield 42Omg. 60 1s hydrochloride (1-)-44-(2-(4-tert-butylphenylsulfanyl)phenyl| trans-2,5-dimethylpiperazine-1-ylacetic acid "YAN NMR (SOSIS, 50O0MHz) 0.76 (d, ЗН), 1.01 (d, ЗН), 1.30 (с, 9Н), 2.4 -2.6 (m, 2H), 2.9-3.0 (m, ЗН), 3.28 (m, 7H), 3.32 (d, 1), 3.48 (d, 1H), 6.65 (d, 71Н), 7.01 (t, 71Н), 7.13 (t, 1), 7.24 (d, 1Н), 7.39 (d, 2Н), 7.47 (d . 14-(2-(4-fluorophenylsulfanyl)phenyl|trans-2,5-dimethylpiperazin-1-yl)ioacetic acid

TN NMR (SOSIZ, 500MHz) 0.80 (d, ЗН), 1.25 (d, ЗН), 2.8-3.0 (m, 2Н), 3.08 (m, 1Н), 3.4 -3.6 (m, ЗН), 3.87 (d, 1), 4.06 (d, 1H), 6.64 (d, 1), 7.07 (m, 1), 7.20 ( m, 1H), 7.26 (m, 1H), 7.32 (dd, 2H), 7.54 (dd, 2H);

LC-MS (t/g2) (MhG); VT-2.24; (UF, EI 80) 9596, 9996; yield: 180 mg. 1e hydrochloride (-/-)-14-(2-(4-tert-butylphenylsulfanyl)phenyl|-2-methylpiperazine-1-ylacetic acid

LC-MS (ti/l) 399.2 (MH"); ET-2.54; purity (UV, EI 50) 10095, 10096; yield: 10.4 mg. 17 hydrochloride (7/-)-14-( 2-(4-isopropylphenylsulfanyl)phenyl|-2-methylpiperazine-1-ylacetic acid

LC-MS (ti/g) 385.1 (MH"); ET-2.45; purity (UV, EI 50) 8895, 10095; yield: 11 mg. 19 hydrochloride 10. (n)-2-14-( 2-(4-tert-butylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ilyupropionic acid

LC-MS (ti/g) 427.0 (MH"); ET-2.76; purity (UV, EI 50) 8695, 9895; yield: 27 Mmg. 11 hydrochloride 44-(5-chloro-2-(4 -methoxyphenylsulfanyl)phenyl|-2(K)-methylpiperazin-1-yl)ioacetic acid "IN NMR (DMSO, 500 MHz) 1.40 (d, 3H), 3.16 (m, 1H), 3.25-3 .48 (m, 4H), 3.63 (m, 1H), 3.75 (m, 1H), 3.80 (s,

ЗН), 4.15 (d, 1H), 4.30 (d, 1H), 6.55 (d, 1H), 7.02 (d, 2H), 7.13 (dd, 1H), 7, 2 (m, 1H), 7.42 (d2H) t LC-MS (ti/zg) 407.3 (MH"); ET-2.79; purity (UV, EI 50) 9595, 10095; yield: 225mg 1i 44-(2-(4-methoxyphenylsulfanyl)phenyl|-2(K),5(5)-dimethylpiperazine-1-ylacetic acid hydrochloride

TN nMR (DMSO-y6, 500 MHz) 0.85 (d, 3H), 1.30 (d, 3H), 2.95 (t, 71H), 3.05 (m, 2H), 3.53 (d , 1H), 3.60-3.65 (m, 2H), 3.80 (m, ЗН), 3.92 (d, 1H), 4.10 (d, 1H), 6.55 (d, 1H), 7.02 (d, 2H), 7.13 (dd, 1H), 7.2 20 (m, 1H), 7.42 (d, 2H)

LC-MS (ti/g) 387.3 (MH"); KET-2.22; purity (UV, EI 50) 9795, 96.995; yield: b607mg. 1) hydrochloride 44-(5-Chloro-2-( 4-methoxyphenylsulfanyl)phenyl|-2,2-dimethylpiperazine-1-ylacetic acid

TN NMR (DMSO-iv, 500MHz) 1.58 (s, 6H), 3.20 (s, 2H), 3.20-3.60 (sh. m, 4H), 3.80 (s, ЗН) , 3.92 (d, 1H), 4.10 (d, 1H), 6.55 (d, 1H), 6.90 (dd, 1H), 6.96 (d, 2H), 7.13 ( s, 1H), 7.40 (d, 2H) s 25 LC-MS (ti/g) 421.1 (MH"); CT-2.41; purity (UV, EI 50) 9695, 9895; yield: 1.18 mg (5) 1K 44-(5-Chloro-2-(4-fluoromethylphenylsulfanyl)phenyl|-2-methylpiperazin-1-yl)ioacetic acid hydrochloride

