The pyrimidine compound(options), and a pharmaceutical composition having affinity for dopamine d3 receptors

 

(57) Abstract:

The invention relates to new pyrimidine compounds or their salts with pharmaceutically acceptable acids and pharmaceutical compositions based on them. The proposed compounds are selective ligands of the dopamine D3-receptor, which regioselective intervene in the limbic system and due to low affinity for D2the receptor have fewer side effects than classical neuroleptics. The compounds may find application in the pharmaceutical industry for the treatment of diseases associated with dopamine D3-receptor antagonists, or as compounds having affinity for D3-receptors, for example, diseases such as disorders of the Central nervous system, in particular schizophrenia, depression, neurosis and psychosis, as well as for the treatment of sleep disorders and as antihistamines. The pyrimidine compounds correspond to the General structural formulas I and I' respectively. In this case B means the remains of formulas a, b and d, And means alkylene, which may include or be associated with a pyrimidine ring via O, S, NR4, CONR4, NR4CO, COO, OCO, and double or triple bond, R1, R2, R3nez is 1-4-alkyl; R4is hydrogen, C1-4-alkyl; R5matter R4; Ar denotes phenyl, pyridyl, pyrimidinyl, triazinyl, which may be substituted and condensed with Ph or 5-6-membered nonaromatic carbocyclic ring, possibly substituted C1-4-alkyl. Pharmaceutical composition having affinity for D3the receptor includes an active substance-pyrimidine compound of the formula I and physiologically acceptable diluent and/or excipient. 3 S. and 18 C.p. f-crystals, 10 PL.

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or

The treatment of these and other disorders is drugs that interact with dopamine receptors.

By 1990 pharmacologically were distinctly recognized two subclass of dopamine receptors, namely D1and D2- receptors.

Sokolov and others, Nature, 1990, 347: 146-151, found the third subclass, namely D3- receptors. Basically they are expressed in the limbic system, D3receptors differ structurally from the D1and D2receptors approximately half of the amino acid residues.

The effect of neuroleptics usually attributed to their affinity for D2- receptors. This podgy as neuroleptics, have high affinity for D2- receptors, but only low affinity to the D3- receptors.

DE-A 19 46 172 describes heterocyclic ethers of the formula

,

where R1denotes single, unsaturated, nitrogen-containing heterocyclic system which may be substituted by lower alkyl, lower alkoxy, phenylalkyl or phenyl,

R2denotes phenyl which is not substituted or is substituted by lower alkyl or lower alkoxy or chlorine atoms or bromine and which may contain 1 or 2 nitrogen atom in the cycle, and A denotes a linear or branched alkylene with 2-6 carbon atoms. These compounds possess - sympatholytic activity and thus have a sedative, hypotensive and vasodilator effects.

It has been unexpectedly found that certain pyrimidine compounds have high affinity for dopamine D3-receptor and low affinity for D2the receptor. Thus, they are selective D3-ligands.

This invention relates to the use of pyrimidine compounds of General formula I:

,

where A represents C1-C18-alkylene, which may include at least one

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or

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R1, R2, R3chosen independently from one another from H, halogen, OR4, NR4R5, SR4, CF3CN, CO2R4and C1-8-alkyl not substituted or is substituted by OH, OC1-C8-alkyl or halogen;

R4denotes H, C1-C8-alkyl, unsubstituted or substituted by OH, OC1-C8-alkyl or halogen;

R5has the meanings given for R4or denotes COR4or CO2R4;

Ar denotes phenyl, pyridyl, pyrimidyl or triazinyl, where Ar can have from one to four substituents which are selected, independently from each other, OR5C1-C8- alkyl, C2-C6-alkenyl, C2-C6-quinil, halogen, CN, CO2R4, NO2, SO2R4, SO3R4, NR4R5, SO2NR4R5, SR4, CF3, CHF2a 5 - or 6-membered aromatic or nonaromatic of carbocycle and 5 - or 6-membered aromatic or non-aromatic heterocycle with 1 to 3 heteroatoms, which are selected from O, S and N, where the cycle can be unsubstituted or substituted C1-C8-alkyl, Hal, OC1-C3-alkyl, OH, NO2, CF3and physiologically acceptable acid to obtain a pharmaceutical composition for the treatment of diseases, associated with the dopamine D3-receptor antagonists or substances with affinity for D3-receptors.

