Diphenylene heterocyclic compounds, pharmaceutical composition and method of treatment

 

(57) Abstract:

The invention relates to diphenylvinyl heterocyclic compounds of formula 1 in which Het denotes a fragment selected from the group consisting of (A) - (H). The compounds are modulators of activated calcium potassium (BK) channels with large conductance and, therefore, suitable for the protection of nerve cells, especially in the treatment or prevention of ischemic attack. The invention relates also to a method of treatment using the novel compounds and to pharmaceutical compositions containing these compounds. 3 C. and 16 h.p. f-crystals, 1 PL.

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The invention is directed to new diphenylene heterocyclic derivatives which are modulators of activated calcium potassium (BK) channels with large conductance and, therefore, suitable for the protection of nerve cells, especially in the treatment or prevention of ischemic attack. This invention relates also to a method of treatment using the novel compounds and to pharmaceutical compositions containing these compounds.

BACKGROUND OF THE INVENTION

Currently it is generally accepted that cardiac postupyushey decade has developed several therapeutic approaches to minimize brain damage, associated with acute coronary disease, including inhibitors of AMPA /kainate, N-methyl-D-aspartate (NMDA) and inhibitors of reuptake of adenosine. The purpose of this invention is to provide new compounds that will modulate potassium channels, in particular activated calcium (BK) potassium channels with large conductance, which is useful to reduce damage to nerve cells in the onset of coronary disease.

Potassium channels play a key role in regulating the potential of the cell membrane and modulating the excitability of the cells. Potassium channels are regulated by the voltage, cell metabolism, ion of calcium and processes, mediated by receptors [Cook, N. S., Trends in Pharmacol. Sciences (1988), 9, p. 21-28; and Quast, U. and Cook, N. S., Trends in Pharmacol. Sciences (1989), 10, p. 431-435]. Activated calcium potassium (KCa) channels are a group of ion channels, for which the total is dependent on intracellular calcium ions. Activity TOCachannels are regulated by intracellular [Ca2+], membrane potential and phosphorylation. On the basis of their single-channel conductance in solutions of symmetric K+TOCathe channels are divided into three subclasses: large conductivity is Simens, the unit of conductivity). Activated calcium potassium channels (BK) with high conductivity are many excited cells, including nerve cells, heart cells and various types of smooth muscle cells [Singer, J. J. and Walsh, J. V., Pflbgers Archiv. (1987) 408. p. 98-111; Bary, I. and Escande, D., Pflbgers Archiv. (1989) 414 (Suppl. 1), p. S168-S170; and Ahmed, F. et al., Br. J. Pharmacol. (1984) 83, p. 227-233].

Potassium ions play a key role in the regulation of the remaining membrane potential in most of the excited cells and in the maintenance of transmembrane voltage near the equilibrium potential of K+(EC) equal to about 90 mV. It was shown that the opening of potassium channels shifts the potential of the cell membrane towards the potassium equilibrium potential of the membrane (EC), leading to hyperpolarization of the cell [Cook, N. S., Trends in Pharmacol. Sciences (1988), 9, p. 21-28] . Hyperpolarization cells show reduced sensitivity to potentially dangerous stimuli depolarization. BK channels, which are regulated by the voltage and intracellular Ca2+, limit depolarization and calcium intake, and can be particularly effective at blocking dangerous stimuli. Therefore, the hyperpolarization of the cell through the opening of BK channels may lead to the protection of ner ' man is discussed in the publication S. Trivedi, et al., in Biochemical and Biophysical Research Communications, (1995), 213. No.2, p. 404-409.

Described a number of synthetic and natural compounds with activity, contributing to the opening of VK. Avena pyrone extracted from seed oats avena sativa, has been described as the connection opening of the VC channel when using a lipid bilayer technique (WO 93/08800, published may 13, 1993). 6-Bromo-8-(methylamino)-imidazo[1,2-a] pyrazin-2-carbonitrile (SCA-40) is described as a substance that opens the VC channel based on limited electrophysiological experiments [Laurent, F. et al., Br. J. Pharmacol. (1993) 108. p. 622-626] . When using epitopes outdoors found that the flavonoids, Phloretin, affects the opening of activated Ca2+ potassium channels in metallisierung nerve fibers of Xenopus laevis [Koh, D-S., et al., Neuroscience Lett. (1994) 165. p. 167-170].

In the application EP-A2-0435177, published July 3, 1991, describes substituted triazolone Formula (i)

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where R and R2denote C1-4alkyl, C1-4alkoxy, halogen or trifluoromethyl and R2)m denotes methylendioxy; R1denotes hydrogen or C1-4alkyl and m and n is 0, 1 or 2.

These compounds have anticonvulsant effects. You should note that in the compounds of Formula (i) R cannot be >/BR>where R denotes halogen, trifluoromethyl, C1-4alkyl or C1-4alkoxy; n = 0, 1, or 2; R2denotes hydrogen or C1-3alkyl; and R4represents C1-3alkyl.

These compounds of the Formula (ii) have the ability to improve memory. You should note that in the structure (ii) heterocycles have only one substituted phenyl ring.

U.S. patent 3971803, issued to S. Rosenberger and K. Schwarzenbach July 27, 1976, relates to compounds of the Formula (iii)

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where R1denotes alkyl, cycloalkyl or aralkyl;

R2denotes hydrogen or R4;

R3denotes hydrogen or C1-4alkyl;

Y and Z independently represent O or S;

R4means: (1) if m=1, C1-8alkylene, -CxH2x-Q-CyH2y- (Q represents O or S, x and y denote integers whose sum equals 2-4), phenylene, diphenylene, or naphthalene, or

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or (2) if m= 2, alkylen, alkylenedioxy group, alkylenediamine group, diphenylene or naphthalene residue. These compounds are antioxidants for organic polymers.

Application EP-A1-0533276, published March 24, 1993 discloses compounds of the Formula (iv)

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where one of R or Q denotes o-Zam the AMI.

In U.S. patent 5116858 in the name of Y. Hayashi et al. on may 26, 1992, describes 4-imidazolone with the activity of inhibitors of lipid peroxidase. They have the Formula (v)

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where X4denotes H, halogen, alkyl or alkoxy, p is 1-3, Y denotes the =C=O or =C(OH)-, R1 denotes cycloalkyl, alkenyl or aralkyl and R2and R3denote H or different hydrocarbon or hydrocarbonoxygen.

A. E. Wilder Smith in Arzneim. Forsch. (1967) 67. No.17, p. 768-772 described the fabrication and study of compounds of Formula (vi)

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where X denotes H or C1and n is 1 or 2. The compounds have activity against tuberculosis. The compounds of Formula (vi) do not cover substituted in p-position to the hydroxyl group of the connection.

In U.S. patent 5436252, S. M. Sorensen et al., from 25.07.1995 described the treatment of neurodegenerative conditions using 5-aryl-3H-1,2,4-triazole-3-ones of the Formula (vii)

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where Ar denotes phenyl, naphthyl or aromatic heterocycle, R1denotes hydrogen or lower alkyl, R2denotes lower alkyl, R stands for alkyl, alkoxy, hydroxy, halogen or trifluoromethyl, n=0-2 or (R)n-Ar together represent methylenedioxyphenyl. Formula (vii) does not cover diphenylene connection.

None of these and is.

THE INVENTION

This invention provides a new diphenylene heterocyclic derivatives of General formula

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where "Het" refers to a fragment selected from the group consisting of (A)-(H):

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where Z is independently for each case selected from O or S; Ra, Rband Rceach independently selected from hydrogen, halogen, HE, CF3, NO2or -(-NH-CO - CH2-)p-NRfRgprovided that Rcis not hydrogen; and Raand Rbdenote hydrogen; Rcmay be a heterocycle selected from the group comprising imidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl and pyridin-2-yl; Rdand Reeach independently selected from hydrogen, halogen, CF3, NO2or imidazol-1-yl; m, n and p each independently selected from O or 1; and Rfand Rgeach independently represents hydrogen, C1-4alkyl; or Rfand Rgtaken together with the nitrogen atom to which they are attached, form a heterocycle selected from the group consisting of N-methylpiperazine, research, thiomorpholine, N-benzylpiperazine and imidazolinone.

This invention also covers non-toxic pharmaceutically acceptable salt, cosily and methods of their use.

A DETAILED DESCRIPTION OF THE INVENTION

This invention provides a new diphenylene heterocyclic derivatives which are potent opening activated calcium potassium channels with a high conductivity (BK channel), which have the Formula 1

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where "Het" refers to a fragment selected from the group consisting of (A)-(H):

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where Z is independently for each case selected from O or S; Ra, Rband Rceach independently selected from hydrogen, halogen, HE, CF3, NO2or -(-NH-CO - CH2-)p-NRfRgprovided that Reis not hydrogen; and Raand Rbdenote hydrogen; Rcmay be a heterocycle selected from the group comprising imidazol-1-yl. morpholinomethyl, M - methylimidazol-2-yl and pyridin-2-yl; Rdand Reeach independently selected from hydrogen, halogen, CF3, NO2or imidazol-1-yl; m, n and p each independently selected from 0 or 1; and Rfand Rgeach independently represents hydrogen, C1-4alkyl; or Rfand Rgtaken together with the nitrogen atom to which they are attached, form a heterocycle selected from the group consisting of N-methylpiperazine, morph the e method of treatment or prevention of disorders due to the discovery of activated calcium K+ channels (BK channels), a large conductance, in mammals in need thereof, which consists in the introduction to such mammal a therapeutically effective amount of the compounds of Formula 1 or its non-toxic farmatsevticheskii acceptable salt. The compounds of Formula 1 are preferred for the treatment of ischemia, convulsions, asthma, irritable bowel syndrome, migraine, traumatic brain injury, erectile dysfunction in men, urinary incontinence and other diseases that are sensitive to the activity of BK channels.

Deputy "Z" are independently selected from O or S. it Should be borne in mind that when Z represents oxygen, the oxygen atom may be part of the ether linkages (C-O-C) or carbonyl (C=O) group, and when Z represents sulfur, the sulfur atom may be part of the thioester (C-S-C) or thiocarbonyl (C=S) group.

Suitable are optical isomers and other isomers heterocyclic fragments (A)-(H), and all isomers of compounds of Formula 1 in General. You can use prodrugs and other forms.

The term "C1-4alkyl" used in the description and the claims (unless the context requires otherwise) denotes a linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, image the term "halogen" denotes bromine, chlorine, iodine and fluorine, and the term "halogen" denotes an anion, bromide, chloride or iodide.

The term "Het" as used in the description and in the claims (unless specified otherwise) that includes all the heterocycles denoted by Formulas (a) to (H), in which each heterocycle is disubstituted and attached two links, as shown in the structural Formula. Further, it should be borne in mind that the accession of the phenyl groups may be, for example, in the provisions of the 4.5 or 5.4; 3,5 - or 5.3; 1,5 - or 5.1 - and there may be other isomers fragments "Het" (a) to (H).

The term "nontoxic pharmaceutically acceptable salt" used in this description and the claims, encompasses non-toxic salt accession acids and bases. Suitable acids are sulfuric, phosphoric, hydrochloric, Hydrobromic, itestosterone, citric, acetic, benzoic, cinnamic, fumaric, almond, phosphoric, nitric, mucus acid, setinova, palmitic, heptane, etc., Suitable inorganic bases such as alkali and alkaline earth metals include the Foundation of such metals as sodium, potassium, magnesium, calcium, etc.

In General pharmaceutically acceptable salt image is n, the activity of salt. In some cases, they have physical properties that make them desirable for pharmaceutical compounds, such as solubility, lack of hygroscopicity, the ability to pressing at reception of tablets and compatibility with other ingredients with which the substance is used for pharmaceutical purposes. Salts are usually obtained by mixing the compounds of Formula 1 with the selected acid or base, preferably in solution, using excess traditionally used inert solvents such as water, simple ether, benzene, methanol, ethanol, ethyl acetate and acetonitrile. They can also be obtained by metathesis or treatment with ion-exchange resin under conditions when suitable ion salts of the compounds of Formula 1 have been replaced by another ion under conditions that allow the selection of the target product, for example, by deposition from a solution or by solvent extraction or elution or retention in ion-exchange resin.

Some compounds in this invention can exist in the form of a solvate, including hydrated forms, such as the monohydrate, dihydrate, trihydrate, hemihydrate, tetrahydrate, etc. Compounds may be true solvate, while the other is vorites. The person skilled in the art it is obvious that the solvated forms are equivalent and nonsolvated also included in the scope of this invention.

When implementing the method according to this invention, the term "therapeutically effective amount" means the amount of each active component of the composition that is sufficient to have a significant favorable impact on the patient, namely the healing of an acute disease caused by the opening of activated calcium K+ channels of large conductance, or to increase the speed of healing such diseases. In the case of individual active ingredient, administered separately, this term refers to that particular ingredient. In the case of a mixture, this term refers to the total number of active ingredients, which leads to a therapeutic effect, while introducing them to the mixture sequentially or simultaneously. The terms "treatment, therapy, used in this description and in the claims, means the prevention or improvement of conditions, reduction of tissue damage and/or symptoms associated with dysfunction of polarization and conductivity of the cell membranes.

The compounds of Formula 1 could the changes which are obvious to the expert.

1.2-Diarylpyrazole

Triazolone type I and II receive, as shown in Reaction schemes 1 and 2 (see the end of the description). For example, phenylacetic acid or benzoic acid (where n= 0) activate in the form of their anhydrides and exercise combined with aniline. Received amides III and IV treated with pentachloride phosphorus in benzene under reflux and intermediate aminoalkoxide catch anhydrous hydrazine with getting amerzone V and VI, respectively. Cyclization of amerzone processing carbonyl diimidazol in THF leads to the formation of triazolinones cyclic system. Demethylation completed by heating triazolone at 225oC in the presence of pyridine hydrochloride, and then produce good yields (~45-55%).

The reaction scheme 3-5 (see end of description) illustrate obtaining several related ring systems. Triazolin VII obtained from hamidrasha V processing 1,1'-thiocarbonyldiimidazole in THF, followed by demethylation with pyridine hydrochloride (Reaction scheme 3). Condensation of the same hamidrasha V bromide with a cyanide in the presence of sodium bicarbonate results in aminotriazole VIII after demethylation more sensitive aminotri the ANO on the Reaction scheme 4, get capture intermediate aminoalkoxide III and IV diethylacetal of aminoacetaldehyde. Heating acetals under reflux in benzene with trap Dean-stark causes cyclization with the formation of the imidazole ring, which is subjected to demethylation with pyridine hydrochloride with receiving systems IX and X. the Third imidazole XI is obtained by condensation of aniline with 5-chloro-2-methoxybenzaldehyde. Intermediate Imin treated with toiletrieschoice in a basic environment with the formation of the imidazole IX after demethylation BBr3.