LC-MS (ti/g) 445.1 (MH"); ET-2.50; purity (UV, EI 50): 8895, 7290; yield: 20 mg; 11! hydrochloride 44-(5-chloro-2- (3-methoxyphenylsulfanyl)phenyl)|-2(K)-methylpiperazine-1-ylacetic acid

TN NMR (DMSO-av, 500 MHz) 1.32 (d, ZN), 3.05 (m, 1H), 3.10-3.40 (m, 4H), 3.50-3.60 (m, 2H), 4.10 (d, b» 30 AN), 4.24 (d, 1H), 6.82 (d, 1H), 6.95 (m, ЗН), 7.11 (dd, 1H) , 7.2 (c, 1H), 7.38 (dd, 1H) y

LC-MS (ti/g) 407.2 (MH"); KET-2.41; purity (UV, EI 50) 99.695, 10095; yield: 1.26g. 1t hydrochloride 14-I(I2-biphenyl-4 -yloxy)phenyl|-2-methylpiperazine-1-ylacetic acid p

TN nMR (DMSO-iv, 500MHz) 7.60 (m, 4H), 7.40 (m, 2H), 7.32 (m, 1H), 6.95-7.20 (m, 6H), 5 ,00-6,50 (w, "0 1H), 4,00-4,10 (m, 1H), 3,80-3,90 (m, 1H), 3,20-3,50 (m, 6H), 3.05-3.15 (m, 1H), 1.17 (m, ЗН) 35 LC-MS (t/2) 403.0; CT-2.45; purity: (UV, EI 50) 96,790, 99490; output: 0.116g (43906). -

Example 2 2a Hydrochloride of (1/-)-14-I(2-(4-methylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylacetic acid

A solution of (2-(4-methylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine (1mg, 0.00 mmol) and diisopropylethylamine (0.02 mL, 0.11 mmol) was added to 4-(chloroacetoxymethyl|phenoxymethylpolystyrene (100 mg, with

O.09 mmol). The reaction mixture was stirred by shaking overnight at 70 °C. The resin was filtered and washed with M,M-dimethylformamide (4ml), methanol (4ml) and dichloromethane (4ml). The resin was suspended in a 1:11 mixture of trifluoroacetic acid and dichloromethane (1.5 ml) and shaken at room temperature for 1 hour. The resin was filtered and washed with dichloromethane (ml). Organic extracts were collected and evaporated under vacuum. The crude product was purified by preparative LC-MS. -I LC-MS (ti/zg) 371.1 (MN"); ET-2.24; purity (UV, EI 50) 10095, 10095; yield: 1.bmg.

The following compounds were obtained in a similar way: me) 26 hydrochloride (-/-)-14-12-(4-isopropylphenylsulfanyl)phenyl)|)trans-2,5-dimethylpiperazine-1-ylacetic acid ka LC-MS (ti/g) 399.0 (MH"); CT-2.48; purity (UV, EI 50) 98.395, 10095; yield: 2.2mg; sl 50 islst hydrochloride (17-)-14-(2--2,4- dimethylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazin-1-yl)acetate (Che) LC-MS (ti/l) 385.0 (MH"); ET-2.37; purity (UV, EI 50) 99.8965, 10095; yield: 4.7 mg; 24 (h/-)-2-14-(2-(4-tert-butylphenylsulfanyl)phenyl|-3-methylpiperazine-1-ylylpropionic acid hydrochloride

LC-MS (ti/g) 386.7 (MH"); KET-2.14; purity (UV, EI 50) 91.995, 99.295; yield: 3.2 mgH; 2e hydrochloride (/-)-14-(2 -(4-isopropylphenylsulfanyl)phenyl|piperazin-1-yl)ioacetic acid

GF! LC-MS (ti/g) 370.8 (MH"); ET-2.35; purity (UV, EI 50) 89.095, 99.996; yield: 3.2 MmgH; 21 hydrochloride (4-/-)-2- 4--2--4-methoxyphenylsulfanyl)phenyl|-3-methylpiperazine-1-ylpropionic acid di LC-MS (ti/g) 386.7 (MH"); KET-2.63; purity (UV, EI 50) 91.995, 99.295; yield: 3.2 mg.

Pharmacological testing The compounds of the present invention were tested according to a well-known and reliable glycine uptake quantification test.

Capture |ZNI-Glycine

Cells transfected with human SIUT-16 were plated in 9b-well plates. Before the experiment, the cells were washed twice with HB5 (10mM Nerez-Tris (pH 7.4), 2.5mM KSI, 1mM Sasi», 2.5mM Mo50O,) and pre-incubated b5 with the tested compound for b minutes. Then, 10 mM ZN-glycine was added to each well and the incubation was continued for 15 minutes. Cells were washed twice with HB5. Scintillation liquid was added and the tablets were counted on a Tikh scintillation counter (UmaiIas).