The invention also relates to pyrimidine compounds of formula I':

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where A, B, Ar, R1, R2and R3have the meanings given in PP 1-8, and their salts with physiologically acceptable acids, excluding the compounds of formula

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where R1represents OH or SH, R2and R3denote, independently of one another, H, C1-C6-alkyl, OC1-C6-alkyl, SC1-C6-alkyl, CO2H, OH, SH, NR4R5or halogen, where R4and R5denote H or C1-C6-alkyl, A denotes SC1-C6-alkylen, NHC1-C6-alkylene or N(C1-C6-alkyl)-C1-C6-alkylen, B denotes --N N--, and Ar denotes phenyl, having one or more substituents, which are selected from C1-C4-alkyl, OC1-C4-alkyl, SC1-C4-alkyl, NO2, CF3, F, Cl or Br.

Used according to this invention, the compounds are selective ligands of the dopamine D3-receptor, which regioselective intervene in the limbic system and because of their low affinity for D2the receptor field is s for the treatment of diseases, associated with the dopamine D3-receptor antagonists or substances with affinity for D3-receptors, for example, for the treatment of Central nervous system disorders, in particular schizophrenia, depression, neurosis and psychosis. In addition, they can be used to treat sleep disorders and as antihistamines.

Within the scope of this invention and the claims, the following terms have the following meanings:

Alkyl (also in radicals, such as alkoxy, alkylamino and so on) denotes a linear or branched alkyl group with 1-8 carbon atoms, preferably 1-6 carbon atoms, especially with 1-4 carbon atoms. The alkyl group may have one or more substituents, which are selected independently of one another from OH and OC1-C8-alkyl.

Examples of alkyl groups are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

Alkylene denotes linear or branched radicals, preferably with 2-15 carbon atoms, particularly preferably 3-10 carbon atoms.

Alkylene group can include at least one of the aforementioned groups. It may be same to the chain with a pyrimidine residue. The latter is preferable. When Allenova circuit includes a double or triple bond, it contains at least three carbon atoms in the chain.

Halogens are F, Cl, Br, and I, in particular Cl, Br, I.

R1, R2and R3represent, preferably, independently of one another, H, C1-C8-alkyl, NR4R5, SR4or or4where and R5independently from each other, represent H or C1-C8-alkyl.

Ar preferably has one or two substituent, which is selected independently of one another from the group consisting of OR5C1-C8-alkyl, Hal, CN, CO2R4, NO2, SO2R4, SO3R4, NR4R5, SO2NR4R5, SR4, CF3, CHF2a 5 - or 6-membered aromatic or 6-membered aromatic or nonaromatic a heterocycle with 1-3 heteroatoms, which are selected from O, S and N, where the cycle can not be replaced or substituted C1-C8-alkyl, Hal, OC1-C8-alkyl, OH, NO2, CF3and where Ar can also be condensed to carbocycle or heterocycle of the type specified above.

If Ar has one or two deputies, they are preferably in the m-position.

, CHF2, CN, NO2, OR4, NR4R5C1-C8-alkyl, OC1-C8-alkyl, phenyl and SR4where R4and R5denote H or C1-C8-alkyl. If one of the substituents represents C1-C8is alkyl, the preferred branched group, in particular isopropyl or tert-butyl.

Ar preferably has at least one Deputy and denotes, in particular:

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where D1D2and D3represent, independently from each other, CR or N, and R, X and Y represent H or are above or below the value.

Ar preferably denotes unsubstituted or substituted phenyl, 2-, 3 - or 4-pyridinyl or 2-, 4(6) or 5-pyrimidinyl.