Appendix 2-aminoacetophenone to 5-chloro-2-methoxyisatin, as shown in Reaction scheme 5, the results in 2 - oxaprotiline XII, which after dissolution in concentrated sulfuric acid at OoC cichlisuite and after demethylation tribromide boron results in imidazolone XIII. Imidazolidin XIV is obtained by condensation of N-(5 - chloro-2-methoxyphenyl)urea with phenylglyoxal followed by demethylation with action trichromate boron.

1-Aryl-3-benzenetriol

Synthesis of 1-aryl-3 - benzenetriol shown in Reaction schemes 6 and 8-10 (see the end of the description). Oxadiazoline received known in the literature is MINICOM. To produce the same products also use the second method - alkylation of oxadiazolones benzyl alcohols in the reaction conditions, Mitsunobu. When Y=H, demethylation tribromide boron results in product XV. In the case of analogues, when Y=NHAc, methylamine derivatives hydrolyzing a 10% mixture of HCl/ethanol under reflux with the formation of anilines and demethylation leads to the formation of products of structure XVI.

Another similar, chlorinated XVII, obtained by demethylation and selective chlorination by sulfurylchloride in the presence of catalytic amounts of diisobutylamine before hydrolysis of the acetate.

For some analogs (namely, when X' =2-pyridinyl, 1 - imidazole, 1-methyl-2-imidazole, ethylmethylamino or 4 - morpholinylmethyl) predecessors of benzyl alcohols to the reaction of Mitsunobu are not commercially available. Obtaining these compounds shown in Reaction scheme 7.

Reaction scheme 7 (see the end of the description).

For all compounds, benzyl alcohols obtained by recovery of the aldehyde or complex ester. Aryl ring is subjected to functionalization by combining or alkylation.

The reaction C3=F, R4=CF3) is carried out by substitution of fluorine-imidazole with getting XVIII after demethylation with pyridine hydrochloride (Reaction scheme 8).

In one example oxadiazolones system reacts easily with the reagent Lawesson education tinawag analog XIX after demethylation trichromatism forest.

Reaction scheme 9 reflects the modification of aniline with obtaining several derivatives of handling bromoacetylation and subsequent alkylation (QN = morpholine, thiomorpholine, N - methylpiperazine, N-phenylpiperazine, N-benzylpiperazine, dimethylamine) to obtain after demethylation product XX.

The conversion of aniline in the same isocyanate or isothiocyanate, adding diethylacetal of aminoacetaldehyde and cyclization results in imidazolone (thione) XXI.

Triazolone receive, as shown in Reaction scheme 10. Alkylation of amoxiclave in DMF in the presence of sodium hydride leads to the formation of products XXII and regioisomer (not shown) in the form of a mixture (1:1). The products are purified by chromatography on silica gel and toxiciity subjected to hydrolysis in 10% HCl/ethanol to obtain triazolinones cycle. Hydrolysis of the acetate also occurs in these conditions shall heterocycly

Reaction scheme 11 (see the end of the description).

Alkylation of chlorzoxazone bromo-4- (trifluoromethyl)acetophenone in the environment sodium hydride/DMF) allows you to get benzooxazole XXIV with a good yield (Reaction scheme 11). Subsequent treatment with ammonium acetate under reflux in acetic acid medium causes a rearrangement with the formation of imidazolone XXV.

Oxadiazole XXVI shown in Reaction scheme 12 (see the end of the description), is obtained by acylation of phenylhydrazine activated benzoic acids. Cyclization of the resulting hydrazide carbonyl diimidazol leads to the formation of oxadiazolones cycle, hydrolysis (as above, when N=NHAc) before demethylation tribromide boron allows you to get XXVI.

A number of triazolone receive, as shown in Reaction scheme 13 (see the end of the description).

Condensation glyoxalic acids with phenylhydrazine in the environment of ethanol under reflux leads to the production of carboxylic acids XXVII. Processing diphenylphosphorylacetate led to the formation of isocyanates, which are due to intramolecular rearrangements turn after demethylation tribromide boron in triazolone XXVIII. Regioisomer the substitution as shown in Reaction scheme 14 (see end of description).

According to one preferred variant of the invention the compounds have the Formula (1a) or Formula (1b)

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where Ra-Reidentified above. In the preferred compounds of the Formula (1a) or Formula (1b) Raand Rbdenote H, HE, NH2or Cl; Redenotes Cl; Rdand Redenote CF3or H; m=0, n=0 or 1.

According to another preferred variant of the invention the compounds have the Formula (1c)

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where Ra-Reabove. In the preferred compounds of the Formula (1c) Raand Rbdenote H, HE, NH2or Cl; Rcdenotes Cl; Rdand Redenote H, CF3or Cl; m=0 or 1 and n=0.

According to another preferred variant, the compounds correspond to the Formula (1d) or the Formula (1e)

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where Raand Rbrepresent hydrogen, hydroxyl, chlorine or NH2; Rcdenotes chlorine; Rdand Redenote hydrogen, trifluoromethyl, fluorine or chlorine. Usually it is preferable that at least one of Rdand Remeant trifluoromethyl or chlorine.

According to another preferred variant of Shalagina, HE, CF3, NO2or -(-NH-CO-CH2-)p-NRfRgprovided that Rwithdoes not denote hydrogen; and when Raand Rbdenote hydrogen; Rcmay be a heterocycle selected from the group consisting of imidazol-1-yl, morpholinomethyl, N-Mei-2-yl and pyridin - 2-yl; Rdand Reeach independently selected from hydrogen, halogen, CF3, NO2or imidazol-1-yl; m, n and p are each independently 0 or 1; and Rfand Rgeach independently represents hydrogen, C1-4alkyl; or Rfand Rgtaken together with the nitrogen atom to which they are attached, form a heterocycle selected from the group comprising N - methylpiperazine, morpholine, thiomorpholine, N-benzylpiperazine, imidazoline.

According to another preferred variant, the compounds correspond to the Formula (1g)

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where Raand Rbdenote H, OH, or C1 NH2; Rcdenotes chlorine; Rdand Redenote H, CF3or C1. Usually it is preferable that at least one of Rdand Remeant CF3or C1 in the compounds of Formula (lg).

According to another preferred variant, the compounds correspond to the Formula (1h)

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where R/SUP> denote hydrogen, trifluoromethyl or chloro. Usually it is preferable that at least one of Rdand Remeant CF3or C1 in the compounds of Formula (1h).

Preferred compounds include:

4-(5-chloro-2-hydroxyphenyl)-5-[3,5-bis(trifluoromethyl)phenyl] - 2,4-dihydro-3H-1,2,4-triazole-3-one;

4-(5-chloro-2-hydroxyphenyl)-5- [4-(trifluoromethyl)phenyl] -2,4-dihydro-3H-1,2,4-triazole-3-one;

4-(5 - chloro-2-hydroxyphenyl)-5-[3-(trifluoromethyl)phenyl] -2,4-dihydro-3H - 1,2,4-triazole-3-one;

4-(5-chloro-2-hydroxyphenyl)-5-(4-forfinal)- 2,4-dihydro-3H-1,2,4-triazole-3-one;

4-[2-hydroxy-5- (trifluoromethyl)phenyl] -5-[4-(trifluoromethyl)phenyl] -2,4-dihydro-3H - 1,2,4-triazole-3-one;

4-(5-chloro-2-hydroxyphenyl)-5- [[(trifluoromethyl)phenyl] methyl] -2,4-dihydro-3H-1,2,4-triazole-3-one;

4-(5-chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl] -2,4 - dihydro-3H-1,2,4-triazole-3-tion;

4-chloro-2-[2-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl]phenol;

5-(5-chloro-2 - hydroxyphenyl) -4-[4-(trifluoromethyl) phenyl]-2,4-dihydro-3H-1,2,4 - triazole-3-one;

5-(5-chloro-2-hydroxyphenyl)-4-[[4- (trifluoromethyl)phenyl]methyl]-2,4-dihydro-3H-1,2,4-triazole-3-one

4-chloro-2-[1-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]phenol;

4-chloro-2-[1-phenyl-1H-imidazol-1-yl]phenol;

4-chloro-2-[3-amino[5-[4- (trifluoromethyl)phenyl] -4H-1,2,4-triazole-4-dihydro-5-phenyl-2H-imidazol-2-he;

3-[(4 - amino-5-chloro-2-hydroxyphenyl)methyl] -5-[3,4-dichlorophenyl] -1,3,4 - oxadiazol-2(3H)-he;

3-[[4-(amino)-5-chloro-2-hydroxyphenyl)methyl] - 5-[3,5-dichlorophenyl] -1,3,4-oxadiazol-2(3H)-he;

3-[(4-amino-5 - chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4 - oxadiazol-2(3H)-he;

3-[2-hydroxyphenyl) methyl] -5-[4- (trifluoromethyl) phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2 - hydroxyphenyl) methyl]-5-[4-(trifluoromethyl) phenyl 1-1,3,4 - oxadiazol-2(3H)-he;

3-[[2-hydroxy-5-chlorophenyl] methyl] -5-[3,5 - bis(trifluoromethyl)phenyl] -1,3,4-oxadiazol-2(3H)-it:

3-[(5-chloro-2 - hydroxyphenyl)methyl] -5-[4-fluoro-3-(trifluoromethyl)-phenyl]-1,3,4 - oxadiazol-2(3H)-it:

3-[[2-hydroxy-5-chlorophenyl] methyl] -5-[2-chloro-5- (trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[2-hydroxy-5-chlorophenyl] methyl] - 5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxyphenyl)methyl] -5-[2-fluoro-4-(trifluoromethyl)- phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[(4-amino-3,5-dichloro-2-hydroxyphenyl)methyl] -5- [3,4-dichlorophenyl] -1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxy phenyl)methyl] -5-[2- (1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)- it:

3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[2-(1H-imidazol-1-yl)-3- (trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[2-hydroxy-5-(4-morpholinylmethyl)phenyl]methyl]-5-[4- (triptime the]-1,3,4-oxadiazol-2(3H)-he;

3-[[2-hydroxy-5- (2-pyridinyl)phenyl]methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4 - oxadiazol-2(3H)-he;

3-[[5-(1-methyl-1 H-imidazol-2-yl)-2 - hydroxyphenyl] methyl] -5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazol - 2(3H)-he;

3-[[2-hydroxy-5-(1-methyl-1H-imidazol-2-yl)phenyl] methyl] -5-[3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-it:

3-[[2-hydroxy-5-(1H-imidazol-1-yl)phenyl]methyl]-5- [4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[2-hydroxy-5-(1H-imidazol-1-yl)phenyl]methyl]-5-[3,5 - bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

N-[2-chloro-4- [[1,5-dihydro-5-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-1-yl] methyl] -5-hydroxyphenyl]-4-morpholinoethyl;

N-[2-chloro-4- [[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-3 - yl] methyl]-5-hydroxyphenyl]-4-thiomorpholine;

N-[2-chloro-4- [[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol - 3-yl] methyl]-5-hydroxyphenyl]-4-methyl-1-piperazineethanol;

N-[2 - chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl] -1,3,4 - oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-phenyl-1 - piperazineethanol;

N-[2-chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl]- 1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-benzyl-1 - piperazineethanol;

N-[2-chloro-4- [[2,3-dihydro-2-oxo-5- [4- (trifluoromethyl) phenyl] -1,3.4-oxadiazol-3-yl]methyl]-5 - hydrox the phenyl]-4-methyl-1-piperazineethanol;

N-[2-chloro-4-[[2,3 - dihydro-2-oxo-5-[naphthas-2-yl] -1,3,4-oxadiazol-3-yl] methyl]-5 - hydroxyphenyl]-4-morpholinoethyl;

3-[(5-chloro-2-hydroxyphenyl) methyl] -5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazol-2(3H)-tion;

3-[[5-chloro-4-(2,3-dihydro-2-oxo-1H-imidazol-1-yl)-2-hydroxy - phenyl] methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[5-chloro-4-(2,3-dihydro-2-thio-1H-imidazol-1-yl)-2 - hydroxyphenyl] -methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol - 2(3H)-he;

2-[(4-amino-5-chloro-2-hydroxyphenyl)methyl]- 2,4-dihydro-5-[4-(trifluoromethyl) phenyl]-3H-1,2,4-triazole-3-one:

2-[(4-amino-5-chloro-2-hydroxyphenyl)methyl] -2,4-dihydro-5- [3,4 - dichlorophenyl]-3H-1,2,4-triazole-3-one;

2-[(5-chloro-2 - hydroxyphenyl)methyl] -2,4-dihydro-5-[4-(trifluoromethyl)-phenyl]-3H - 1,2,4-triazole-3-one;

5-[(4-amino-5-chloro-2-hydroxyphenyl)-3-[4- (trifluoromethyl)-phenyl]-1,3,4-oxadiazol-

5-[(4-amino-5 - chloro-2-hydroxyphenyl)-3-phenyl-1,3,4-oxadiazol-

5-(5 - chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-

5-[(4-amino-5-chloro-2-hydroxyphenyl)-3-[3,4-dichlorophenyl] - 1,3,4-oxadiazol-

1-(5-chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)- phenyl] - -triazole-5-he;

1-(5-chloro-2-hydroxyphenyl)-3-[2-(trifluoromethyl)-phenyl] - -triazole-5-he; -

1-(5-chloro-2-hydroxyphenyl)-3-[3,5-bis(trifluoromethyl)-phenyl] - -triazole-5-he;

1-(5-CHL is methyl)-phenyl]- - triazole-5-it; and

5-[5-chloro-2-hydroxyphenyl)-2,4-dihydro-2 -[4- (trifluoromethyl)phenyl] - triazole-3-one.

According to this aspect of the invention provides a method of treatment or protection from health disorders mediated by the opening of activated calcium K+ channels (BK channels) with high conductivity in a mammal, in need, which is specified in the introduction to the mammal a therapeutically effective amount of the compounds of Formula 1 or its non-toxic pharmaceutically acceptable salt, MES or hydrate. The compounds of Formula 1 are preferred in the treatment of ischemia, convulsions, asthma, irritable bowel syndrome, migraine, traumatic brain injury, erectile dysfunction in men and urinary incontinence and other disorders sensitive to the activity of BK channels. It is most preferable to use the compounds of Formula 1 in the treatment of cerebral ischemia.

According to another aspect, the invention provides pharmaceutical compositions comprising at least one compound of Formula 1 in a mixture with a pharmaceutical additive, carrier or diluent.

