The triazole compounds and pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to novel triazole compounds of the General formula (1), where a denotes a linear or branched C1-C18-alkylenes group which may comprise at least one group which is selected from O, S, CONH, COO,3-C6-cycloalkene or double or triple bond; In denotes the radical of formula (a), (b) or (C); R1denotes H, NH2WITH3-C6-cycloalkyl or1-C8-alkyl, which is not substituted or substituted OS1-C8-alkyl; R2denotes H, HE, C1-C8-alkyl, C3-6-cycloalkyl, CF3, CN, NR3R4, SR3or CO2R3where R3denotes N or C1-C8-alkyl, a R4denotes H, C1-C8-alkyl, or COR3where R3stands WITH1-C8-alkyl; Ar represents naphthyl, phenyl with 1-2 substituent selected from C1-C8-alkyl, CF3, CHF2, NO2, SR3, SO2R3where R3means1-C8-alkyl; and pyridyl, pyrimidyl or triazinyl, which have from 1 to 3 substituents selected from C1-C8-alkyl, C2-C6-alkenyl, C2CO2R3where R3means1-C8-alkyl, phenyl which may be substituted with halogen, alkoxy or fenoxaprop, C3-C6-lalouche possibly condensed, phenylalkylamine or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms, which may be condensed with a benzene ring. The compounds of this invention have high affinity for dopamine D3receptors and can therefore be used for treating disorders that respond to dopamine D3-ligands. Also described pharmaceutical composition based on compounds of formula (1). 2 S. and 9 C.p. f-crystals, 10 PL.

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or

The invention relates to triazole compounds and to the use of such compounds. These compounds possess valuable therapeutic properties and can be used for the treatment of diseases associated with dopamine D3receptor ligands.

The described connections discussed here and possessing physiological activity. U.S. patents-And-4338453, 4408049 and 4577020 describe triazole compounds having anti-allergic activity.

FR-A 2551439 describes compounds of the formula

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where n is AET hydrogen, halogen, lower alkoxy or CF3and

Z represents phenyl, substituted with halogen, or denotes an unsubstituted or substituted radical of 2-pyridine, 2-pyrimidine, 3-pyrimidine, 3-pyridine, 2-quinoline or 3-benzothiazole.

These compounds have antidepressant activity. J. Med. Chem. 37 (1994) 1060-1062 describes the connection formulas

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It has a high affinity for D2D3, 5-HT1Aand1A- adrenergic receptors and exhibits a high and selective activity in animal models, leading to thoughts about protivopsychoticheskogo impact on human health.

Nerve fibers receive their information through, among others, G-proteinsathome receptors. There are many compounds which have their impact through these receptors. One of them is dopamine.

Published data confirming the presence of dopamine and its physiological effects as a neurotransmitter. Responsive to dopamine cells associated with the etiology of schizophrenia and Parkinson's disease. These and other disorders are treated with drugs that interact with dopamine receptors.

By 1990 were distinctly recognized two subclasses of dopamimetic 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 is confirmed by recent studies of receptor binding. According to them most of dopamine antagonists such as neuroleptics, have high affinity for D2-receptors, but only low affinity to the D3-receptors.

Unexpectedly found that the compounds according to this invention have high affinity for dopamine D3receptors, and extremely low affinity for D2the receptor. Thus, they are selective D3-ligands.

Therefore, this invention relates to triazole compounds of formula 1

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where a denotes a linear or branched C1-C18- alkylenes group which may comprise at least one group which is selected from O, S, NR3, CONR3, NR3CO, COO, OCO, C3-C6-cycloalkene or double or triple bond,

In denotes the radical of the formula

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or a1-C8-alkyl, which is unsubstituted or substituted HE OC1-C8-alkyl or halogen;

R2matter listed for R1or denotes CF3, SR3, halogen or CN;

R3denotes H or C1-C8-alkyl, unsubstituted or substituted HE OS1-C8-alkyl, phenyl or halogen;

R4has the meanings given for R3or denotes COR3or CO2R3;