When one of the substituents of the radical Ar represents 5 - or 6-membered heterocycle, examples of such cycles are pyrrolidine, piperidine, morpholine, piperazine, pyridine, 1,4-dichloropyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazol, pyrazole or thiadiazole.

When one of the substituents of the radical Ar represents carbocyclic radical, in particular a phenyl, cyclopentyl or cyclohexyl.

When Ar represents a condensed carbocyclic is - or tetrahydroquinolin, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole or benzotriazol.

The preferred embodiment includes the use of compounds of formula I, where A represents C1-C10-alkylene, which may contain at least one group which is selected from O, S, NR3, cyclohexene and double or triple bond.

Especially preferred compounds of formula I are those compounds in which A represents C3-C10-alkylene, which may include at least one group selected from O, S, NR4and double or triple bond.

Another preferred embodiment includes the use of compounds of formula I, where R1, R2and R3denote, independently of one another, H, C1-C8-alkyl, which may be replaced by OH, OC1-C8-alkyl or halogen, or OH, OC1-C8-alkyl, SR4or NR4R5where R4and R5, independently of one another, denote H or C1-C8-alkyl;

Ar denotes phenyl, pyridyl or pyrimidyl, which may have one, two, three or four deputies, chosen from H, C1-C8-alkyl which may be substituted by OH, OC1 is to be replaced by OH, OC1-C8-alkyl or halogen, or CHF2, CF3CN, halogen, C2-C6-alkenyl, C2-C6-quinil, C5-C6-cycloalkyl, phenyl, naphthyl and 5 - or 6-membered heterocyclic aromatic radical with 1 to 3 heteroatoms, which are selected from O, N and s

Another preferred embodiment includes the use of compounds of formula I, where In denotes

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or

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Another preferred embodiment is the use of compounds of formula I where Ar denotes phenyl, having one to four substituents which are selected, independently from each other, from H, C1-C8-alkyl which may be substituted by OH, OC1-C8- alkyl or halogen, or phenyl, naphthyl, pyrrolyl, CN, NO2, CF3, CHF2, halogen, SO2R4or SR4where R4denotes H or C1-C8-alkyl, or where the substituents chosen independently from each other from C1-C8-alkyl, phenyl, CF3, CHF2, CN, NO2, halogen, OC1-C8-alkyl or SR4where R4denotes H or C1-C8-alkyl.

Another preferred embodiment is the use of compounds of formula I, where R14, SR4or NR4R5where R4and R5, independently of one another, denote H or C1-C8-alkyl; R2denotes H, OR4or C1-C8-alkyl and R3denotes H.

Another preferred embodiment includes the use of compounds of formula I where Ar denotes pyrimidinyl with 1-3 substituents, which are selected independently of one another from H, C1-C8-alkyl, phenyl, naphthyl, C5-C6-cycloalkyl, OH, OC1-C8-alkyl, halogen, CN, NO2, CF3, CHF2and 5 - or 6-membered heterocyclic aromatic or non-aromatic radical with 1 to 3 heteroatoms, which are selected from O, N and s

Another preferred embodiment is the use of compounds of formula I where Ar represents pyridinyl with 1-4 substituents, which are selected independently of one another from H, C1-C8-alkyl, phenyl, naphthyl, OH, OC1-C8-alkyl, halogen, CF3CN, C2-C6-alkenyl, C2-C6-quinil and 5 - or 6-membered heterocyclic aromatic radical with 1 to 3 heteroatoms, which are selected from O, N and s

The invention also includes salts of acidic joining connection of the organic and inorganic acids are hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids that may be used is described in Fortschritte der Arznei-mittelforschung. Volume 10, pages 224 and subsequent., Birkhauser Verlag, Basle and Stuttgart, 1966.

The compounds of formula I [sic] can have one or more centers of asymmetry. Therefore, the invention includes not only the racemates, but also the corresponding enantiomers and diastereoisomers. The invention also includes in each case tautomeric forms.