Biological activity

Potassium (K+) channels, not only at
proteins that are commonly found in cells, indicating their Central role in the regulation of a number of key cell functions [Rudy, B., Neuroscience, 25: 729-749 (1988)]. As widely distributed as the class of K+ channels placed differentially as individual members of this class or family [Gehlert, D. R. et al., Neuroscience, 52: 191-205 (1993)]. In General, activation of K+ channels in cells, especially in the induced cells, such as nerve cells and muscle cells, leads to hyperpolarization of the cell membrane or in the case of depolarized cells, re-polarization. In addition to acting as a "retainer" endogenous membrane potential, K+ channels can respond to these important changes in the cells, as changes in the intracellular concentration of ATP or intracellular concentration of calcium (Ca2+). A key role of K+ channels in the regulation of various functions of the cells makes them particularly important targets for therapeutic intervention [Cook, N. S., Potassium channels: Structure, classification, function and therapeutic potential. Ellis Horwood, Chinchester (1990)] . One class of K+ channels activated Ca2+ To+ channels of large conductance (BK or BK channels) is regulated by the transmembrane potential, the concentration of intracellular Ca2+ and a number of other facto the conductance of a single channel (usually more than 150 PSM) and a high degree of specificity for K+ (BK) channels show that a small number of channels could have a strong influence on the conductivity of the membranes and stimulation of cells. In addition, the increase in the probability of opening channels with the increasing concentration of intracellular Ca2+ indicates the involvement of BK channels in the modulation-dependent Ca2+ processes such as secretion and muscle contraction [Asano, M., et al., J. Pharmacol. Exp. Ther., 267: 1277-1285 (1993)].

Substances that open BK channels, affect cells by increasing the probability of opening of these channels [Mscow, M. S., et al., J. Neurophysiol. , 71: 1873-1882 (1994): and Olesen, S.-P., Exp. Opin. Invest. Drugs, 3: 1181-1188 (1994)]. This increase in the probability of opening a separate VC channels together leads to the hyperpolarization of cell membranes, especially in depolarized cells caused a significant increase in conductivity of the whole cell-mediated VK.

The ability of compounds described in this application to open BK channels and lead to increased migration (+) out of the cell-mediated VK, were evaluated in terms of fixation potential by determining the ability of these compounds to increase the transport of ions out of the cell, mediated by cloned VK mammals (mSlo or hSlo), heterologic 189-193 (1994)]. Two used VK designs are almost identical in structure, protein homologues, they had a pharmacologically identical action by the inventors research. To distinguish VK transfer and native current (background, not VK) transfer used specific and potent blocker of BK channels, namely the toxin, called iberiotoxin (IBTX) [Galvez, A., et al., J. Biol. Chem, 265: 11083-11090 (1990)] in supermaximal concentration (50 nm). The relative contribution of migration through BK channels in the transfer of ions from the cells was determined by subtracting the migration continued in the presence of IBTX (not include migration), migration profiles obtained in all other conditions of the experiment (control, drug and flushing). It was determined that at the tested concentrations of the compounds do not affect native not include the transfer in oocytes. All compounds were tested at least 5 oocytes in concentrations of 1, 5 or 20 μm; the effect of selected compounds of Formula 1 VK migration expressed as a percentage of control IBTX-sensitive transfer and shown in Table 1. Recording was carried out using standard two-electrode method for determining potential [Stuhmer, W., et al. Methods in Enzymology, Vol. 207: 319-the Anna potential value-60mV to +mV in increments of 20 mV. Experimental environment (modified solution Bart) had the following composition (in mm): NaCl (88), NaHCO3(2,4), KCl (1,0), HEPES (10), MgSO4(0,82), Ca(NO3)2(0,33), CaCl2(0,41); pH 7.5.

To determine the ability of these compounds to reduce the loss of cells in the neural ischemia used a standard model of permanent focal ischemia, including blockage of the middle cerebral artery in rats with spontaneous hypertension (MCAO model) [Tamura, A., et al. Journal of Cerebral Blood Flow and Metabolism, Volume 1, 53-60 (1981)].

Selected compounds were evaluated in models of focal stroke, including permanent occlusion of the middle cerebral artery (MCAO), in rats with spontaneous hypertension. This technique leads to extensive neocortical infarction measured by exclusion of vital dyes in the number of slices in the brain 24 hours after MCAO. This experience of connection was injected intravenously or intraperitoneally two hours after occlusion. For example, in this model, the compound from Example 82 significantly reduced the size of cortical infarction by approximately 14 % intraperitoneal injection (10 mg/kg) as a single bolus over 2 hours after occlusion of the middle cerebral above tests in vitro and in vivo show the compounds according to this invention are potent opening activated calcium K+ channels (BK channels) large conductivity. Thus, the compounds according to the invention is suitable for treatment of disorders in humans, resulting from dysfunction of the polarization and conductivity of the cell membrane and can preferably be used for the treatment of ischemia, convulsions, asthma, irritable bowel syndrome, migraine, traumatic brain injury, erectile dysfunction in men, urinary incontinence and other disorders sensitive to the activation of the activity of BK channels. It is most preferable to use the compounds of Formula 1 for the treatment of cerebral ischemia.

Therefore, the compounds of Formula 1 or the pharmaceutical compositions containing them, are suitable for the treatment, mitigation or elimination of violations related to BK channels. Such violations include ischemia, convulsions, asthma, irritable bowel syndrome, migraine, traumatic brain injury, erectile dysfunction in men, urinary incontinence, and other disorders sensitive to the action of substances, opening potassium channels.

According to another aspect, the invention includes pharmaceutical companies who meet or diluent.

According to another aspect of the invention relates to a method of treatment or prevention of disorders responsive to opening of potassium channels in a mammal, which includes an introduction to the specified mammal a therapeutically effective amount of the compounds of Formula 1 or its non-toxic pharmaceutically acceptable salt, MES or hydrate.

According to another aspect of the invention relates to a method of treating ischemia in a mammal, which includes an introduction to the specified mammal a therapeutically effective amount of the compounds of Formula 1 or its non-toxic pharmaceutically acceptable salt, MES or hydrate.

For use in the treatment of pharmacologically active compounds of Formula 1 are normally introduced in the form of a pharmaceutical composition containing as the principal active substance, at least one such compound in combination with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients conventional method.

Pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, vnutri media the composition may be in the form of tablets can be placed in a hard gelatin capsule in powder or pellet form or it can be in the form of pellets or tablets. A solid carrier can contain conventional excipients such as binding agents, fillers, lubricating agents for tablets, shredders, wetting, etc., If desired, the tablet may contain a film coating that is applied by known methods. If you use a carrier liquid, the drug may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injection equipment, aqueous or non-aqueous liquid suspension or may be in the form of a dry product, mixed with water or other medium before use. Liquid preparations can contain conventional additives, such as suspendresume agents, emulsifiers, wetting and non-aqueous media (including edible oils), stabilizers, as well as fragrances and/or dyes. For parenteral administration the carrier is usually a sterile water, at least for the most part, although it can also be used saline solutions, glucose solutions, etc., Suspension for injection can also be used, in this case, you can apply the usual suspend the market, buffer agents, etc., Especially useful for the introduction of compounds of Formula 1 directly parenteral. Pharmaceutical compositions receive conventional methods suitable for the desired preparation containing appropriate quantities of the active substance, namely the compounds of Formula 1 according to the invention. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 17th edition, 1985.

The dose of the compounds of Formula 1, required to achieve a therapeutic effect will depend not only on factors such as age, weight and sex of the patient and the method of introduction, but also on the degree of activity of potassium channels and the activity of the specific compound used to treat a particular disease. The dose of specific compounds can be introduced in the form of a dosage form and this form is selected by the person skilled in the art, given the level of activity. The decision about the specific dosage (and how many times to take your medicine) takes the doctor, and this dose may vary depending on the specific circumstances, to obtain the desired therapeutic effect.

A suitable dose of a compound of Formula 1 or a pharmaceutical composition containing this compound to a mammal, including chelovechestva active ingredient from about 0.1 μg/kg to 100 mg/kg weight of the patient. For parenteral administration, the dose may range from 1 μg/kg to 100 μg of the patient's weight in the case of intravenous administration. The active ingredient is introduced or preferably continuously, or in equal doses one to four times per day. However, usually give a small dose and the dosage is gradually increased until, until the optimal dose for the patient.

However, it should be borne in mind that the number of input connections is determined by the doctor depending on the particular circumstances, including the type of disease, type of the selected connection, the method of administration, age, weight of the patient, his reaction and the degree of spread of the disease.

The following examples are given to illustrate the invention and do not limit the invention, many modifications of the invention includes in its scope.

DESCRIPTION OF THE SPECIFIC FORMS OF EMBODIMENT OF THE INVENTION

In the following examples all temperatures are indicated in degrees Celsius. Melting points were determined using a capillary device Gallenkamp'a to determine the melting temperature, the temperature was not adjusted. Proton magnetic resonance (1H NMR) was determined on the device Bruker AC 300. All spectra were taken in Ocalan (TMS) and constants megatonnage combinations specified in Hertz (Hz). Cleavage is indicated as follows: s, singlet; d, doublet; t, triplet; q, Quartet; m, multiplet; br, broad peak; dd, doublet of doublet: bd, broad doublet, dt, doublet of triplet; bs, broad singlet, dq, doublet of Quartet. Infrared (IR) spectra using potassium bromide (KBr) was filmed spectrometer Perkin Elmer 781 from 4000 cm-1up to 400 cm-1that was calibrated by the absorption of a polystyrene film at a wavelength of 1601 cm-1the values are given in reciprocal centimeters (cm-1). Mass spectra of low-resolution (MS) and the apparent molecular (MN+) or (M-N) was determined using Finnigen TSQ 7000. Mass high resolution spectra were determined on a Kratos MS50 FAB method with the use of cesium iodide/glycerol as an internal standard. The results of elemental analysis are given in percent by weight.

Nigelegashie preparative examples illustrate how to obtain intermediate products and methods of producing products in accordance with the invention. Specialists in this field it is obvious that a corresponding change of the starting compounds and methods of synthesis examples below will also be within the scope of this invention.

Preparatory example N 1

Examples 1-6

< / BR>
PR is 3, R2= N)

5-Chloroisatin (5.6 g, 36,3 mmol) dissolved in THF (350 ml) and added dropwise in a nitrogen atmosphere at 0oC add a solution of 3,5 - bis(trifluoromethyl)benzoyl chloride (10.1 g, 36.6 mmol) dissolved in THF (85 ml) followed by the addition of triethylamine (5.3 ml, 1.7 mmol). The solution is stirred for 18 h at 24oC and filtered to remove Et3NHCl. Concentration in a rotary evaporator allows you to remove the solvent and obtain 13,08 g (90 %) of white solids. Recrystallization from a mixture of ethanol/water (2: 1) allows to obtain colorless needle-like particles with a melting point of 151-153oC; IR (KBr, cm-1) 3298, 1654, 1534, 1292, 1276, 1188, 1136, 804;1H NMR (300 MHz, DMSO-d6) : a 3.83 (3H, s), 7,13 (1H, d, J = 8,9 Hz), 7,26 (1H, dd. J = 8,8 Hz, 2.7 Hz), 7.76 (1H, d, J = 2.6 Hz), with 8.33 (1H, br.s), 8,56 (2H, br.s) of 10.25 (1H, br.s): MS(DCl)m/z: 398(MH+).

Analysis, calculated: C16H10ClF6NO2: C, 48,32: H, TO 2.54; N, 3.52.

Found: C, 48,35; H, 2.57 M; N, 3,49.

The following amides obtained by the method similar to that described in Example 1.

Example 2

N-(5-chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzamide

(III2: X = Cl, n = 0, R1= R3= H, R2= CF3)

so pl. 113-115oC

Analysis, calculated: C15H11ClF3NO20,1 H2O: C, 54,34; H, 3,4 NSAID

(III3: X = Cl, n = 0, R1= CF3, R2= R3= H)

so pl. 111-112,5oC

Analysis, calculated: C15H11ClF3NO2: C, 54,65; H, TO 3.36; N, 4.25 IN.

Found: C, 54,62; H, To 3.33; N, 4,19.

Example 4

N-(5-chloro-2-methoxyphenyl)-4-perbenzoic

(III4: X = Cl, n = 0, R1= R3= H, R2= F)

so pl. 131-134oC

Analysis, calculated: C15H11ClF3NO20,05 H2ABOUT: WITH, 59,93; H, 3,99; N, 4,99.

Found: C, 59,86; H, Of 3.97; N, Equal To 4.97.

Example 5

N-(2-methoxy-5-triptoreline)-4-trifluoromethyl-benzamide

(III5: X = CF3, n = 0, R1= R3= H, R2= CF3)

so pl. 132-133oC

Analysis, calculated: C16H11F6NO2: C, 52,90; H, WAS 3.05; N, 3,86.

Found: C, 52,78; H, 3.04 From; N, A 3.87.

Example 6

N-(5-chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzeneacetate

(III6: X = Cl, n =1, R1= R3= H, R2= CF3)

so pl. 115-116oC

Analysis, calculated: C16H13ClF3NO20,1 H2O: C, 55,63; H, OF 3.85; N,06.

Found: C, 55,86; H, And 3.72; N, 3,98.

Examples 7 and 8

< / BR>
Example 7

5-chloro-2-methoxy-N-[4- (trifluoromethyl)phenyl]benzamide (IV-7: n = 0)

so pl. 131, 5mm-132,5oC

Analysis calc"ptx2">

Example 8

5-chloro-2-methoxy-N-[4-(trifluoromethyl)phenyl]benzazimide (IV-8n = 1)

so pl. 112-113oC

Analysis, calculated: C16H13ClF3NO2: C, 55,91; H 3,81; N, 4,07.

Found: C, 55,97; H, Of 3.78; N, 4,07.

Example 9 and 10

< / BR>
Example 9

N-(5-chloro-2-methoxyphenyl)-3.5 - bis(trifluoromethyl)benzylpiperazine-amide (V9: X = Cl, n=0, R1= R3= CF3, R2= N)

N-(5-chloro-2-methoxyphenyl)-3,5 - bis(trifluoromethyl)benzamide (8 g, 20,1 mmol) dissolved in benzene (100 ml) under nitrogen atmosphere and add Piatigorsky phosphorus (4.6 g, 22,1 mmol). The solution is heated under reflux for 3 h and the solvent is removed in a rotary evaporator. The residue is treated with THF (165 ml) and contribute dropwise at 0oC in nitrogen atmosphere to a solution of anhydrous hydrazine (6.4 ml) in the same solvent (165 ml). After keeping at the 24oC for 1 h, the reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (2 x 250 ml), the organic phase is washed with brine and dried over sodium sulfate. Concentration gives of 7.69 g (93%) with a melting point 117-120oC: IR(KBr, = cm-1) 3339, 3252, 1591, 1510, 1384, 1284, 1255, 1182, 1128;1H NMR (300 MHz, CDCl3) : 3,93 (3H, s), to 5.66 (2H, br.s) 5,94 (1H, br. s), 6,25-of 6.26 (1H, m), 6,77-6,84 (2H, m), 7,78 (1H, s), 8,01

Found: C, Of 46.77; H, And 2.83; N, 9,95.