Ar denotes phenyl, pyridyl, pyrimidyl or triazinyl, where Ar can have from one to four substituents which are selected, independently from each other, OR4WITH1-C8-alkyl, C2-C6-alkenyl,2-C6-quinil, halogen, CN, CO2R3, NO2, SO2R3, SO3R3, NR3R4, SO2NR3R4, SR3, CF3, CHF2a 5 - or 6-membered aromatic or nonaromatic of carbocycle and 5 - or 6-membered aromatic or non-aromatic heterocycle with 1 to 4 heteroatoms, which are selected from O, S and N, where carbocycle or heterocycle may be unsubstituted or substituted C1-C8-alkyl, halogen, OC1-C8-alkyl, HE, NO2or CF3and where Ar may also is R>
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and their salts with physiologically acceptable acids.

The compounds of this invention are selective ligands of the dopamine D3-receptor, which regioselective intervene in the limbic system, and due to their low affinity for D2the receptor they have fewer side effects than classical neuroleptics, which is the D2antagonists. Therefore, the connection can be used for the treatment of diseases associated with 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, neuroses and psychoses. In addition, they can be used to treat sleep disorders, nausea and as antihistamines.

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

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 and especially with 1-4 carbon atoms. The alkyl group may have about">

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

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

Alkylene group can contain at least one of the aforementioned groups. It can be the same as the above-mentioned double or triple bond located at any point or at the end of the chain, so that it connects the circuit with radical triazole. The latter is preferable. When Allenova group 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.

R1and R2preferably denote, independently of one another, H, C1-C8-alkyl, NR3R4or or4.

Ar may have one, two, three or four deputies. The substituents are preferably chosen, independently of one another, from halogen, CF3, CHF2, NR3R4, OR4, NO2C1-C8-alkyl, OC1-C8-alkyl, SR3and CN, where R3and R4have the above values.

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, a, R, X and Y represent H or represent substituents of the radical Ar, above or below.

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

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

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

When Ar represents a condensed to carbocycle or heterocycle radical, Ar, in particular, represents a naphthalene, di - or ternately, quinoline, di - or tetrahydropyran, indole, dihydroindole, benzimidazole, benzothiazole, benzothiadiazole, benzopyrrole or benzotriazol.

In preferred means

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or

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A preferred variant, at least one group, which are selected from O, S, NR3, cyclohexene, in particular, 1,4-cyclohexyl, and double or triple bond, where R3have the above values.

Another preferred embodiment includes compounds of formula 1, where

R1denotes H, OR4where R4represents H or C1-C8-alkyl or C3-C6-cycloalkyl or C1-C8-alkyl, unsubstituted or substituted HE OC1-C8-alkyl or halogen;

R2denotes H, C1-C8-alkyl, unsubstituted or substituted HE OC1-C8-alkyl or halogen, or NR3R4where R3and R4denote, independently of one another, H, phenyl-C1-C8-alkyl or C1-C8-alkyl, or4where R4denotes H or C1-C8-alkyl, or CF3;

And matter under item 3; and

Ar denotes phenyl, pyridyl or pyrimidyl, which may have one, two, three or four deputies, chosen from H, C1-C8-alkyl, which is unsubstituted or substituted HE OC1-C8-alkyl or halogen, or or4where R4denotes H, C1-C8-alkyl, unsubstituted or substituted HE OC1-C8the alkyl ilila, 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 compounds of formula 1, where

R1denotes hydrogen or C1-C8-alkyl, unsubstituted or substituted HE OC1-C8-alkyl or halogen;

R2denotes H, C1-C8-alkyl, unsubstituted or substituted HE OC1-C8-alkyl or halogen, or NR3R4where R3and R4independently of one another denote H or C1-C8-alkyl, or4where R4denotes H or C1-C8-alkyl, or CF3;

A stands WITH1-C10-alkylene, which may include oxygen or sulfur atom or the group NR3where R3such as defined above;

Ar denotes phenyl which may have one to four substituents which are selected independently of one another from H, CN, SR3, halogen, C1-C8-alkyl, unsubstituted or substituted HE OC1-C8-alkyl or halogen, or phenyl, naphthyl, OR4, NO2, NR3R4, CHF2and CF3where R3and R4have the following values.