The compounds of formula I' can be obtained by methods similar to the conventional methods described, for example, in A. R. Katritzky, C. W. Rees (ed.), "Comprehensive Heterocyclic Chemistry", lst Edition, Pergamon Press 1984, in particular, Vol. 3, Part 2A; D. J. Brown, "The Pyrimidines", in "The Chemistry of Heterocyclic Compounds", E. G. Taylor (ed.), John Wiley & Sons Inc. NY in particular. Vol. 16 + Suppl.I + II (1985) and Vol. 52 (1994) and are listed here as references to the literature. The method of obtaining compounds include:

i) the interaction of the compounds of General formula II:

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where Y1denotes the standard tsepliaeva group, with a compound of General formula III:

H--Q--Ar;

ii) to obtain the compounds of formula I', where the e, Z1denotes O, S or NR4and A1represents C0-C18alkylen, with the compound of General formula VI:

Y1--A2--B--Ar,

where Y1have the above values, and A2represents C1-C18-alkylene, where A1and A2together contain from 1 to 18 carbon atoms;

iii) to obtain the compounds of formula I', where A includes a group COO, or CONR4:

the interaction of compounds of General formula VII:

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or salts thereof, where Y2denotes OH, OC1-C4-alkyl, Cl or together with CO denotes the activated ester group, and A1have the above meanings, with a compound of formula VIII:

Z1--A2--B-Ar,

where A2have the above values, a Z1denotes OH or other4;

iv) to obtain the compounds of formula I', where A group includes OCO or NR4CO:

the interaction of the compounds of formula IV:

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where Z1represents O or NR4with a compound of formula X:

Y2CO--A2--B--Ar,

where A2, And Y2have the above significance, and R1, R2, R3A, b and Ar have the above values.

Described herein reactions usually occur in solvent p is s can be used, include ethyl acetate, tetrahydrofuran, dimethylformamide, dimethoxyethane, toluene, xylene or a ketone, such as acetone or methyl ethyl ketone.

If necessary there is an acid acceptor. Suitable acid acceptors include inorganic bases such as sodium carbonate or potassium, sodium methylate, sodium ethylate, sodium hydride, or organic bases such as triethylamine or pyridine. The latter can also serve as a solvent.

The crude product emit a standard way, for example, filtering, removing the solvent by distillation or by extraction from the reaction mixture and so on, the compound Obtained can be purified by standard means, for example, by recrystallization from a solvent, by chromatography or by conversion into the acid compound of accession.

Salt acid accession receive a conventional manner by mixing the free base with a suitable acid may, in solution in an organic solvent, e.g. a lower alcohol such as methanol, ethanol or propanol, in a simple ester, such as methyl tributyl ether, ketone, such as acetone or methyl ethyl ketone, or a complex ester, such as ethyl acetate.AMI.

For the treatment of the aforementioned disorders, compounds according to this invention is administered accepted way pills or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). It is also possible introduction with pairs or by spraying through the nasopharynx.

The dose depends on age, condition and weight of the patient and the route of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per day for the pills introduction and from about 1 to 500 mg per day for parenteral administration.

The invention relates also to pharmaceutical compositions containing compounds according to this invention. These compositions are normally in the solid or liquid pharmaceutical medicinal forms, such as tablets, film-coated tablets, capsules, powders, granules, coated with sugar pills, suppositories, solutions or fused forms. In these cases, the active compounds can be processed with conventional pharmaceutical additives, such as binders, fillers, preservatives, dezintegriruetsja agents, flow regulators, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, age). Received by such dosage forms contain from 1 to 99% by weight of active compound.

The following examples serve to illustrate the invention but do not restrict it.