The results of the test showed that all the compounds of the invention showed inhibition below 2000 ОНМ as IS about. In the above analysis. Most of the compounds were in a concentration from 150 NM to 850 NM.

Experiments on microdialysis in rodents showed that the introduction of selected compounds of the invention led to an increased concentration of glycine in the brain. In addition, in a rodent model of psychosis, selected compounds of the invention eliminated symptoms of amphetamine-induced hyperactivity.

Claims (18)

The formula of the invention 1. Compounds of the general formula I (О, ВЗ Р я коник и (Ех НЕ ШХИ (а ) where У is M, C or CH; X is O or 5; т is 1 or 2; с 29 р is 0, 1, 2, C or 4; Ge) d represents 0, 1 or 2; c represents 0, 1, 2 or 3; r represents 0, 1 or 2; 20 O represents C, P-OBE ? or 5-0, where B? is hydrogen or C 1-6 alkyl; FA is OB 9, where BZ is hydrogen, C 1-62-alkyl, aryl or aryl-C 6-alkyl, where aryl can be C) substituted by halogen, CE3, OSE3, CM, MO" or C1-6-alkyl; C1-6 alkyl is phenyl or heteroaryl; each B" individually is C1-6-alkyl, C3-6-cycloalkyl or C3-6 -cycloalkyl-C 4 in-alkyl; x, dashed line represents an optional bond; h- each B is independently selected from the group consisting of C ..in 6-alkyl, or two B attached to the same of the same carbon atom, can form a 3-6-ene spiro-adjoined cycloalkyl; each BK? is independently selected from the group consisting of halogen, cyano, nitro, C 4.v-alk(en/yn)yl, " C. d-aluk(en/yn)yloxy, C. v-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C-v-aluk(en/yn)yl, halogen-C; v-alk(en/yn)yl, halogen-C. v-alkK(en/yn)yloxy, Cz d-cycloalk(en)yl, Cz v-cycloalk(en)yl-C 4 v-alk(en/yn)yl, acyl, t c C. v-alk( en/yn)yloxycarbonyl, Si. β-aluk(en/yn)ylsulfonyl or -MAUV"O, where VZ and KO independently represent "z hydrogen, C.v-aluk(en/yn)yl, Cz β-cycloalk(en)yl, Са in- cycloalk(en)yl-C 4 in-alu(en/yn)yl or aryl, or KU and KO together form a 3-7-membered ring, which optionally contains one more heteroatom; each KZ, by which AK is replaced, is independently selected from the group consisting of halogen, cyano, nitro, - 15 S. d-alyu(en/n)lu, Si v-alyu(en/n)yloxy, S. v- alkene/yn)ylsulfanyl, hydroxy, hydroxy-C4 v-alk(en/yn)yl, halogen-C.4 v-alk(en/yn)yl, halogen-C. β-alu(en/yn)yloxy, Cz d-cycloalk(en)yl, (22) Cz b-cycloalk(en)yl-C 4 6b-alk(en/yn)yl, Si b-alk(en/ Iin)ylsulfonyl, aryl, aryl-C. v-alk(en/yn)yloxy, d) aryl-C. v-alk(en/yn)yl, Si v-aluk(en/yn)yloxycarbonyl, acyl, -MNSO-C. v-alk(en/yn)yl, -"SOME "B", where KE" and 5o B independently represent hydrogen, (Fi. 1---alkK(en/yn)yl, Cz vd-cycloalk(en) sil, p C. β-cycloalk(en)yl-C, "-aluk(en/yn)yl or aryl, or B" together with the nitrogen to which they are attached form Me, a 3-7-ene ring, which optionally contains one more heteroatom; or ME'ZV"", where KZ and BC"? independently represent hydrogen, С 4 в-aluk(en/yn)yl, Са в-cycloaluk(en)yl, ря C. в-cycloalk(en)yl-С 4 в-aluk(en/yn)yl or aryl ; or ZB", together with the nitrogen to which they are attached, form a 3-7 membered ring, which optionally contains one more heteroatom; or two adjacent B C substituents together (F) form a ring condensed with the AK ring, selected from the group consisting of co udo y y - on Sh 1 1 zh b5 "E and E" | E where MU represents O or 5, and K' and K" represent hydrogen or C. v-alkyl; or two adjacent KZ substituents together form a heteroaryl containing one or two heteroatoms condensed with AK; or their acid addition salts. 2. Compound according to claim 1, where M is M. 3. A compound according to any of the above items, where X is 5. 4. A compound according to any of the above-mentioned points, where СО) represents С. 5. A compound according to any of the above items, where A is OH. 19 6. A compound according to any of the above items, where p is 1 or 2. 7. A compound according to any of the above-mentioned items, where t is 1. 8. A compound according to any of the above items, where d is 0. 9. A compound according to any of the above items, where r is 0 or 1. 10. A compound according to any of the above items, where z is 1 or 2. 11. A compound according to any of the above items, wherein AK is phenyl, thiophene, pyridyl, pyrimidyl, thiazolyl, imidazolyl or benzothiazolyl. 