10-alkylen, OS3-C10-alkylen or NR3-C3-C10-alkylen, where R3denotes H or C1-C8-alkyl;

R1denotes H or C1-C8-alkyl;

R2means of the above radicals;

B means:

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or

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Ar denotes phenyl, which has from one to four substituents, independently of one another denote H, C1-C8-alkyl, OC1-C8-alkyl, CHF2, CF3or CN.

In particular, the Ar has two Deputy, which are localized in positions 3 and 5, one of the substituents is CF3, CHF2or C1-C8-alkyl, and the other Deputy denotes H or C1-C8-alkyl.

Another preferred embodiment includes compounds of formula 1, where

Ar denotes pyrimidinyl with 1-3 substituents, which are selected independently of one another from H, C1-C8-alkyl, phenyl, naphthyl,5-C6-cycloalkyl, HE OC1-C8-alkyl, halogen, CN, CF3, CHF2and 5 - or 6-membered heterocyclic aromatic radical with 1 to 3 heteroatoms, which are selected from O, N and S;

R1denotes H or C1-C8-alkyl, nezamedin and OR4where R3and R4denote independently of one another, H, C1-C8-alkyl or phenyl-C1-C8-alkyl;

A stands WITH1-C10-alkylene, which may include at least one group which is selected from O, S, NR3where R3denotes H or C1-C8-alkyl, and double or triple bond; and

B is as defined above.

Another preferred embodiment includes compounds of formula 1, where

Ar represents pyridinyl, which has from one to four substituents, the substituents independently of one another are selected from H, C1-C8-alkyl, phenyl, naphthyl, HE OC1-C8-alkyl, halogen, CF3CN, C2-C6-alkenyl, C2-C6-quinil and 5 - or 6-membered aromatic heterocyclic radical with 1 to 3 heteroatoms, which are selected from O, N and S;

R1denotes H, C1-C8-alkyl, C3-C6-cycloalkyl or or4where R4denotes H, or C1-C8-alkyl, substituted or unsubstituted HE OC1-C8-alkyl or halogen; and

R2And and such as defined above.

The invention also includes salts of acidic accession compounds f and inorganic acids include hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Other acids that may be used is described in Fortschritte der Arzneimittelforschung. Vol. 10, R. 224 and subsequent Birkhuser Verlag, Basle and Stuttgart, 1966.

The compounds of formula 1 can have one or more centers of asymmetry. Therefore, the invention includes not only the racemates, but also the corresponding enantiomers and diastereomers. The invention also includes in each case tautomeric forms.

The compounds of formula 1 can be obtained by methods similar to conventional methods, for example described in Houben Weyl "Handbuch der Organishen Chemie", 4th Ed., Thieme Verlag, Stuttgart 1994. Vol. E8/d, R. 479 and subsequent; and A. R. Katritzky, C. W. Rees (ed.) "Comprehensive Heterocyclic Chemistry", 1st Ed. Pergamon Press 1984, in particular vol. 5, part 4a, R. 733 and the next, and is given here as reference literature.

Methods for 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-B-Ar;

ii) to obtain the compounds of formula 1, where a denotes the ATO is denotes Oh, S or NR3and1represents C1-C18-alkylen, with the compound of General formula VI:

Y1-AND2-B-Ar

where Y1have the above values, and2represents C1-C18-alkylene, where a1and2together contain from 1 to 18 carbon atoms;

iii) to obtain the compounds of formula 1, where a includes a group COO, or CONR3:

a) interaction of the compounds of General formula VII:

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where Y2IT denotes, OC1-C4-alkyl, Cl or together with CO denotes the activated carboxyl group, and a1have the above meanings, with a compound of formula VIII:

Z1-A2-B-Ar,

where A2have the above meanings and Z1IT denotes or other3;

iv) to obtain the compounds of formula l, where a includes a group OCO or NR3CO:

a) interaction of the compounds of formula IV:

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where Z1represents O or NR3with a compound of formula X:

Y2CO-AND2-B-Ar,

where and Y2have the values indicated above, and where R1, R2A , B and Ar have the above values.