EXAMPLE 1

4- [3-(4-{3-Triptoreline}piperazinil)propylthio]pyrimidine

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a) 1-(3-Chlorophenyl)-4-(3-triptoreline)piperazine

30 g (0.13 mol) of m-triftormetilfullerenov, 23 g (0.146 mol) of 1-bromo-3-chloropropane and 15 g (0.148 mol) of triethylamine in 200 ml of THF is refluxed for 4 hours. Cooled, followed by filtration with suction and concentrated. The viscous residue is dissolved in ethyl acetate, washed with water, dried over MgSO4and then concentrate. The residue contains 39 g of product as yellow oil (quantitative yield).

b) 4-[3-(4-(3-triptoreline-piperazinil)propylthio]- pyrimidine

1.5 g (13.4 mmol) of 4-mercaptopyrimidine, 4.3 g (14 mmol) of 1- (3-chloropropyl)-4-(3-triptoreline)piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF was stirred at 100oC for 1 hour. The mixture is then poured into 5% hydrochloric acid and extracted with MTB (tert. butyl) simple ether. The aqueous phase is alkalinized with sodium hydroxide solution and then extracted with ethylacetate: CH2Cl2/CH3OH = 98/2). Obtain 3.0 g of the product as a yellowish oil (= 59% yield).

PMR [ M. D.]: 1.95 (2H); 2.55 (2H); 2.65 (4H); 3.25 (6H); 7.06 (3H); 7.15 (1H); 7.35 (1H); 8.33 (1H); 8.9 (1H).

EXAMPLE 2

2-[5-(4-{3-Triptoreline}piperazinil)Intermarket] -pyrimidine

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a) 2-(5-Chlorphentermine)pyrimidine

2.8 g (25 mmol) of 2-mercaptopyrimidine, 4.64 g (25 mmol) of 1 - bromo-5-chloropentane and 2.58 g (25.5 mmol) of triethylamine in 100 ml of THF is refluxed for 4 hours. After cooling, filtration with suction and concentration the residue is cleaned chromatography (mobile phase: cyclohexane/ethyl acetate = 92/8). Obtain 2.8 g of product (= 52% yield).

b) 2-[5-(4-{3-Triptoreline}piperazinil)Intermarket] pyrimidine

2.8 g (12.9 mmol) of 2-(5-chlorphentermine) pyrimidine, 3.27 g (14.2 mmol) of m-triftormetilfullerenov and 1.44 g (14.2 mmol) of triethylamine in 5 ml of DMF was stirred at 90oC for 1 hour. The mixture is then poured into water and extracted three times CH2Cl2and the extracts dried over MgSO4and concentrate. The residue is mixed with tert-butyl methyl ether and filtered off with suction and the mother liquor concentrate. Purification by chromatography (mobile phase: CH2CI2/CH3OH = 97/3) leads to 4.07.33 (1H); 8.5 (1H).

The compounds listed in table 1 below are obtained in a similar way.

The compounds listed in tables 2-6 below, can be obtained in a similar way.

EXAMPLES OF PHARMACEUTICAL FORMS

A) Tablets

Tablets of the following composition is pressed into teletrauma car the conventional way:

40 mg of the substance from example 1

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg of Aerosil (Aerosil ) (chemically pure silicon dioxide in submicron thin dispersion)

6.75 mg of potato starch (pasta 6% concentration)

B) Tablets with sugar coating

20 mg of the compound from example 4

60 mg of the composition engine

70 mg of the composition of the sugar coating

The composition of the core consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinyl pyrrolidone/vinyl acetate 60:40 copolymer. The composition of the sugar coating comprises 5 parts of sucrose, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. Thus obtained is covered with a sugar pill supply subsequently intersolubility shell.

BIOLOGICAL RESEARCH - the study of RECEPTOR Sviazivalisi D3the receptor receives from Res. Biochemicals Internat. To study the binding use appropriate fibroblast Strathmore Rd., Natick, MA 01760-2418 USA.