Example 10

N-(5-chloro-2 - methoxyphenyl)-4-(trifluoromethyl)benzylpiperazine (V10: X = Cl, n = 0, R1= R3= H, R2= CF3)

The above amerson obtained by the method similar to that described in example 9.

so pl. 94-95oC

The mass spectrum of high-resolution computed: C15H13ClF3N3O: 344.0777

Found: 344.077

Dev: 2,2 ppm

Examples 11 and 16

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Example 11

4-(5-chloro-2-methoxyphenyl)-3-[3.5 - bis(trifluoromethyl)phenyl]-2.4-dihydro-3H-1.2.4-triazole-3-one (I11: X=Cl, n=0, R1=R3= CF3, R2= H)

N-(5-chloro-2-methoxyphenyl)-3,5 - bis(trifluoromethyl)benzylpiperazine (4 g, 9.7 mmol) is treated with THF (600 ml) under nitrogen atmosphere. Add 1,1'- carbonyldiimidazole (1.9 grams, 11,72 mmol). The solution is stirred for 18 h at 24oC before removing the solvent in a rotary evaporator. The residue is treated with ethyl acetate (400 ml) and washed with a solution of 0.1 N HCl (100 ml), water (100 ml) and brine before drying MgSO4. Recrystallization from acetonitrile gives of 2.92 g (68,6%) with a melting point of 205.5-207oC. IR (KBr, = cm-1) 3170, 1726, 1504, 1277, 1128;1H NMR (300 MHz, DMSO - d6) : of 3.48 (3H, s), to 7.15 (1H, d, J = 9.0 Hz), 7,55 (1H, dd, J = 8,9 Hz, 2.6 Hz), 7,69 (1H, d,>O2: C, 46,65; H, 2,30; N, 9,60.

Found: C, 46,71; H, 2,20; N, 9,60.

Triazolone of Examples 12 to 18 obtained by the method similar to that described in Example 11.

Example 12

4-(5-chloro-2-methoxyphenyl)-5-[4- (trifluoromethyl)phenyl] -2.4-dihydro-3H-1.2.4-triazole-3-one (I12: X = Cl, n = 0, R1= R3= H, R2= CF3)

so pl. 250-253oC

Analysis, calculated: C15H11ClF3N3O20,03 H2O: C, 51,91; H, A 3.01; N, 11,35.

Found: C, Br52.11; H, 2,97; N, 11,32.

Example 13

4-(5-chloro-2-methoxyphenyl)-5-[3- (trifluoromethyl)phenyl] -2.4-dihydro-3H-1.2.4-triazole-3-one (I13: X = Cl, n = 0, R1= CF3, R2= R3= H)

so pl. 207-209oC

Analysis, calculated: C16H11ClF3N3O2: C 51,98; H, 3,00; N, 11,37.

Found: C, 52,12; H, 2,84; N, 11,51.

Example 14

4-(5-chloro-2-methoxyphenyl)-5-(4-forfinal)-2.4 - dihydro-3H-1,2.4-triazole-3-one (I14: X = Cl, n = O, R1= R3= H, R2= F)

so pl. 270-273oC

Analysis, calculated: C15H11ClFN3O20.02 H2O: C, 56,30; H, 3,48: N, 13,13.

Found: C, 56,25; H, 3,39; N, 13,08.

Example 15

N-[2-methoxy-5-(trifluoromethyl)phenyl] -5-[4- (trifluoromethyl)phenyl]-2.4-dihydro-3H-1.2.4-triazole-3-one (I15: XH11F6N3O2: C, 50,63; H, 2,75; N, 10,42.

Found: C, 50,61; H, 2,66; N, 10,45.

Example 16

4-(5-chloro-2-methoxyphenyl)-5-[[4 - trifluoromethyl)phenyl] methyl]-2.4-dihydro-5-3H-1.2.4-triazole-3-one (I16: X = Cl, n = 1, R1= R3= H, R2= CF3)

so pl. 154-155oC

Analysis, calculated: C17H13ClF3N3O2: C, 53,21; H, 3,41; N, 10,95.

Found: C, 53,10; H, Of 3.46; N, 10,89.

Examples 17 and 18

< / BR>
Example 17

5-(5-chloro-2-methoxyphenyl)-4-[4 - trifluoromethyl)phenyl] -2.4-dihydro-3H-1.2.4-triazole-3-one (II17: n = 0)

so pl. 213-214,5oC

Analysis calculated; C16H11ClF3N3O2: C, 51,19; H, TO 3.02; N, 11,35.

Found: C, 51,84; H, 2,95; N, 11,28.

Example 18

5-(5-chloro-2-methoxyphenyl)-4-[[4 - trifluoromethyl)phenyl] methyl] -2.4-dihydro-3H-1.2.4-triazole-3-one (II18n = 1)

so pl. 134-136oC

Analysis, calculated: C17H13ClF3N3O20,1 H2O: C, 52,94; H, OF 3.45; N, 10,89.

Found: C, 52,94; H, 3,22: N 10,95.

Example 19

4-(5-chloro-2-methoxyphenyl)-5-[4-trifluoromethyl)phenyl] - 2.4-dihydro-3H-1.2.4-triazole-3-tion (Vll19)

< / BR>
N-(5-chloro-2-methoxyphenyl)-4- (trifluoromethyl)benzylpiperazine (2.5 g, 7,27 mmol) dissolved in THF (450 ml) in the atmosphere is a group of 18 h and remove the solvent in a rotary evaporator. The residue is treated with ethyl acetate (400 ml) and washed with a solution of 0.1 N HCl (100 ml), water (100 ml) and brine before drying MgSO4. Recrystallization from acetonitrile gives 1,91 g (68%) with a melting point 275-280oC. IR (KBr, = cm-1) 3080, 3058, 3020, 2916, 1506, 1488, 1322, 1288, 1174, 1130, 1110; 1H NMR (300 MHz, DMSO-d6) : 3,51 (3H, s), 7,17 (1H, d, J = 9.0 Hz), 7,53-EUR 7.57 (3H, m), 7.69 (1H, d, J = 2.6 Hz), to 7.77 (2H, d, J = 8,4 Hz), 14,29 (1H, s); MS(DCl)m/z: 386(MH+).

Analysis, calculated: C16H11ClF3N3OS 0,06 CH3N: C, 49,97; H, 2,90; N, 11,40.

Found: C, 50,03; H, To 2.94; N, 11,07.

Example 20

4-(5-chloro-2-methoxyphenyl)-5-[4-trifluoromethyl)phenyl] -4H - 1.2.4-triazole-3-amine (Vlll20)

< / BR>
N-(5-chloro-2-methoxyphenyl)-4- (trifluoromethyl)benzylpiperazine (1.5 g, 4,36 mmol) dissolved in 1,dioxane (7 ml) and add ciambrone (475 mg, 4,48 mmol). Added dropwise at room temperature a solution of sodium bicarbonate (380 mg in 7 ml of water) and the reaction mixture is stirred for 3 hours Add an additional 7 ml of water to the heterogeneous reaction mixture was then filtered and washed with water. Recrystallization from acetonitrile gives 922 mg (57,3 %) with a melting point 247-248oC. IR (KBr, = cm-1) 3416, 3076, 3052, 1652, 1561, 1504, 1322, 1110; 1H NMR (300 MHz, DMSO-d6) : of 3.60 (3H, s), 5,90 (2H, s), 7,22 (1H, d, J = 9.5 TO THE 3N4O: C, 52,12; H, OR 3.28; N, 15,19.

Found: C, 52,19; H, 3,20; N, 15,29.

Example 21

1-(5-chloro-2-methoxyphenyl)-5-[4-(trifluoromethyl)phenyl]-1H-imidazole (Xl21)

< / BR>
5-chloroisatin (6.0 g, is 38.2 mmol) and 4 - triptoreline (6.6 g, is 38.2 mmol) dissolved in methanol (250 ml) and stirred for 3 hours the Solvent is removed by evaporation and the residue is treated with benzene (200 ml) and the solution is heated with use of Dean-stark to remove traces of methanol, and then the benzene is distilled off. The residue is transferred in DMF and in the atmosphere of nitrogen dosimetrician (7,46 g is 3.82 mmol) and DBU (0.5 ml, is 3.82 mmol). The reaction mixture is stirred at 24oC for 48 h, then diluted with water (1 volume) and extracted with ethyl acetate. The organic phase is washed with water, brine and dried. Chromatography, elution with a mixture of 30% ethyl acetate/benzene gives 1 g (8 %) with a melting point of 158-159oC; IR (KBr, = cm-1) 1504, 1462, 1324, 1260, 1176, 1122;1H NMR (300 MHz, CDCl3) : to 3.49 (3H, s), 6,86 (1H, d, J = 8,9 Hz), 7,20-7,24 (3H, m), 7,32-7,38 (2H, m), 7.48 (2H, d, J = 8.2 Hz); of 7.60 (1H, s); MS(DCl)m/z: 353(MH+).

Analysis, calculated: C17H12ClF3N2O: C, 57,88; H, 3.43 POINTS; N, 7,94.

Found: C, 58,08; H, 3,50; N, To $ 7.91.

Example 22

1-(5-chloro-2-methoxyphenyl)-244- (trifluoromethyl)phenyl]-1H-imidazo the ml) under nitrogen atmosphere and add Piatigorsky phosphorus (3,61 g, 17.3 mmol). The solution is heated under reflux for 2.5 h and then distilled in vacuum solvent and phosphorus oxychloride. The residue is treated with THF (55 ml) and contribute dropwise at 0oC in nitrogen atmosphere to a solution of diethylacetal of aminoacetaldehyde (5 ml, to 34.4 mmol) in the same solvent (50 ml). After stirring for 24oC for 18 h, the reaction mixture was diluted with diethyl ether (1.5 volume) and filtered. The filtrate was concentrated in a rotary evaporator to obtain oil (7,63 g) which was dissolved in benzene (500 ml). Add two equivalent p-TsOHH2O (6 g, 30 mmol) and the solution refluxed with a nozzle Dean-stark within 2 hours the Solution was concentrated in a rotary evaporator and the residue is distributed between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate and the combined organic layers washed with water, brine and then dried over magnesium sulfate. Chromatography on SiO2, elution with a mixture of 10% ethyl acetate/methylene chloride, gives a solid substance with so pl. 4.15 g (75%) with a melting point 117-120oC; IR (KBr, = cm-1) 1504, 1464, 1324, 1284, 1246, 1176, 1122, 1108, 1074, 846;1H NMR (300 MHz, DMSO-d6) : of 3.48 (3H, s), 7,17-7,21 (2H, m), the 7.43 (1H, d, J = 1.3 Hz): 7,51-to 7.59 (4H, m); 7,66 (2H, d, J = 8,4 Hz); MS(DCl)m/z: 353(MH+).

Anal is 2">

The imidazoles of Examples 23 and 24 obtained by the method similar to that described in Example 22.

Examples 23 and 24

< / BR>
Example 23

2-(5-chloro-2-methoxyphenyl)-1-[4-(trifluoromethyl)phenyl] -1H-imidazole (X23: X = CF3)

so pl. 95-106oC

Analysis, calculated: C17H12ClF3N2O: C, 57,89; H, 3.43 POINTS; N, 7,94.

Found: C, 58,20: H, Of 3.56; N, 7,87.

Example 24

2-(5-chloro-2-methoxyphenyl)-1-phenyl-1H-imidazole (X24: X = H)

so pl. 97-102oC

Analysis, calculated: C16H13ClN2O 0,06 H2O: C, 67,24; H, 4,63; N, 9,80.

Found: C, 67,02; H, 4,56: N 9,72.

Examples 25-30

< / BR>
Example 25

4-(5-chloro-2-hydroxyphenyl)-5-[3.5 - bis(trifluoromethyl)phenyl] -2.4-dihydro-3H-1.2.4-triazole-3-one (I25: X = Cl, n = 0, R1= R3= CF3, R2= H)

5-[3,5 - bis(trifluoromethyl)phenyl]-4-(5-chloro-2-methoxyphenyl)-2,4-dihydro-3H - 1,2,4-triazole-3-one (1.6 g, 3.6 mmol) is mixed with pyridine hydrochloride (6.7 g, 58 mmol) and heated at 225oC for 1 h, After cooling, the solid is treated with ethyl acetate (25 ml) and water (15 ml) and exposed to ultrasound (bath) for several minutes in order to separate the solid residue from the walls of the flask, the organic suspension was diluted atilas which leads to solid product of 1.46 g (95%), which is recrystallized from acetonitrile. So pl. 275-278oC. IR (KBr, = cm-1) 3166, 1681, 1314, 1275, 1180, 1140;1H NMR (300 MHz, DMSO-d6) : 6,92 (1H, d, J = 8,8 Hz), 7,38 (1H, dd, J = 8,8 Hz, 2.6 Hz), 7,58 (1H, d, J= 2.0 Hz), to $ 7.91 (2H, s), 8,17 (1H, s), 10,45 (1H, s), to 12.44 (1H, s); MS(DCl)m/z: 424(MH+).

Analysis, calculated: C16H8ClF6N3O2: C, 45,36; H, 1,90; N, 9,92.

Found: C, 45,28; H, 1,89; N, 9,77.

The phenols of Examples 26 to 36 obtained by the method similar to that described in Example 25.

Example 26

4-(5-chloro-2-hydroxyphenyl)-5-[4- (trifluoromethyl)phenyl] -2.4-dihydro-3H-1.2.4-triazole-3-one (I26X = Cl, n = O, R1= R3= H, R2= CF3)

so pl. 292-294oC

Analysis, calculated: C15H9ClF3N3O2: C, 50,68; H, 2,60; N, 11,73.

Found: C, 51,04; H, To 2.74; N, 11,55.

Example 27

4-(5-chloro-2-hydroxyphenyl)-5-[3- (trifluoromethyl)phenyl] -2.4-dihydro-3H-1.2.4-triazole-3-one (I27: X = Cl, n = O, R1= CF3, R2= R3= H)

so pl. reach 232.5-233,5oC

Analysis, calculated: C15H9ClF3N3O20,05 EtOAc: C, 50,70; H, 2,63; N, 11,67.

Found: C, 50,62; H, 2,56; N, 11,64.

Example 28

4-(5-chloro-2-hydroxyphenyl)-5-(4-forfinal)-2.4 - dihydro-3H-1.2.4-triazole-3-one (I28: X = Cl, n = O, R1= RO: C, 54,77; H, 3,00; N, 13,69.