Described herein reactions usually take place in a solvent at a temperature from room temperature up to temperaturethat, 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 is produce in a standard way, for example, filtering, removing the solvent from the reaction mixture by distillation or extraction. 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, for example, in a lower alcohol, such as methanol, ethanol or propanol, in a simple ether such as methyl tert-butyl ether, ketone, such as acetone or methyl ethyl ketone, or a complex ester, such as ethyl acetate.

The above isserpent violations the compounds of this invention administered accepted way orally 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 oral administration 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, disintegrator, the fluidity regulators, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, agents that slow down the release, antioxidants and/or DV is at 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-Methyl-3-[3-(4-{ 3-triptoreline} piperazinil) propylmercaptan]-4H-1,2,4-triazole

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

30 g (0.13 mol) m-triftormetilfullerenov, 23 g (0,146 mol) of 1,3-bramhacharya and 15 g (0,148 mol) of triethylamine in 200 ml of THF is refluxed 4 hours Cooled, and then filtered with suction and concentrated. The viscous residue is dissolved in ethyl acetate, washed with water, dried over MgSO4and then concentrate. The resulting residue contains 39 g of product as yellow oil (quantitative yield).

b) 4-Methyl-3-[3-(4-{ 3-triptoreline}piperazinil) - propylmercaptan] -4H-1,2,4-triazole

of 1.15 g (10 mmol) of 3-mercapto-4-methyl-4H-1,2,4-triazole, 3.1 g (10.1 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 1 h the mixture is Then poured into 5% hydrochloric acid and extracted with ethyl acetate. The aqueous phase is alkalinized with sodium hydroxide solution and then extracted with ethyl acetate and the organic phase is dried over MgSO4and concentrate. The residue is cleaned chromatographic (p is ASS="ptx2">

PMR [, memorial plaques]: 2,02 (2H); to 2.55 (2H); 2,61 (4H); 3,23 (6H); to 3.33 (2H); 3,61 (3H); 7,06 (3H); 7,33 (1H);

Example 2

4-Methyl-3-[5-(4-{ 3-triptoreline} piperazinil) Intermarket]-4H-1,2,4-triazole

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a) 3-(5-Chlorphentermine)-4-methyl-4H-1,2,4-triazole

2,88 g (25 mmol) of 3-mercapto-4-methyl-4H-1,2,4-triazole, with 4.64 g (25 mmol) of 1,5-bramhacharya and 5.58 g (25.5 mmol) of triethylamine in 100 ml of THF is refluxed 4 hours Cooled, followed by filtration with suction, concentrate and purify the residue chromatography (mobile phase: CH2Cl2/CH3HE = 95/5), gain of 1.9 g of product (= 35% yield).

b) 4-Methyl-3-[5-(4-{ 3-triptoreline}piperazinil) - pantellerite] -4H-1,2,4-triazole

1.9 grams (8,66 mmol) of the product of 2A), 2,19 g (9,52 mmol) m-triftormetilfullerenov and 0.96 g (9.52 mmol) of triethylamine in 5 ml of DMF was stirred at 90oC 5 h Then the mixture was poured into water and extracted three times CH2Cl2and the organic phase is dried over MgSO4and concentrate. The residue is mixed with methyl tert-butyl ether and filtered with suction, the mother liquor concentrate. Purification by chromatography (mobile phase: CH2Cl2/CH3HE = 95/5) leads to 2.1 g of product (= 59% yield).

Melting point 70-76oC.

Also the same method can be obtained the compounds included in table 4-8.

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)

of 6.75 mg of potato starch (pasta 6% concentration)

In) 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 copolymer with a ratio of (60: 40). 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 study of receptor binding

1) Test for D3the binding.