Preparation of cells

D3-expressing cells are grown in RPMI-1640 containing 10% serum fetal cow (GIBCO N 041-32400N); 100 IU/ml penicillin and 0.2%-streptomycin (GIBCO, BRL, Gaithersburg, MD, USA). After 48 hours the cells are washed with PBS (phosphate-saline buffer solution) and incubated with 0.05% trypansomiasis PBS for 5 minutes. Then Wednesday will be neutralized and the cells collected by centrifugation at 300 rpm For lizirovania cells precipitate after centrifugation washed briefly lytic buffer (5 mm Tris-HCl, pH 7.4, 10% glycerol) and then incubated at a concentration of lytic buffer 107cells/ml at 4oC for 30 minutes, the Cells are centrifuged at 200 rpm for 10 min and the precipitate after centrifugation stored in liquid nitrogen.

Test binding

To test for D3receptor binding membrane suspended in incubation buffer (50 mm Tris-HCl, pH 7.4, 120 mm NaCI, 5 mm KCl, 2 mm CaCl2, 2 mm MgCl210 µm quinoline, 0.1% ascorbic acid and 0.1% BSA (bovine serum albumin) at a concentration of approximately 106cells/250 μl ispy is th connection. Nonspecific binding is measured using a 10-6M spiperone.

After 60 min of free and bound radioligand separated by filtration through GF/B through the filters glass fiber (Whatman, England) on the collection of cells Skatron'a (Skatron, Lier, Norway) and the filters washed with ice Tris-HCl-buffer, pH 7.4. Collected on filters and radioactivity measured using a liquid scintillation counter Packard'a 2200 CA.

Values of Kidetermined by analysis by the method of nonlinear regression, using the LIGAND program.

2) Test for D2-binding

Preparation of membranes

a) Caudatus nuclei (bullish)

Caudatus nuclei isolated from the brain of a bull and washed with cooled ice 0.32 M sucrose solution. After weighing the material is ground to powder and homogenized in 5-10 volumes of sucrose solution using a homogenizer (Potter - Evehjem'a [sic] (500 rpm). The homogenate was centrifuged at 3000 rpm for 15 minutes (4oC) and the obtained supernatant is again centrifuged for 15 minutes at 40,000 Rev/min Then the residue is washed twice resuspended and centrifuger with 50 mm Tris-HCl, pH 7.4. Membrane prior to use store in liquid nitrogen.

b) Striatum (rats)

Striatum Sprag in 5-10 volumes of sucrose solution, using Potter-Elvehjem-homogenizer (500 rpm). The homogenate was centrifuged at 40,000 rpm for 10 minutes (4oC) and then the residue is washed several times, resuspended and centrifuger with 50 mm Tris-HCl, 0.1 mm EDTA (ethylenediaminetetraacetic acid) and 0.01% ascorbic acid (pH 7.4). The washed residue resuspended in the above buffer and incubated at 37oC for 20 minutes (to destroy endogenous dopamine). Then the membrane is washed twice with buffer and portions frozen in liquid nitrogen. The membrane preparation is kept to a maximum of one week.

Test binding

a)3H-Spiperone (DNizk.)

Membrane nuclear caudatus dissolved in incubation buffer (in mm: Tris-HCl 50, NaCl 120, KCl 5, MgCl21, CaCl22, pH 7.4). Prepare various mixture, 1 ml of each:

The total binding of 400 μg of membranes + 0.2 nmol/l 3H - spiperone (Du Pont de Nemours NET-565).

- Non-specific binding: the same mixture that General binding + 10 μm (+)-butaclamol.

- Test the connection: the same mixture that General binding + increasing concentrations of the test compounds.

After incubation at 25oC for 60 minutes the mixture is filtered through GF/B filters from Steklovolokno 7.4. Collected on filters and radioactivity measured using a liquid scintillation counter Packard'and 2200 CA.

Values of Kidetermined by analysis by the method of nonlinear regression, using the LIGAND program, or converting IC50values, using the formula Cheng a and Prusoff'a.

b)3H-ADTN (DWas.)

Membrane striatum dissolved in incubation buffer (50 mm Tris-HCl, pH 7.4, 1 mm MnCl2and 0.1% of ascorbic acid).

Prepare different mixtures, each 1 ml.

The total binding: 300 µg wet weight + 1 nm3H-ADTN (Du Pont de Nemours, synthesis on order) + 100 nm SCH 23390 (containing D1receptors).