Found: C, 54,77; H, 3.04 From; N, 13,71.

Example 29

[2-hydroxy-5-(trifluoromethyl)phenyl] -5-[4- (trifluoromethyl)phenyl 1-2.4-dihydro-3H-1.2.4-triazole-3-one (I29: X=CF3n = 0, R1=R3=H, R2= CF3)

so pl. 270-274oC

Analysis, calculated: C16H9F6N3O2: C, 48,88; H, 2,42; N, 10,69.

Found: C, 49,36; H, 2,24; N, 10,82.

Example 30

4-(5-chloro-2-hydroxyphenyl)-5-[[4 - trifluoromethyl)phenyl] methyl]-2.4-dihydro-3H-1.2.4-triazole-3-one (I30: X-Cl. n = l, R1=R3=H, R2= CF3)

so pl. 270-274oC

Analysis, calculated: C16H11ClF3N3O2: C 51,98; H, 3,00; N, 11,37.

Found: C, 51,92; H, 2,88: N, 11,23.

Example 31

4-(5-chloro-2-hydroxyphenyl)-5-[4 - trifluoromethyl)phenyl] -2.4-dihydro-3H-1.2.4-triazole-3-tion (Vll31)

< / BR>
so pl. 274-276oC

The mass spectrum of high resolution

calculated: C16H9ClF3N3OS: 372.0185

Found: 372.0197

Dev: 3,2 ppm

Example 32

4-chloro-2-[2-[4-(trifluoromethyl)phenyl]-1H-1.2.4 - imidazol-1-yl]phenol (IX32)

so pl. 252-254oC

< / BR>
Analysis, calculated: C16H10ClF3N2O: C, 56,74; H, 2,98; N, 8,27.

Found: C, 56,65; H, To 2.94; N, 8,14.

Examples33: n = 0)

so pl. 236-238,5oC

Analysis, calculated: C15H9ClF3N3O2of 0.1 EtOAc:

WITH, 50,75; H, A 2.71; N, 11,53.

Found: C, 50,97: H, Of 2.81; N, 11,32.

Example 34

5-(5-chloro-2-hydroxyphenyl)-4-[[4 - trifluoromethyl)phenyl] methyl]-2.4-dihydro-3H-1.2.4-triazole-3-one (II34n = 1)

so pl. 217-219oC

Analysis, calculated: C16H11ClF3N3O2O. 1H2O: C, 51,72; H, 3.04 FROM; N, 11,31.

Found: C, 51,95: H, 2.90; N, 11,31.

Examples 35 and 36

< / BR>
Example 35

4-chloro-2-[1-[4-(trifluoromethyl)phenyl] -1H-imidazol-2 - yl] phenol (X35: X = CF3)

so pl. 110-112,5oC

Analysis, calculated: C16H10ClF3N2O-0,01 H2O: C, 56,52; H, A 3.01; N, 8,24.

Found: C, 56,68; H, 2,86; N, 8,18.

Example 36

4-chloro-2-[1-phenyl-1H-imidazol-2-yl]phenol (X36: X = H) so pl. 137-138,5oC

Analysis, calculated: C15H11ClN2O: C, 66,55: H, 4.10; N, 10,35.

Found: C, 66,76; H, 4,24; N, 10,26.

Example 37

4-chloro-2-[3-amino-[5-[4-(trifluoromethyl)phenyl] -4H - 1.2.4-triazole-4-yl] phenol (Vlll37)

< / BR>
4-(chloro-2-methoxyphenyl)-5-[4- (trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-amine (1.5 g, 4.1 mmol) is treated with methylene chloride (formed suspension), cooled to 0oC in the atmosphere SUP>C for 18 h, was added 1 N sodium hydroxide (80 ml), the solvent is removed in a rotary evaporator and the residue is treated with ethyl acetate and sufficient THF to molar dissolution. After washing with 0.1 N HCl solution and brine solution, dried over MgSO4. Chromatography, elution with a mixture of 1% AcOH/5% methanol in dichloromethane, to give 795 mg (55%). So pl. 147-155oC.

The mass spectrum of high resolution

calculated: C15H10ClF3N4O: 355.0574

Found: 355.0566

Dev: 2,3 ppm

Example 38

1-(5-chloro-2-hydroxyphenyl)-5-[4- (trifluoromethyl)phenyl]-1H-imidazole (Xl38)

< / BR>
The above-mentioned phenol is obtained using BBr3according to the method described in example 37.

So pl. 220-225oC

Analysis, calculated: C16H10ClF3N2O0,15H20:, 56,06; H, TO 2.94; N, 8,17.

Found: C, 55,65; H, To 2.94; N, 7,81.

Preparative example N 2

Example 39

N-(5-chloro-2-methoxyphenyl)-N'-(2-oxo-2-phenylethyl)urea (XII39)

< / BR>
5-chloro-2-methoxyphenylalanine (5,3 g, 29 mmol) dissolved in THF (250 ml) under nitrogen atmosphere and heated to 60oC. To this solution was added 2-aminoacetophenone HCl (5 g, 29 mmol) and then triethylamine (3.8 g, 30 mmol). After stirring for techm sodium carbonate, brine and dried over MgSO4. Concentration gives a solid, which was washed with diethyl ether, 6 g (65%). So pl. 171-173oC. IR (KBr, = cm-1) 3336, 1706, 1644, 1600, 1560, 1482, 1262, 1220, 1182, 1126;1H NMR (300 MHz, CDCl3) : with 3.79 (3H, s), 4,84 (2H, d, J = 4.3 Hz), 5,97 (1H, br.s) of 6.71 (1H, d, J = 8.7 Hz), to 6.88 (1H, dd, J = 8,7 Hz, 2.5 Hz), 7,97-of 8.00 (2H, m), 8,18 (1H, d, J = 2.5 Hz); MS(DCl)m/z: 319(MH+).

Analysis, calculated: C16H15ClN2O3: C, 60,28; H, 4,74; N, 8,79.

Found: C, 60,17; H, With 4.64; N, 8,70.

Example 40

1-(5-chloro-2-methoxyphenyl)-1.3-dihydro-2H-imidazol - 2-he (Xlll40)

< / BR>
(5-chloro-2-methoxyphenyl)-N'-(2-oxo-2 - phenylethyl)urea (4 g, 12.7 mmol) is added to a chilled (0oC) concentrated sulfuric acid and stirred for 3 hours, the Reaction mixture was poured on ice water (2 volumes) and extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine and dried over MgSO4. Recrystallization from a mixture of diethyl ether / acetonitrile give 1.35 g (36%). So pl. 133 - 134oC: IR (KBr, = cm-1) 2962, 1628, 1576, 1236, 1144, 1130;1H NMR (300 MHz, CDCl3) : 3,90 (3H, s), 6,77 (1H, d, J = 8.6 Hz), 6.91 (1H, dd, J = 8,6 Hz, 2.5 Hz), 7,16 (1H, s), 7,22-7,27 (1H, m), 7,35-7,40 (2H, m), 7,51-of 7.55 (3H, m), 8,29 (1H, d, J = 2.5 Hz); MS(DCl)m/z: 301(MH+).

Analysis, calculated: C16H13ClN2O2the Idro-5-phenyl-2H - imidazol-2-he (XIII41)

< / BR>
The above-mentioned phenol is obtained using BBr3according to the method described in example 37.

So pl. 190-192oC

Analysis, calculated: C16H11ClN2O2: C, 62,83; H, 3.87; N, 9,77.

Found: C, 62,87; H, To 3.92; N, 9,82.

Preparative example N 3

Example 42

1-(5-chloro-2-methoxyphenyl)-5-phenyl-2.4 - imidazolidinedione (XIV42)

< / BR>
N-(5-chloro-2-methoxyphenylacetone (1 g, 5 mmol) and the monohydrate of phenylglyoxal (760 mg, 5 mmol) is treated with absolute ethanol (100 ml) and acetic acid (1 ml) and add 1 ml conc. HCl. The reaction mixture is heated to boiling under reflux for 3.5 h and left to stand for 24oC for 18 h, then concentrated in a rotary evaporator. The residue is dissolved in ethyl acetate, washed with saturated sodium carbonate solution and brine. Recrystallization from a mixture of methylene chloride/hexane gives 1 g (63%). So pl. 200oC. IR (KBr, = cm-1) 3168, 3064, 1772, 1701, 1504, 1444, 1426, 1408, 1260, 1190, 1150;1H NMR (300 MHz, CDCl3) : 3,59 (3H, s), ceiling of 5.60 (1H, s), to 6.80 (1H, d, J = 8,8 Hz), 7,14-7,37 (7H, m), of 8.92 (1H, br.s); MS(DCl)m/z: 317(MH+).

Analysis, calculated: C16H13ClN2O3: C, 60,67; H, 4,13; N, 8,84.

Found: C, 60,47; H, 4,12; N, 8,80.

Example 43

1-(5-chloro-2-HYDR the BBr3according to the method described in example 37.

So pl. 235-236oC

Analysis, calculated: C15H11ClN2O3: FROM, TO 59.51; H, 3,66; N, 9,25.

Found: C, 59,27; H, 3,66; N, 9,51.

Preparative example N 4

Oxadiazolones source materials obtained in accordance with the procedure described in M. D. Mullican. et al., J. Med. Chem., 36, 1090 (1993).

Examples 44-55

< / BR>
Example 44

3-[[4-(acetylamino)-5-chloro-2-methoxyphenyl] methyl]- 5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-he (XV44: X' = Cl, Y = NHAc, R1= R4= H, R2= R3= Cl)

5-(3,4-dichlorophenyl)-1,3,4 - oxadiazol-2(3H)-he (2.0 g, 8,66 mmol), N-[4-(methyl bromide)-2-chloro-5 - methoxyphenyl] ndimethylacetamide [JP 49049929] (2.2 g, 8,67 mmol), K2CO3(1.9 grams, of 13.8 mmol) and KI (cat.) in acetonitrile (50 ml) is refluxed for 18 hours After cooling, the reaction mixture was poured into water (300 ml), vigorously stirred and filtered. Recrystallization from aqueous acetonitrile gives pale yellow crystals of 2.2 g (57.8 per cent). So pl. 200-201,5oC. IR (KBr. = cm-1) 3340, 1804, 1404, 1041, 850, 736;1H NMR (300 MHz, CDCl3) : of 2.21 (3H,s), 3,83 (3H, s), to 4.87 (2H, s), 7,22 (1H, s), 7,49 (1H, d, J = 8,4 Hz), 7,60 (1H, dd, J = 8,4 Hz, 2.0 Hz), to 7.64 (1H, br.s), 7,86 (1H, d, J = 2.0 Hz), 8,11 (1H, s) MS(ES)m/z: 440(MH+).

Analysis, calculated: C18H14ClI received by way similar to that described in Example 44.

Example 45

3-[[4-(acetylamino)-5-chloro-2-methoxyphenyl] methyl]-5-[3.5-dichlorophenyl 1-1.3.4 oxadiazol-2(3H)-he (XV45: X' = Cl, Y = NHAc, R1= R3= H, R2= R4= Cl)

So pl. 144-145oC

Analysis, calculated: C18H14Cl3N3O4: C, 48,84; H, 3,19; N, 9,49.

Found: C, 48,83; H, 3,35; N, 9,72.

Example 46

3-[[4-(acetylamino)-5-chloro-2-methoxyphenyl]methyl]-5-[ 4-(trifluoromethyl)phenyl]-1.3.4-oxadiazol-2(3H)-he (XV46: X' = Cl, Y = NHAc, R1= R2= R4= H, R3= ClF3)

So pl. 202-205 are,5oC

Analysis, calculated: C19H15ClF3N4O40,1 H200,1 THF:

WITH, 51,69; H, TO 3.58: N, TO 9.32.

Found: C, 51,71; H, 3,49; N, 9: 30 A.m.

Example 47

3-[[4-(acetylamino)-5-chloro-2-methoxyphenyl]methyl]-5- ([1.1'-biphenyl]-4-yl)1-1.3.4 oxadiazol-2(3H)-he (XV47: X' = Cl, Y = NHAc, R1= R2= R4= H, R3= Ph)

So pl. 203-204oC

Analysis, calculated: C24H20ClN3O3: C 64,07; H, 4,48; N, 9,34.

Found: C, 64,02; H, To 4.52; N, Of 9.21.

Example 48

3-[[4-(acetylamino)-5-chloro-2-methoxyphenyl] methyl] - 5-(2-naphthalenyl)-1.3.4-oxadiazol-2(3H)-he (XV48: X' = Cl, Y = NHAc, R1= R4= H, R3= R4= -C2H2-

Example 49

3-[2-methoxyphenyl] methyl] -5-[4-(trifluoromethyl)phenyl] - 1.3.4-oxadiazol-2(3H)-he (XV49: X' IS H, Y = H, R1= R2= R4= H, R3= CF3)

So pl. 107,5-108,5oC

Analysis, calculated: C17H13F3N2O3: C, 58,29; H, 3,74; N, 8.00.

Found: C, 58,30; H, 3,61; N, Of 7.90.

Example 50

3-[(5-chloro-2-methoxyphenyl)methyl] -5-[4- (trifluoromethyl)phenyl]-1.3.4-oxadiazol-2(3H)-he (XV50: X' = Cl, Y = H, R1=R2=R4=H, R3= CF3)

So pl. 144-145oC

Analysis, calculated: C17H12ClF3N2O30,1 H2ABOUT: WITH, 52,81; H, 3,91; N, 7,25.

Found: C, 53,03; H, 3,20; N, 7,31.

Example 51

3-[(2-methoxy-5-chlorophenyl)methyl] -5-[3,5 - bis(trifluoromethyl)phenyl] -1,3,4-oxadiazol-2(3H)-he (XV51: X'=Cl, Y=H, R1=R3-H, R2=R4=CF3)

So pl. 127-128oC

Analysis, calculated: C18H11ClF6N2O3: C, 47,75; H, AT 2.45; N, TO 6.19.

Found: C, 47,83; H, 2,42; N, 6,17.

Example 52

3-[[2-methoxy-5-chlorophenyl] methyl] -5-[2-chloro-5- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-2(3H)-he (XV52: X'= Cl, Y= H, R1-Cl, R3=R2=H, R4=CF3)

So pl. 151-152oC

Analysis, calculated: C17H11
3-[[2-methoxy-5-chlorophenyl] methyl]-5-[3.5 - dichlorophenyl]-1.3.4-oxadiazol-2(3H)-he (XV53: X' = Cl, Y = H, R1= R3= H, R2= R4= Cl)

So pl. 172-173oC

Analysis, calculated: C16H11Cl3N2O3: C, 49,83; H, 2,87; N, 7,26.