Preparation of cells

D3-expressing cells are grown in RPMI-1640 containing 10% fetal serum cows (GIBCO N 041-32400N), 100 u/ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, MD, USA). After 48 h, the cells washed with PBS (phosphate-saline buffer solution) and incubated with 0.05% trypansomiasis PBS for 5 minutes and Then the medium is 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 to 7.4 with 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 with 120 mm NaCl, 5 mm KCl, 2 mm CaCl2, 2 mm MgCl210 µm quinoline, of 0.1% ascorbic acid and 0.1% BSA (bovine serum albumin) at a concentration of approximately 106cells/250 μl of the test mixture and inquire the practical binding measure, using 10-6M spiperone.

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

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

2) Test for D2the binding.

Preparation of membranes

a) Caudatus nuclei (bullish)

Caudatus nuclei isolated from the brain of a bull and washed with cooled ice of 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-Elvehjem'a (500 rpm). The homogenate was centrifuged at 3000 rpm for 15 min (4oC) and the resulting supernatant centrifuged again for 15 min 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 Spragne-Dawley rats washed with cooled ice 0,32 M is, using a Potter homogenizer-Elvehjem'a (500 rpm). The homogenate was centrifuged at 40,000 rpm for 10 min (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 of 7.4). The washed residue resuspended in the above buffer and incubated at 37oC 20 min 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, a pH of 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 min the mixture was filtered through GF/B filters from Steklovolokno,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 of 7.4, 1 mm MnCl and 0.1% ascorbic acid).

Prepare different mixtures, each 1 ml.

The total binding: 300 µg wet weight + 1 mm3H-ADTN (Du ont de Nemours, synthesis on order) + 100 nm SCH 23390 (containing D1receptors).

- Non-specific binding: the same mixture that General 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 min, the mixture was 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 7,4. Collected on filters and radioactivity measured using a liquid scintillation counter Packard'and 2200 CA.

Assessment of ateneu show a very good affinity and high selectivity for D3-receptor. Obtained for the presented compounds results are collected in table 9.

For comparison, the compound of the formula

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(U.S. patent 4577020; example 3) is subjected to the above test D3-linking. The obtained Ki4100 [nm]; i.e., the connection really has no affinity for D3the receptor.

1. The triazole compounds of General formula 1

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where a denotes a linear or branched C1-C18-alkylenes group which may comprise at least one group which is selected from O, S, CONH, COO, C3-C6-cycloalkyl, or double or triple bond;

In denotes the radical of the formula

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< / BR>
or

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R1denotes H, NH2C3-C6-cycloalkyl or C1-C8-alkyl, which is not substituted or substituted OS1-C8-alkyl;

R2denotes H, HE, C1-C8-alkyl, C3-C6cycloalkyl, CF3, CN, NR3R4, SR3or CO2R3,

where R3denotes N or C1-C8-alkyl, a R4denotes H, C1-C8-alkyl, or COR3where R3in this case, means only C1-C8-alkyl;

AG denotes N. 3, SO2R3, CO2R3where R3in this case, means only C1-C8-alkyl, OR4where R4in this case, means only C1-C8-alkyl, and pyridyl, pyrimidyl or triazinyl, which have from 1 to 3 substituents selected from C1-C8-alkyl, C2-C6-alkenyl, C2-C6-quinil, halogen, CN, CF3, OR4where R4means hydrogen or C1-C8-alkyl, CO2R3where R3in this case, means only C1-C8-alkyl, phenyl which may be substituted with halogen, alkoxy or fenoxaprop, C3-C6-cycloalkyl possibly condensed, phenylalkylamine or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms, which may be condensed with a benzene ring,

or its salt with a physiologically active acids.