- Non-specific binding: the same mixture that for total binding, + 50 nm spiperone.

- Test the connection: the same mixture that General binding + increasing concentrations of the test compounds.

After incubation at 25oC for 60 minutes the mixture is filtered through GF/B filters glass fiber (Whatman, England) on the collection of cells Skatron'a (Zinsser, Frankfurt) and the filters washed with ice 50 nm Tris-HCl-buffer, pH 7.7. Collected on filters and radioactivity measured using a liquid scintillation counter Packard'and 2200 CA.

is the invention show a very good affinity and high selectivity for D3-receptor. Obtained for the presented compounds results are collected in the following table 7.

Table 8 presents data biological testing of compounds 1-5.

Table 9 shows the physico-chemical characteristics of the compounds according to examples 193-238. In this table, the left column indicates the radical, confirmed the specific example of obtaining.

Table 10 shows the selectivity of compounds.

1. The pyrimidine compound of the formula 1

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where A represents C1-C15-alkylene, which may include or may be associated with the pyrimidine ring via at least one group selected from O, S, NR4, CONR4, NR4CO, COO, OCO, and double or triple bond;

B denotes

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or

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R1, R2, R3chosen independently from one another from H, halogen, OR4, NR4R5, SR4, CF3, CO2R4and C1-C8-alkyl;

R4denotes H, C1-C8-alkyl, which is not substituted or substituted with halogen;

R5has the meanings given for R4;

Ar denotes phenyl, pyridyl, pyrimidyl or triazinyl, where Ar may have one to , the which is not substituted or substituted with halogen, C1-C8-alkyl, C2-C6alkenyl, C2-C6-quinil, halogen, CN, CO2R4, NO2,

SO2R4, NR4R5, SO2NR4R5, SR4, CF3, CHF2, Ph, 5 - or 6-membered nonaromatic carbocycle and 5 - or 6-membered aromatic or nonaromatic a heterocycle containing a nitrogen atom, where the cycle can not be replaced or substituted C1-C8-alkyl, Hal, OC1-C8-alkyl, NO2and where Ar may be condensed with a Ph or a 5 - or 6-membered nonaromatic carbocyclic ring, which ring can be substituted or not substituted OC1-C8-alkyl,

and their salts with physiologically acceptable acids, with the exception of compounds of the formula

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where R1represents OH or SH, R2and R3independently of one another denote H, C1-C6-alkyl, OC1-C6-alkyl, SC1-C6-alkyl, CO2H, OH, SH, NR4R5or halogen, where R4and R5denote H or C1-C6-alkyl, A denotes SC1-C6-alkylen;

B denotes

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Ar denotes phenyl which may have one or more substituents selected from, the except for the following compounds:

hydrochloride of 2-[2-(4-o-tolyl)-piperazine-1-yl] -ethoxy-4,6-dimethyl-pyrimidine;

hydrochloride of 2-[2-(4-m-tolyl)-piperazine-1-yl] -ethoxy-4,6-dimethylpyrimidine;

hydrochloride of 2-[2-(4-p-tolyl)-piperazine-1-yl] -ethoxy-4,6-dimethylpyrimidine;

hydrochloride of 2-[2-(4-phenyl)-piperazine-1-yl]-ethoxy-4,6-dimethylpyrimidine.

2. The pyrimidine compound of General formula 1 under item 1, in which Ar is pyridium, pirimidinom or triazinium and where Ar may have 1 to 3 substituent defined in paragraph 1.

3. The pyrimidine compound of the formula 1 on p. 1, where A represents C3-C10-alkylene, which can be interrupted and which can be linked to the pyrimidine ring, the radicals selected from oxygen or sulfur and double or triple bond, or its physiologically acceptable salt.