Found: C, 49,75; H, 2,86; N, 7,31.

Example 54

3-[(5-chloro-2-methoxyphenyl] methyl] -5[2-fluoro-4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-2(3H)-he (XV54: X' = Cl, Y = H, R1= F, R1= R3= H, R2= R4= CF3)

So pl. 126-128oC

Analysis, calculated: C17H11ClF4N2O3: C, 50,70; H, 2,75; N, OF 6.96.

Found: C, 50,55; H, 2,66; N, 7,07.

Example 55

3-[(5-chloro-2-methoxyphenyl] methyl] -5-[4-fluoro-4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-2(3H)-he (XV55: X' = Cl, Y = H, R1= R4= H, R2= CF3, R3= F)

So pl. 118-119oC

Analysis, calculated: C17H11ClF4N2O3: C, 50,70; H, 2,75; N, OF 6.96.

Found: C, 50,70; H, 2,72; N, 7,01.

Examples 56 and 57

< / BR>
Example 56

3-[(5-chloro-2-methoxyphenyl]methyl]-5- [2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl]-1.3.4-oxadiazol-2(3H)-he (XVII56)

3-[(5-chloro-2-methoxyphenyl] methyl] -5-[2-fluoro-4- (trifluoromethyl)phenyl] -1,3,4-oxadiazol-2(3H)-he (1.2 g, of 2.97 mmol) and imidazole (the sodium (135 mg, 4.6 mmol) (80%), the reaction mixture is heated at 80oC for 3 hours the Solution was diluted with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed with water, brine and dried over MgSO4. (Concentration) chromatography on SiO2, elution with a mixture of 15% ethyl acetate/chloroform gives of 1.16 g (61%).

So pl. 143,5-151oC

Analysis, calculated: C20H14ClF3N4O3: C, 53,29; H, 3,13; N, 12,43.

Found: C, 53,36; H, 2,95; N, 12,24.

The following imidazole obtained by the method similar to that described in Example 56.

Example 57

3-[(5-chloro-2-methoxyphenyl]methyl]-5-[4-(1H-imidazol-1-yl)-3- (trifluoromethyl)phenyl]-1.3.4-oxadiazol-2(3H)-he (XVII57)

So pl. 148-150oC

Analysis, calculated: C20H14ClF3N4O3: C, 53,29; H, 3,13; N, 12,43.

Found: C, 53,15; H, 3,10; N, 12.24.

Example 58

Methyl ester of 4-(acetylecholine)-5-chloro-2 - methoxybenzoic acid

< / BR>
Methyl ester of 4-(acetylamino)-5-chloro-2-methoxybenzoic acid (10.0 g, 38,08 mmol) dissolved in anhydrous THF (250 ml) under nitrogen atmosphere and add portions of 1.23 g of sodium hydride (80%, of 41.0 mmol). Add methyl iodide (2.5 ml, 40,1 mmol) and the reaction mixture is boiled with opactiy. Water is added and the solution was concentrated in a rotary evaporator, the residue is treated with ethyl acetate and washed with water, brine, dried over MgSO4. Chromatography on SiO2, elution with a mixture of 55 % ethyl acetate hexane to give 4.77 g, (45%): so pl. of 105.5-107oC; IR (KBr, = cm-1) 3040, 1712, 1662, 1242;1H NMR (300 MHz, DMSO-d6) : 1,72 (3H,s), of 3.07 (3H, s), with 3.79 (3H, s), of 3.84 (3H, s), 7,41 (1H, s), 7,81 (1H. s); MS(DCl)m/z: 272(MH+).

Analysis, calculated: C12H14ClNO4: C, 53.05; H, 5,19; N, 5,15.

Found: C, 53,05; H, Of 5.05; N, 4,96.

Example 59

4-(ethylmethylamino)-5-chloro-2-methoxybenzimidazole

< / BR>
Methyl ester of 4-(acetylamino)-5-chloro-2-methoxybenzoic acid (2.0 g, 7.36 mmol) is treated with anhydrous THF (50 ml) and 40 ml of diethyl ether. Add portions of alumoweld lithium (558 mg, 14.7 mmol) and the reaction mixture stirred for 2 h, then cooled to 0oC and neutralize 1 N sodium hydroxide solution. The resulting suspension is filtered and the filtered salt vigorously washed with THF. The filtrate was concentrated in a rotary evaporator to obtain 1.6 g (89.5% of oil, representing a mixture of 5:1 of the product and 4-(acetylecholine)-5-chloro-2 - methoxybenzimidazole. Product:1H NMR (300 MHz, DMSO - d6) : of 1.06 (3H, t, J = 7.03 is Hz), 2,69 (3H, s), 3,01 (vinylmethyl)lensmeter

< / BR>
Stage A: 4-[(4-methoxyphenyl)methyl]morpholine. Intermediate (intermediate product)

4-methoxybenzylamine (25 g, of 0.16 mol), morpholine (14 g, of 0.16 mol) and potassium carbonate (22 g, of 0.16 mol) is treated with acetonitrile and add K1 (8.7 g, a 0.04 mol). The reaction mixture was refluxed for 18 h, filtered, the filtrate concentrated azeotrope distillation with benzene, get 17,5 g (88%) as an oil; IR (film ) = cm-1) 2956, 2806, 1514, 1246, 1118, 866; 1H NMR (300 MHz, DMSO-d6) : to 2.29 (4H, br.s) to 3.35 (2H, s), 3,53 (4H, t, J = 4.4 Hz), 3,71 (3H, s), 6,86 (2H, d, J = 8.5 Hz), 7,19 (2H, d, J = 8.5 Hz); MS(DCl)m/z: 208(MH+).

Stage b: 2-methoxy-5-(4-morpholinylmethyl)lensmeter

4-[(4-methoxyphenyl)methyl] morpholine (5 g, 24,1 mmol) and the solvent N,N, N',N',N"-pentamethyldiethylenetriamine (PMDTA) (5,4 ml, 26.0 mmol) cooled to -78oC in anhydrous THF under nitrogen atmosphere, and added with a syringe 20 ml Deut. -BuLi (1.3 M, 26.0 mmol). The reaction mixture is stirred for 2 h and added DMF (3.5 ml, 40 mmol) and then slowly brought to room temperature. The solution is concentrated and the residue is treated with ethyl acetate, washed with brine and dried.

The resulting aldehyde is treated with methanol (500 ml) under nitrogen atmosphere and add portions at room temperature borohydride the evaporator. The residue is distributed between ethyl acetate and water and the organic phase washed with brine. Chromatography on SiO2, elution with a mixture of methanol/ethyl acetate/ hexane (1: 2: 7), gives 2.3 g (40%) of the alcohol as an oil; IR (film, = cm-13400, 2810, 1612, 1500, 1250, 1116, 1034;1H NMR (300 MHz, DMSO-d6) : 2.30 (4H, br.s) to 3.36 (2H, s), of 3.54 (4H, t, J = 5.6 Hz), to 3.73 (3H, s), to 4.46 (2H, d, J = 5.6 Hz), 4,99 (1H, t, J = 5.6 Hz), 6,85 (1H, d, J = 8,3 Hz), 7,10 (1H, dd, J = 8,2 Hz, 1.6 Hz), 7,30 (1H, s); MS(DCl)m/z: 238(MH+).

Example 61

Methyl ester 5-(1H-imidazol-1-yl)-2-methoxybenzoic acid

< / BR>
Methyl ester of 5-bromo-2-methoxybenzoic acid (5 g, of 20.4 mmol), imidazole (1.4 g, to 20.6 mmol) and potassium carbonate (2.6 g, of 20.7 mmol) in DMF under nitrogen atmosphere heated to 145oC and add portions of copper iodide (1.5 g, 7.9 mmol). The reaction mixture is stirred at this temperature for 18 h, then cooled and filtered through a layer of celite. The filtered salt thoroughly washed with methanol and the filtrate was concentrated in vacuo, the residue is treated with ethyl acetate, washed with water, brine and dried. Chromatography on SiO2, elution with a mixture of methanol/ethyl acetate/hexane (1: 1: 3), gives 3 g (63%); IR (KBr, = cm-13430, 1726, 1512, 1232, 1068;1H NMR (300 MHz, D6) / : of 3.80 (3H, s), 3,85 (3H, s), 7,07 (1H, s), 7,27 (1H, d, J = 8,8 Hz), 7,69 (1H, s), 7,76-7,82 (2 the th air 5-(1H-imidazol-1-yl)- 2-methoxybenzoic acid (2.0 g, 8.6 mmol) cooled to 0oC in anhydrous THF (50 ml) under nitrogen atmosphere and add alumoweld lithium. The reaction mixture was stirred for 18 h at 24oC and add water (0.7 ml), and then cautiously added dropwise to a 15% sodium hydroxide solution (0.7 ml). The resulting suspension is filtered and concentrated to obtain 1.3 g (74%).1H NMR (300 MHz, DMSO-d6) : 3,81 (3H, s) to 4.52 (2H, d, J = 4.3 Hz), 5,18 (1H, br.s),? 7.04 baby mortality-7,06 (2H, m), the 7.43 (1H, dd, J - 8.7 Hz, 2.8 Hz), 7,52 (2H, d, J = 2,8 Hz), 7,58 (1H, s), 8,07 (1H, s). MS(DCl)m/z: 205(MH+).

Example 63

2-methoxy-5-(1-methyl-1H-imidazol-2-yl)lensmeter

Stage A: [(5-bromo-2-methoxyphenyl)methoxy] dimethyl(1.1-dimethyl - ethyl)silane

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5-bromo-o-anisaldehyde (30 g of 0.14 mol) dissolved in THF (30 ml) and 500 ml of methanol. Add portions over 10 min borohydride sodium (8 g, 0.21 mol), the solution stirred for 3 h and neutralized with 5% HCl solution. The solvent is removed in a rotary evaporator and the residue is treated with ethyl acetate, washed with 1N HCl solution, water, brine and dried over MgSO4. Concentration causes of 29.4 g (97,2%) oil.

Alcohol (20,0 g, 0,092 mol), tert.-butyldimethylsilyl chloride (15,28 g of 0.10 mol) and imidazole (13,82 g of 0.20 mol) is stirred in DMF (100 ml) for 18 hours the Solution was poured into water (250 ml) and extracted with cm is the Concentration of the oil, which crystallizes upon standing, and 29.9 g (98%); so pl. 28-29,5oC; IR (KBr, = cm-1) 2954, 2930, 1488, 1464, 1258, 1094;1H NMR (300 MHz, DMSO-d6) : is 0.06 (6H, s) to 0.89 (9H, s in), 3.75 (3H, s), 4,63 (2H, s), make 6.90 (1H, d, J = 8.6 Hz), 7,37 (1H, dd, J = 8.6 Hz, 2.6 Hz), 7,42 (1H, d, J = 2.5 Hz); MS(DCl)m/z: 331 (MH+).

Analysis, calculated: C14H23BrO2Si: C, 50,75; H, 7,00.

Found: C, 50,89; H, 6,95.

Stage b: 2-methoxy-5-(1-methyl-1 H-imidazol-2-yl)lensmeter

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n-Utility (5,2 ml of 2.5 M in hexane) is added dropwise to N-methylimidazole (2 g, 24.4 mmol) in THF (26 ml) in nitrogen atmosphere at -78oC and the solution stirred for 2.5 h, then added zinc chloride (3.33 g, 24.4 mmol) dissolved in 22 ml of the same solvent, and the cold bath removed. After 30 min was added tetrakis(triphenylphosphine)palladium(0) (172 mg, 0.15 mmol), and then [(5-bromo-2-methoxyphenyl)methoxy]dimethyl(1,1 - dimethylethyl)silane (9.7 g, of 29.3 mmol) in solution in THF (14 ml). The reaction mixture is stirred at the boil under reflux for 2 h, cooled to room temperature, add additional zinc chloride (6,77 g, 24.4 mmol), dissolved in 30 ml of THF, and the solution was again refluxed for 3 hours the Solvent is removed in a rotary evaporator, add a solution of disodium salussola and dried (MgSO4). Clean flash chromatography on SiO2 (elution with 35% THF /benzene) gives 4,32 g (53%).

The product is treated with THF (45 ml) and added dropwise 17 ml of a solution of Tetra-n-butylammonium fluoride (1 M in THF, was 9.33 mol). The reaction mixture is stirred for 4 hours, add a solution (5 ml) of ammonium chloride and then a saturated solution of NaCO3and extracted with ethyl acetate. The organic phase is washed with brine and concentrated. Recrystallization from ethyl acetate gives 2,22 g (79%); so pl. 116,5-118oC; IR (KBr, = cm-1) 3170, 1612, 1506, 1478, 1358, 1252, 1054;1H NMR (300 MHz, DMSO-d6) : of 3.69 (3H, s), 3,81 (3H, s), a 4.53 (2H, d, J = 5.7 Hz), 5,16 (1H, t, J = 5.7 Hz), 6,92 (1H, d, J = 1.1 Hz), 7,01 (1H, d, J = 8.5 Hz), 7,18 (1H, d, J = 1.0 Hz), to 7.50 (1H, dd, J = 8,5 Hz, 2.2 Hz), to 7.68 (1H, d, J = 2.2 Hz); MS(DCl)m/z: 219(MH+).

Analysis, calculated: C12H14N2O2: C 66,04; H, 6,47; N, 12,84.

Found: C, 66,13; H, 6,09; N, 12,84.

Example 64

2-methoxy-5-(2-pyridinyl)lensmeter

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2-pyridine derivative obtained by the method similar to that described in Example 63.

So pl. 92-93oC; IR (KBr, = cm-1) 3324, 1584, 1562, 1436, 1272, 1042, 782;1H NMR (300 MHz, DMSO-d6) : is 3.82 (3H, s), 4,56 (2H, d, J = 5.7 Hz), 5,13 (1H, t, J = 5.7 Hz), 7,02 (1H, d, J = 8.6 Hz), 7.23 percent-7,27 (1H, m), to 7.77-7,86 (2H, m), 7.94 (1H, dd, J = 8.6 Hz, 2.4 Hz), 8,17 (1H, d, J = 2.3 Hz), 8,59-to 8.62 (1H, m); MS(DCl)m/z: 216(MH+).

Examples 65-67

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Example 65

3-[[2-methoxy-5-(4-morpholinyl yl)phenyl]methyl]-5-[4-(trifluoromethyl)phenyl]-1.3.4-oxadiazol - 2(3H)-he (XV65: X' morpholinylmethyl, Y = H, R1= R2= R4- H, R3= CF3)

5-[4-(trifluoromethyl)phenyl] -1,3,4-oxadiazol-2(3H)-he (1 g, 4.3 mmol), 2-methoxy-(4-morpholinylmethyl)benzyl alcohol (1,05 g, 4.3 mmol) and triphenylphosphine (1.1 g, 4.3 mmol) dissolved in THF (100 ml) at 0oC in nitrogen atmosphere. Added dropwise diethylazodicarboxylate (0.68 ml, 4.3 mmol) and the solution stirred for 18 h at 24oC. Concentration (chromatography) on SiO2 and elution with a mixture of 20% THF / benzene gives 1.35 g (70%), recrystallized from diethyl ether. So pl. 124-125oC.