2. Connection on p. 1 of formula 1, where R1denotes H, NH2or C1-C8-alkyl, unsubstituted or substituted OC1-C8-alkyl; R3denotes N or C1-C8-alkyl; AG denotes naphthyl, phenyl with 1-2 substituent selected from C1-C8-alkyl, CF3, CHF2, NO2, SR3, SO where R4in this case, means only C1-C8-alkyl, and pyridyl, pyrimidyl or triazinyl, which have from 1 to 2 substituents selected from C1-C8-alkyl, halogen, CN, CF3, OR4where R4means hydrogen or C1-C8-alkyl, CO2R3where R3in this case, means only C1-C8-alkyl, phenyl which may be substituted with halogen, alkoxy or fenoxaprop, C3-C6-cycloalkyl possibly condensed, phenylalkylamine or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms, which may be condensed with a benzene ring;

A, B, R2matter under item 1.

3. Connection under item 1 or 2 of formula 1, where a represents C1-C10-alkylene, which may contain at least one group which is selected from O, S, cyclohexene, or double or triple bond.

4. The compound according to any one of paragraphs.1 - 3 of formula 1, where R1denotes N or C1-C8-alkyl, unsubstituted or substituted OS1-C8-alkyl; R2denotes H, HE, C1-C8-alkyl, CF3, NR3R4where R3and R4denote, independently of one another, H or C1HF2or or4where R4in this case, means only C1-C8-alkyl, and pyridyl, or pyrimidyl, which have from 1 to 2 substituents selected from C1-C8-alkyl, halogen, CN, CF3, OR4where R4means hydrogen or C1-C8-alkyl, phenyl, C3-C6-cycloalkyl or 5-membered aromatic heterocycle with 1 or 2 nitrogen atoms.

5. The compound according to any one of paragraphs.1 - 3 of formula 1, where R1denotes N or C1-C8-alkyl, unsubstituted or substituted OC1-C8-alkyl; R2denotes H, HE, C1-C8-alkyl, NR3R4where R3and R4denote, independently of one another, H, or C1-C8-alkyl, or CF3; And represents C1-C10-alkylene, which may include an oxygen atom or sulfur; Ar represents phenyl which may have one to two substituents which are selected, independently from each other, from C1-C8-alkyl, NO2, CHF2, CF3, SR3or or4where R3and R4denote C1-C8-alkyl.

6. Connection on p. 5 of formula 1, where a denotes SC3-C10-alkylen, OS3-C10-alkylen; R1denotes N or Cthe t phenyl, which has from one to two substituents, which independently of one another denote C1-C8-alkyl, OC1-C8-alkyl, CHF2, CF3.

7. Connection on p. 6, where AG has one or two substituent, which are localized in position 3 or position 5, where one of the substituents represents CF3, CHF2or C1-C8-alkyl, and the other Deputy represents C1-C8-alkyl.

8. Connection on p. 1 of formula 1, where Ar pirimidil, which has from one to three substituents that are independently from each other selected from C1-C8-alkyl, phenyl, HE OC1-C8-alkyl, halogen, CN, CF3or 5-membered aromatic heterocycle with 1 or 2 N atoms;1denotes N or C1-C8-alkyl, unsubstituted or substituted OS1-C8-alkyl; R2denotes H, NR3R4where R3and R4denote independently from each other H, C1-C8-alkyl; represents C1-C10-alkylene, which may include at least one group which is selected from O, S, or double or triple bond; B is as defined under item 1.

9. Connection on p. 1 of formula 1, where Ar represents pyridyl, which has from about, C1-C8-alkyl, halogen, CF3CN, C2-C6-alkenyl, C2-C6-quinil or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms: R1denotes H, C1-C8-alkyl, C3-C6-cycloalkyl; R2And and as defined under item 8.

10. The connection of a triazole of the General formula 1 or its salt according to any one of paragraphs.1 to 9 to obtain a pharmaceutical composition exhibiting affinity and high selectivity for the dopamine D3-receptors.

11. The pharmaceutical composition exhibiting affinity and high selectivity for the dopamine D3receptors containing the active compound and pharmaceutical additives, characterized in that the active compounds it contains a compound of General formula 1 on p. 1.

 

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