4. The pyrimidine compound of the formula 1 on p. 1, where R1, R2and R3independently of one another denote H, C1-C8-alkyl or OH, OC1-C8-alkyl, SR4or NR4R5where R4and R5independently of one another denote H or C1-C8-alkyl; Ar represents phenyl, pyridyl or pyrimidyl, which may have one, two, or three substituent selected from C2, CF3, halogen, C2-C6-alkenyl, C2-C6the quinil, C5-C6-cycloalkyl, phenyl, naphthyl, pyrroline, pyrrolidine, and its salts with physiologically acceptable acids.

5. The pyrimidine compound of the formula 1 on p. 4, where B denotes

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or its physiologically acceptable salt.

6. The pyrimidine compound of formula 1 under item 4 or 5, where R1denotes H, C1-C8-alkyl, OR4, SR4or NR4R5where R4and R5independently of one another denote H or C1-C8-alkyl; R2denotes H, OR4or C1-C8-alkyl and R3denotes H, or its physiologically acceptable salt.

7. The pyrimidine compound of formula 1 according to any of paragraphs.1 - 6, where Ar denotes phenyl with 1 to 3 substituents, which independently of each other selected from C1-C8-alkyl, OC1-C8-alkyl or phenyl, naphthyl, pyrrolyl, CN, NO2, CF3, CHF2, halogen, SO2R4or SR4where R4denotes H or C1-C8-alkyl, and salts thereof with physiologically acceptable acids.

8. The pyrimidine compound of formula 1 under item 7, where the substituents Ar are selected from C1-C81-C8-alkyl, and physiologically acceptable salts.

9. The pyrimidine compound of formula 1 under item 7 or 8, wherein Ar has one or two Deputy, in each case in the m-position, or its physiologically acceptable salt.

10. The pyrimidine compound of formula 1 according to any one of paragraphs.1 - 6, where Ar represents pyridinyl with 1 to 3 substituents which are selected from C1-C8-alkyl, phenyl, naphthyl, OH, OC1-C8-alkyl, halogen, CN, CF3C2-C6-quinil, and its physiologically acceptable salt.

11. The pyrimidine compound of formula 1 according to any one of paragraphs.1 - 6, where Ar represents pyridinyl having 1 to 3 substituent, which is selected from the group consisting of C1-C8-alkyl, phenyl, naphthyl, C5-C6cycloalkyl, OH, OC1-C8-alkyl, halogen, CF3, CN, NO2, CHF2, SO2R4or SR4where R4is H, C1-C8-alkyl, pyrrolyl, or its physiologically acceptable salt.

12. The pyrimidine compound of the formula 1 on p. 11, where A is A C2-C15-alkylene related to the pyrimidine ring through S, or its physiologically acceptable salt.

13. The pyrimidine compound of formula 1 according to p. 11 or 12, where Ar is
olila, CN, NO2, CF3, CHF2OC1-C8-alkyl, halogen, SO2R4or SR4where R4is H or C1-C8-alkyl, or a physiologically acceptable salt.

14. The pyrimidine compound of the formula 1 on p. 13, where X and Y independently are a group selected from C1-C8-alkyl, CF3and CHF2or its physiologically acceptable salt.

15. The pyrimidine compound of formula 1 according to p. 14, where A is A C2-C15-alkylene associated with pyrimidine ring S, or its physiologically acceptable salt.

16. The pyrimidine compound of formula 1 according to p. 15, where B is , or its physiologically acceptable salt.

17. The pyrimidine compound of formula 1 according to p. 16, where R1, R2, R3independently selected from H, C1-C8-alkyl or or4where R4is H, C1-C8-alkyl, or a physiologically acceptable salt.

18. The pyrimidine compound according to p. 1 formula

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19. The pyrimidine compound of General formula 1

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selected from the group:

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and their physiologically acceptable salts.

20. Connect is nnow with disabilities caused by the action of the dopamine D3-ligand.

21. Pharmaceutical composition having affinity for the dopamine D3receptors, comprising an active ingredient and a physiologically acceptable diluent and/or excipient, wherein the active substances it contains a pyrimidine compound according to any one of paragraphs.1 - 19.

 

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,

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