Analysis, calculated: C22H22F3N3O4: C, 58,80; H, IS 4.93; N, 9,35.

Found: C, 58,70; H, To 4.81; N, 9,16.

The following oxadiazole obtained according to the method of Mitsunobu, similar to that described in Example 65.

Example 66

3-[5-chloro-4-[(ethylmethylamino)-2-methoxyphenyl] methyl]-1,3,4-oxadiazol-2(3H)-he (XV66: X' - ethylmethylamino, Y = H, R1= R2= R4= H, R3= CF3)

So pl. 105-107oC.

Analysis, calculated: C20H19ClF3N3O3: C, 54,37; H, 4,33; N, 9,51.

67: X' = 2 - pyridinyl, Y = H, R1= R2= R4H, R3= CF3)

So pl. 165-166oC.

Analysis, calculated: C22H16F3N3O3: C, 61,83; H, OF 3.77; N, 9,83.

Found: C, 60,48; H, A 3.87; N, 9,66.

Examples 68-69

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Example 68

3-[(4-amino-5-chloro-2-methoxyphenyl)methyl] -5- [3.4-dichlorophenyl] -1.3.4-oxadiazol-2(3H)-he (XVI68: R1= R4= H, R2- R3= Cl)

N-[2-chloro-4-[[1,5-dihydro-5-oxo-3-[3,4 - chlorphenyl]-1,2,4-oxadiazol-1-yl] methyl]-5-methoxyphenyl]ndimethylacetamide (1 g, 2.45 mmol) is treated with absolute ethanol (110 ml) add a solution of concentrated HCl (11 ml) and the reaction mixture refluxed for 1 h the Solvent is removed in a rotary evaporator and the residue is treated with ethyl acetate (solubility add a little THF) and washed with a solution of NaHCO3, brine and dried (MgSO4). Concentration gives 903 mg (92%). So pl. 196-197,5oC;1H NMR (300 MHz, DMSO-d6) : of 3.69 (3H, s), 4,74 (2H, s), to 6.57 (1H, s), of 6.68 (3H, br.s), 7,17 (1H, s), of 7.70 (1H, dd, J = 8,4 Hz, 1.9 Hz), to 7.77 (1H, d, J = 8,4 Hz), 7,89 (1H, d, J = 1.9 Hz).13C NMR (75 MHz, DMSO-d6) : 156,70, 152,43, 150,49, 144,06, 134,23, 132,23, 131,65, 130,15, 126,90, 125,41, 124,04, 112,81, 109,16, 99,40, 55,63, 44,06; MS(DCl)m/z: 400(MH+).

Example 69

3-[(4-amino-5-chloro-2-methoxide is H, R3= CF3)

The above aniline obtained by the method similar to that described in Example 68.

So pl. > 190oC (decomp.).

Analysis, calculated: C17H13ClF3N3O31,0 H2O: C, 46.81 / BBL; H, 3,24; N, 9,63.

Found: C, 46,97; H, 3,19; N, 9,54.

Examples 70-74

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Example 70

2-bromo-N-2-chloro-4-[[1.5-dihydro-5-oxo-3-[4- (trifluoromethyl)phenyl] -1.2.4-oxadiazol-1-yl]methyl]-5 - methoxyphenyl]ndimethylacetamide (XIX70: QN=Br)

3-[(4-amino-5-chloro-2 - methoxyphenyl)methyl] -5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol - 2(3H)-he (3 g, 7.5 mmol) and pyridine (0.68 ml, to 8.41 mmol) dissolved in THF (35 ml) under nitrogen atmosphere and cooled to 0oC. is Added dropwise bromoacetamide (to 0.72 ml, compared to 8.26 mmol) and the reaction mixture stirred for 18 h at 24oC, and then distributed between ethyl acetate (400 ml) and 0.1 N HCl solution (50 ml). The organic phase is washed with a saturated solution of NaHCO3and brine and dried over MgSO4. Add activated carbon (500 mg) and the solution is filtered through a layer of celite. Concentration gives 3.8 g (98%): so pl. 140 - 182oC (decomp.); IR (KBr, = cm-1) 3348, 2972, 1784, 1672, 1594, 1234, 1168, 1066;1H NMR (300 MHz, DMSO-d6) : of 3.77 (3H, s), is 4.15 (2H, s), the 4.90 (2H, s), 7,47-of 7.48 (2H, m), 7,86 (2H, d, J = 8,4 Hz), of 7.96 (1H, d, J = 8,3 Hz), of 9.30 P CLASS="ptx2">

Found: C, 43,68; H, Of 2.54; N, To 7.77.

Example 71

N-[2-chloro-4-[[1.5-dihydro-5-oxo-3-[4- (trifluoromethyl)phenyl] -1.2.4-oxadiazol-1-yl] methyl 1-5 - methoxyphenyl] -4-morpholinoethyl (XIX71: QN= morpholine)

2-bromo - N-2-chloro-4-[[1,5-dihydro-5-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,4 - oxadiazol-1-yl] methyl] -5-methoxyphenyl] ndimethylacetamide (1 g, 1.9 mmol), morpholine (167 mg, 1.9 mmol), potassium carbonate (262 mg, 1.9 mmol) and KI (78 mg) was dissolved in acetonitrile (100 ml) and refluxed for 3.5 hours, the Reaction mixture was filtered, concentrated in a rotary evaporator and the residue is treated with ethyl acetate and washed with water and brine. Recrystallization from acetonitrile gives 900 mg (90%). So pl. 178-179oC; IR (KBr, = cm-1) 3434, 2848, 1772, 1696, 1528, 1324, 1118;1H NMR (300 MHz, DMSO-d6) : of 2.56 (4H, br.s) 3,18 (2H, s), the 3.65 (4H, t, J = 4.3 Hz), of 3.78 (3H, s), 4,88 (2H, s), to 7.50 (1H, s), 7,88 (2H, d, J = 8.5 Hz), of 7.96 (1H, d, J = 8,4 Hz), of 8.04 (1H, s), 9,94 (1H, s); MS(ESI)m/z: 527 (MH+).

Analysis, calculated: C23H22ClF3N4O5: C, 52,43; H, 4,21; N, 10,63.

Found: C, 52,31; H, 4,08; N, 10,56.

Connection Examples 72-74 obtained by the method similar to that described in Example 71.

Example 72

N-[2-chloro-4-[[2.3-dihydro-2-oxo-5-[4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-3-yl]methyl]-5 - methoxyphenyl]-4-methyl-1-PIP: C24H25ClF3N5O4: C, 53,39; H, OF 4.67; N, 12,97.

Found: C, 53,34: H, 4,72; N, 12,80.

Example 73

N-[2-chloro-4-[[2.3-dihydro-2-oxo-5-[4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-3-yl]methyl]-5-methoxyphenyl]- 4-phenyl-1-piperazineethanol (XIX73: QN= N-methylpiperazin)

So pl. 228-230oC.

Analysis, calculated: C29H27ClF3N5O4: C, 57,89; H, TO 4.52; N, 11,63.

Found: C, 57,90; H, Of 4.54; N, 11,59.

Example 74

N-[2-chloro-4-[[2.3-dihydro-2-oxo-5-(4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-3-yl] methyl]-5-methoxyphenyl]- 2-(dimethylamino)ndimethylacetamide (XIX74: QT= dimethylamine)

So pl. 140-143,5oC.

Analysis, calculated: C21H20ClF3N4O40,1 H20:

WITH, 51,81; H, 4,19; N, 11,51.

Found: C, 51,42; H, 4,24; N, 10,90.

Example 75

3-[(-5-chloro-2-methoxyphenyl)methyl] -5-[4- (trifluoromethyl)-phenyl] -1.3.4 - oxadiazol-2(3H)-tion (XVIII75)

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3-(-5-chloro-2-methoxyphenyl)-5-[4- (trifluoromethyl)-phenyl] -1,3,4-oxadiazol-2(3H)-tion (1 g, 2.7 mmol) and reagent Lawesson (800 mg, to 1.98 mmol) is refluxed in toluene (50 ml) for 18 hours Add another 400 mg of the reagent and the reaction refluxed 48 hours Concentration (chromatography) is tilby ether / ethyl acetate to give 800 mg (77%). So pl. 158 - 159oC; IR (KBr, = cm-1) 3456, 1608, 1492, 1450, 1332, 1318, 1250, 1166, 1112;1H NMR (300 MHz, DMSO-d6) : is 3.82 (3H, s), at 5.27 (2H, s), was 7.08 (1H, d, J = 8.6 Hz), 7,34-7,40 (2H, m), to 7.93 (2H, d, J = 8.5 Hz), 8,07 (2H, d, J = 8,3 Hz); MS(DCl)m/z: 401 (MH+).

Analysis, calculated: C17H12ClF3N2O2S: C, 50,94; H, TO 3.02; N, 6,99.

Found: C, 50,87; H, 3,00; N? 7.04 Baby Mortality.

Examples 76-77

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Example 76

3-[[5-chloro-4-(2.3-dihydro-2-oxo-1H-imidazol - 1-yl)-2-methoxyphenyl] -methyl]-5-[4-(trifluoromethyl)phenyl]-1.3.4 - oxadiazol-2(3H)-he (XX76: X = O)

5-[(4-amino-5 - chloro - 2 - methoxyphenyl)methyl]-5-[4-(trifluoromethyl)-phenyl] -1,3,4 - oxadiazol-2(3H)-he (1,14 g, 2.9 mmol) and triethylamine (1.0 ml, 6.8 mmol) is treated with anhydrous THF (20 ml) and contribute dropwise via syringe in a 20% solution of phosgene in toluene at 0oC in nitrogen atmosphere. The reaction is stirred for 2.5 h at 24oC, diluted with diethyl ether (1 volume) and filtered through a layer of celite. Concentration in a rotary evaporator gives a solid, which was dissolved in dichloromethane (50 ml) under nitrogen atmosphere and add aminoacetaldehyde (0,42 ml, 2.9 mmol). The solution is stirred for 3 h and concentrated to remove solvent. The residue is treated with 25 ml of formic acid (88%) and stirred for 18 h at 24oC. the Formic acid is removed in the ro is m and dried. Concentration (chromatography) on SiO2, elution with a mixture of 45% /THF / benzene, give 850 mg (65%); so pl. 201-202oC; IR (KBr, = cm-1) 3314, 1792, 1694, 1330, 1236, 1136;1H NMR (300 MHz, CDCl3) / : 3,86 (3H, s), equal to 4.97 (2H, s), 6,38 (2H, br.s) of 6.99 (1H, s), 7,40 (1H, s), 7,71 (2H, d, J = 8,4 Hz), 7,94 (2H, d, J = 8,2 Hz), 10,28 (1H, br.s); MS(ESI)m/z: 465(MH+).

Analysis, calculated: C20H14ClF3N4O40,1 H2ABOUT: WITH, 51,20; H, A 3.06; N, 11,94.

Found: C, 51,18; H, 3,10; N, 11,99.

Example 77

3-[[5-chloro-4-(2.3-dihydro-2-thio-1H-imidazol-1-yl)- 2-methoxyphenyl] -methyl]-5-[4-(trifluoromethyl)phenyl]-1.3.4-oxadiazol - 2(3H)-he (XX77: X = S)

The above-mentioned compound obtained by the method similar to that described in Example 76, using thiophosgene instead of phosgene.

So pl. 184-185oC.

Analysis, calculated: C20H14ClF3N4O3S: C, 49,75; H, 2,92; N, 11,60.

Found: C, 49,56; H, 2,82; N, 11,53.

Examples 78-80

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Example 78

3-[(4-amino-5-chloro-2-hydroxyphenyl)methyl] -5- [3.4-dichlorophenyl]-1.3.4-oxadiazol-2(3H)-he (XVI78: R1= R4= H, R2= R3= Cl)

3-[(4-amino-5-chloro-2-methoxyphenyl)methyl] -5-[3,4 - dichlorophenyl] -1,3,4-oxadiazol-2(3H)-he (903 mg, 2.25 mmol) is treated with dichloromethane (55 ml) and cooled to 0oC in the atmosphere and the 24oC and make dropwise at 0oC with vigorous stirring in 200 ml of a saturated solution of NaHCO3. The product is extracted with ethyl acetate (solubility add a little THF), washed with brine and dried over MgSO4. Rubbing with hot methanol to give 853 mg (97%); so pl. 202-203oC; IR (KBr, = cm-1) 3364, 3296, 1804, 1166, 738;1H NMR (300 MHz, DMSO-d6) : 4,72 (2H, s), 5,31 (2H, s), of 6.29 (1H, s), 7,40 (1H, s), 7,71 (2H, dd, J = 8,4 Hz, 2.0 Hz), 7,78 (1H, d, J = 8,4 Hz), of 7.90 (1H, d, J = 1.9 Hz), to 9.57(1H, s); MS(ESI)m/z: 384 (MH+).

Analysis, calculated: C15H10Cl3N3O3: C, 46,60; H, 2,61; N, 10,87.

Found: C, 46,56; H, 2,52; N, To 10.62.

The following phenols, Examples from 79 to 107 obtained by the method similar to that described in Example 78, using BBr3.

Example 79

3-[[4-(amino)-5-chloro-2-hydroxyphenyl] methyl] -5- [3.5-dichlorophenyl] -1.3.4-oxadiazol-2(3H)-he (XVI79: R1 = R3 = H, R2 = R4 = Cl)

So pl. 219-220oC.

Analysis, calculated: C15H10C13N3O3: C, 46,60; H, 2,61; N, 10,87.

Found: C, 46,49; H 2,80; N, 10,65.

Example 80

3-[(4-amino-5-chloro-2-hydroxyphenyl] methyl] -5-[ 3.4-(trifluoromethyl)phenyl] -1.3.4-oxadiazol-2(3H)-he (XVI80: R1= R2= R4= H, R3= CF3)

So pl. 210-212oC.

Found: C, 49,68; H, 2,73; N, 10,99.

Examples 81-87

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Example 81

3-[2-hydroxyphenyl)methyl] -5-[4- (trifluoromethyl)phenyl]-1,3.4-oxadiazol-2(3H)-he (XV81: X' = H, Y = H, R1= R2= R4= H, R3= CF3)

So pl. 181-182oC.