12. A compound according to any one of claims 1 - 11, where AK is phenyl, g and d are both 0, p is 1 or 2, c is 1 or 2, r is 0 or 1, t is 1, BC! represents СНа, A represents ОН, O represents C, Y represents M, and X represents 5. с » 13. The compound according to claim 12, where KZ is independently selected from halogen, C. v-alkyl or C. v-alkyl. at 14. Compound according to claim 13, where is VE? selected from the group consisting of SI, E, OSH z, tert-butyl, 2-propyl or methyl. 15. A compound according to any of the previous clauses, where KE represents SN." Gee! 16. The compound according to claim 1, where the indicated compound is: (17-)-14-(2--4-methoxyphenylsulfanyl)phenyl|)trans-2,5-dimethylpiperazine-1-ylacetic acid; o (17-)-14-(2-(4-chlorophenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ilioacetic acid; Ge (1-)-44-(2-(4-tert-butylphenylsulfanyl)phenyl )trans-2,5-dimethylpiperazine-1-ylacetic acid; (17-)-14-(2-(4-fluorophenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylylacetic acid; o (1-)- 44-(2-(4-tert-butylphenylsulfanyl)phenyl)|-2-methylpiperazine-1-ylacetic acid; - (1/-)-14-(2-(4-iso-propylphenylsulfanyl)phenyl|-2-methylpiperazine -1-yl)acetic acid; (3-/-)-2-14-(2-(4-tert-butylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylpropionic acid; 14-(5-chloro -2-(4-methoxyphenylsulfanyl)phenyl|-2(K)-methylpiperazine-1-ylacetic acid; "14-(2-(4-methoxyphenylsulfanyl)phenyl|-2(K),5(5)-dimethylpiperazine-1 -yl acetic acid; 4-fluoromethylphenylsulfanyl)phenyl|-2-methylpiperazine-1-ylacetic acid; 14-(5-chloro-2-(3-methoxyphenylsulfanyl)phenyl|-2(K)-methylpiperazine-1-ylacetic acid; "" ( 1 -)-14-(2-(4-phenylphenyloxy)phenyl|-2-methylpiperazine-1-acetic acid; (17-)-44-(2--4-methylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-acetic acid; (1-)-14-(2-(4-isopropylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazin-1-yl)acetic acid; -And (17-)-14-(2-(-2,4-dimethylphenylsulfanyl)phenyl|trans-2,5-dimethylpiperazine-1-ylacetic acid; (1--)-2-14-(2-(4 -tert-butylphenylsulfanyl)phenyl|-3-methylpiperazin-1-yl)propionic acid; b t14-(2-(4-isopropylphenylsulfanyl)phenyl|-piperazine-1-yl)ic acid; ko (4-)-2-4A4- 12-(4-methoxyphenylsulfanyl)phenyl|-33-methylpiperazin-1-ylpropionic acid; or their pharmaceutically acceptable acid addition salts. 17. A pharmaceutical composition containing a compound according to claims 1-16 or its pharmaceutically acceptable (Che) acid addition salt and at least one pharmaceutically acceptable carrier or diluent. 18. Use of a compound according to claims 1-16 or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicinal product for the treatment of diseases selected from the group consisting of schizophrenia, including both positive and negative symptoms of schizophrenia, and other psychoses, and in improving cognitive function in conditions in which cognitive processes are reduced, i.e., Alzheimer's disease, dementia F, due to multiple heart attacks, dementia in AIDS, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases in which the brain is damaged by internal or external influences, such as head injury or stroke, and seizure disorders such as epilepsy, muscle spasticity or myoclonus. in 19. A method of treating a disease selected from the group consisting of schizophrenia, including both positive and negative symptoms of schizophrenia, and other psychoses, and in improving cognitive function in conditions in which cognitive processes are reduced, i.e., Alzheimer's disease, dementia due to multiple heart attacks, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or diseases in which the brain is damaged by internal or external influences, such as head trauma or stroke, Her seizure disorders such as epilepsy, muscle spasticity or myoclonus in a living organism of an animal, including a human, in which a therapeutically effective amount of the above-mentioned compound is administered according to paragraphs 1-16 or its pharmaceutically acceptable acid addition salt. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 7, 15.07.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. with (8) (22) yu s (Se) and - shi s ;" -And (22) name) with 50 3e) F) name) 60 b5