Analysis, calculated: C16H11F3N2O3: C, 57,15; H, 3,30; N, 8,33.

Found: C, 57,14; H, 3,35; N, 8,19.

Example 82

3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4- (trifluoromethyl)phenyl]-1.3.4-oxadiazol-2(3H)-he (XV82: X' = Cl, Y = H, R1= R2= R4= H, R3- CF3)

So pl. 217-218oC.

Analysis, calculated: C16H10ClF3N2O3: C, 51,84; H, 2,72; N, 7,56.

Found: C, 51,88; H, 2,58; N, EUR 7.57.

Example 83

3-[[2-hydroxy-5-[chlorophenyl)methyl] -5-[3.5 - bis(trifluoromethyl)phenyl] -1.3.4-oxadiazol-2(3H)-he (XV83: X' = Cl, Y = H, R1= R3= H, R3= R4= CF3)

So pl. 171-172oC.

Analysis, calculated: C17H9ClF6N2O3: C, 46,54; H, 2,07; N, 6,39.

Found: C, 46,82; H, 2,07; N, 6.30-In.

Example 84

3-[(5-chloro-2-hydroxyphenyl)methyl] -5-[4-fluoro-3- (trifluoromethyl)-phenyl]-1.3.4-oxadiazol-2(3H)-he (XV84X' = Cl, Y = H, R1= R4= H, R2= CF3, R4= F2,30; N, 7,21.

Found: C, 49,15; H, 2,16; N, 7,17.

Example 85

3-[[2-hydroxy-5-chlorophenyl] methyl] -5-[2-chloro-5- (trifluoromethyl)-phenyl]-1.3.4-oxadiazol-2(3H)-he (XV85: X' = Cl, Y = H, R1= Cl, R2= R3= H, R4= CF3)

So pl. 177-179oC.

Analysis, calculated: C16H9C12F3N2O3: C, 47,43; H, 2,24; N, 6,91.

Found: C, 47,40; H, 2,24; N, Of 6.96.

Example 86

3-[[2-hydroxy-5-chlorophenyl] methyl] -5-[3.5 - dichlorophenyl]-1.3.4-oxadiazol-2(3H)-he (XV86: X' = Cl, Y = H, R1= R3= H, R2= R4= Cl)

So pl. 207-209oC.

Analysis, calculated: C16H9Cl3N2O3: C, 48,48; H, 2,44; N, 7,54.

Found: C, 48,51; H, 2,37; N, To 7.61.

Example 87

3-[5-chloro-2-hydroxyphenyl)methyl] -5-[2-fluoro-4- (trifluoromethyl)-phenyl] -1.3.4-oxadiazol-2(3H)-he (XV86: X' = Cl, Y = H, R1= F, R2= R4= H, R3-CF3)

So pl. 202-204,5oC.

Analysis, calculated: C16H9ClF4N2O3Of 0.1 EtOAc: C, 49,55; H, 2,49; N, 7,05.

Found: C, 49,57; H, Of 2.51; N, 6,91.

Examples 88-89

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Example 88

3-[(4-acetylamino)-3,5-dichloro-2 - hydroxyphenyl)methyl] -5-[3.4-dichlorophenyl] -1.3.4-oxadiazol - 2(3H)-he (XVII88: Y = NHAc, R1= R4oC in nitrogen atmosphere and add 20 ml trichromate boron (1.0 M in CH2Cl2). The reaction mixture was stirred for 18 h at 24oC and make dropwise into 250 ml of a saturated solution of NaHCO3at 0oC with vigorous stirring. The product is extracted with ethyl acetate and THF (added for solubility), washed with brine and dried over MgSO4get 1,9 g (98%).

The obtained phenol (1 g, 2.3 mmol) is treated with toluene (150 ml) and add a catalytic amount of diisobutylamine (3,5 ml) and then Sulfuryl chloride (0.3 ml, 3.7 mmol). The solution is heated under 68oC for 72 h and add Sulfuryl chloride (1,63 ml, 20.3 mmol) until the reaction is complete. The precipitate is filtered off, washed with toluene and dried to obtain 879 mg (81%). Recrystallization gives: so pl. 246-247oC; IR (KBr, = cm-1) 3379, 3231, 1780, 1657, 1473, 1409, 1134;1H NMR (300 MHz, DMSO-d6) : 2,05 (3H, s), equal to 4.97 (2H, s), 5,31 (2H, s), 7,45 (1H, s), 7,73-7,81 (2H, m), 7,92-of 7.96 (2H, m), 9,81 (1H, s), of 10.01 (1H, s); MS(ESI)m/z: 460 (MH+).

Analysis, calculated: C17H11Cl4N3O4-0,05 H2O: C, 44,01; H, 2,41; N, 9,06.

Found: C, 43,85; H, 2,33; N, 9,23.

The chlorination is carried out soglasna)methyl] -5-[3.4 - dichlorophenyl] -1.3.4-oxadiazol-2(3H)-he (XVII89: Y = NH2, R1= R4= H, R2= R3= Cl)

3-[(4-acetylamino)-3,5-dichloro-2 - hydroxyphenyl)methyl] -5-[3,4-dichlorophenyl] -1.3,4-oxadiazol-2(3H)- he (521 mg, 1.1 mmol) is treated with absolute ethanol (60 ml) and add a solution of concentrated HCl (12 ml). The solution is refluxed for 22 h, while adding more hydrochloric acid (6 ml) until the reaction is complete. After cooling, the precipitate is filtered off and dried to obtain 299 mg (63%); so pl. 200,5-202oC; IR (KBr, = cm-1) 3343, 1780, 1609, 1447, 1289, 1214, 1166;1H NMR (300 MHz, DMSO-d6) : a 4.83 (2H, s), of 5.48 (2H, s), 7,17 (1H, s), 7,69-7,73 (1H, m), 7,75 for 7.78 (1H, m), of 7.90-7,81 (1H, m), 9,49 (1H, s); MS(ESI)m/z: 418 (MH+).

Analysis, calculated: C15H9Cl4N3O4: C, 42,79; H, 2,16; N, 9,98; Cl, 33,68.

Found: C, 42,71; H, 2,09; N, 9,77; Cl, 34,11.

Example 90-91

< / BR>
Example 90

3-[(5-chloro-2-hydroxyphenyl)methyl]- 5-[2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl]-1.3.4-oxadiazol - 2(3H)-he (XVIII90: 2-Im 4-CF3)

So pl. 242-243oC.

Analysis, calculated: C19H12F3N4O3: C, 52,25; H, 2,77; N, 12,83.

Found: C, 51,99; H, 2,72; N, 12,46.

Example 91

3-[(5-chloro-2-1-hydroxyphenyl)methyl] -5-[4-(1H - imidazol-1-yl)-3-(trifluoromethyl)phenyl]-1.3.4-oxadiazol-2(3H)-SUB>4
O30,25 H2About; Of 0.1 EtOAc: C, 51,77; H, 2,98; N, 12,45.

Found: C, 51,60; H, 2,73; N, To 12.44.

Examples 92-98

< / BR>
Example 92

3-[[2-hydroxy-5-(morpholinylmethyl) phenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1.3.4-oxadiazol - 2(3H)-he (XV92: X' morpholinylmethyl, Y = H, R1= R2= R4= H, R3= CF3)

The foam.

Analysis, calculated: C21H20F3N3O40,1 H20; 0,2 C6H6: C 58,94; H, 4,32; N, 9,34.

Found: C, 58,97; H, Of 4.44; N, 8,86.

Example 93

3 -[5-chloro-4-[(ethylmethylamino)-2-hydroxyphenyl]methyl] -5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he (XV93: X' ethylmethylamino, Y = H, R1= R2= R4= H, R3= CF3)

So pl. 132-133oC.

Analysis, calculated: C19H17ClF3N3O3: C, 53,34; H, 4,01; N, 9,82.

Found: C, 53,09; H, 3,90; N, 9,82.

Example 94

3-[[2-hydroxy-5-(2-pyridinyl)phenyl] methyl] -5-[4- (trifluoromethyl)-phenyl] -1.3.4-oxadiazol-2(3H)-he (XV94: X' = 2 - pyridinyl, Y = H, R1= R2= R4= H, R3= CF3)

So pl. 198-200oC.

Analysis, calculated: C21H14F3N3O31,0 H2O; 1,0 HCl: C, 53,91; H, 3,66; N, 8,98.

Found: C, 53,65; H, 3,55; N, 9,00.

)- he (XV95: X'= 1-methyl-1H-imidazol-2-yl, Y = H, R1= R2= R4= H, R3= CF3)

So pl. 177-180oC.

Analysis, calculated: C20H15F3N4O30,15 H2O: C, 57,32; H, 3,68; N, 13,37.

Found: C, 57,48; H, 3,66: N 12,95.

Example 96

3-[[2-hydroxy-5-(1-methyl-1H-imidazol-2 - yl)phenyl] methyl] -5-[3.5-bis(trifluoromethyl)phenyl] -1.3.4-oxadiazol - 2(3H)-he (XV96: X' = 1-methyl-1H-imidazol-2-yl, Y = H, R1= R3= H, R2= R4= CF3)

So pl. 203-206oC.

Analysis, calculated: C21H14F6N4O30,1 H2O: C, 51,82; H, 2.96; N, 11,51.

Found: C, 51,63; H, To 2.94; N, 11,50.

Example 97

3 -[[2-hydroxy-5-(1H-imidazol-2-yl) phenyl]methyl]-5-(4-(trifluoromethyl)phenyl] -1,3,4-oxadiazol - 2(3H)-he (XV97: X' = 1H-imidazol-1-yl, Y = H, R1- R2= R4- H, R3= CF3)

Analysis, calculated: C19H13F3N4O3: C, 56,72; H, 3,26; N, 13,93.

Found: C, 56,63: H, 3,22: N, 13,90.

Example 98

3 -[[2-hydroxy-5-(1H-imidazol-1-yl) phenyl]methyl]-5-[3.5-bis(trifluoromethyl)phenyl] -1.3.4 - oxadiazol-2(3H)-he (XV98: X' = 1H-imidazol-1-yl, Y = H, R1= R3= H, R2= R4= CF3)

So pl. 209-211oC.

Analysis, bycicle/P> Examples 99-106

< / BR>
Example 99

N-[2-chloro-4-[[1.5-dihydro-5-oxo-3-[4- (trifluoromethyl)phenyl] -1.2.4-oxadiazol-1-yl] methyl] -5 - hydroxyphenyl]-4-morpholinoethyl (XX99: QN= morpholine)

So pl. 240-241oC.

Analysis, calculated: C22H20ClF3N4O5: C, 51,52; H, 3,93; N, 10,92.

Found: C, 51,49; H, 3,91; N, 10,80.

Example 100

N-[2-chloro 4-[[2.3-dihydro-2-oxo-5-[4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-3-yl] methyl] -5 - hydroxyphenyl]-4-thiomorpholine (XX100: QN= thiomorpholine)

So pl. 250-252oC.

Analysis, calculated: C22H20ClF3N4O4S: C, 49,96; H 3,81; N, 10,59.

Found: C, 50,15; H, Of 3.96; N, 10,35.

Example 101

N-[2-chloro-4-[[2.3-dihydro-2-oxo-5-[4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-3-yl]methyl]-5 - hydroxyphenyl]-4-methyl-1-piperazineethanol, dihydrochloride (XX101: QN= N-methylpiperazin)

So pl. > 220oC (decomp.).

Analysis, calculated: C23H23ClF3N5O42.06 to HCl; 0,7 EtOH; 0,2 H2O: C, 46,02; H, 4,70; N, 11,00.

Found: C, 46,97; H, Of 4.67; N, 10,77.

Example 102

N-[2-chloro-4-[[2.3-dihydro-2-oxo-5-[4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-3-yl]methyl]-5 - hydroxyphenyl]-4-phenyl-1-piperazineethanol, DIAC is
H25ClF3N5O41,75 HCl; 0,15 H2O: C, 51,53; H, TO 4.17; N, OF 10.73.

Found: C, 51,81; H, 4,33; N, 9,92.

Example 103

N-[2-chloro-4-[[2.3-dihydro-2-oxo-5-[4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-3-yl] methyl]-5 - hydroxyphenyl]-4-benzin-1-piperazineethanol (XX103: QN= M - methylpiperazin)

So pl. 187,5-190oC.

Analysis, calculated: C29H27ClF3N5O4: C, 57,86; H, TO 4.52; N, 11,63.

Found: C, 57,89; H, 4,36: N, 11,53.

Example 104

N-[2-chloro-4-[[2.3-dihydro-2-oxo-5-[4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-3-yl]methyl]-5 - hydroxyphenyl]-2-(dimethylamino)ndimethylacetamide, dihydrochloride (XX104: QN= dimethylamino)

So pl. > 233oC (decomp.).

Analysis, calculated: C20H18ClF3N5O41,0 HCl; 0.5 In EtOH; 0,1 H20:, 46,79; H, ANDROID 4.04; N, 10,70.

Found: C, 46,53; H, 3,99; N, At 10.64.

Example 105

N-[2-chloro-4-[[2.3-dihydro-2-oxo-5[1.1'- biphenyl)-1.3.4-oxadiazol-3-yl] methyl] -5-hydroxyphenyl] -4-methyl-1 - piperazineethanol, bisdigitoxoside (XX105: CF3= Ph, QN= N-methylpiperazin)

So pl. 244-247oC.

Analysis, calculated: C28H28ClN5O42,0 HCl;0,34 H2O: C, 54,86; H, OF 5.05; N, 11,42.

Found: C, 54,33; H, Is 4.93; N, 11,10.

acetamid, the dihydrochloride (XX106: CF3= benzo, QN= morpholine)

So pl. 170,5-176oC.

Analysis, calculated: C25H23ClN4O51,0 HCl; 0.5 H2O: C, 55,57; H, OF 4.66; N, 10,37.

Found: C, 55,49; H, 4,59; N, Of 10.21.

Example 107

3-[5-chloro-2-hydroxyphenyl)methyl] -5-[4- (trifluoromethyl)phenyl] -1.3.4-oxadiazol-2(3H)-tion (XIX107)

< / BR>
So pl. 192-194oC (decomp.).

Analysis, calculated: C16H10ClF3N2O2S: C, 49,69; H, 2,61; N, 7,24. Found: C, 49,82; H, 2,77; N, 7,14.

Examples 108 and 109

< / BR>
Example 108

3-[[5-chloro-4-(2.3-dihydro-2-oxo-1H - imidazol-1-yl)-2-hydroxyphenyl] -methyl]-5-[4-(trifluoromethyl)phenyl]- 1.3.4-oxadiazol-2(3H)-he (XXI108: X = O)

So pl. 231-233oC.

Analysis, calculated: C19H12ClF3N4O4: C, 50,40; H, TO 2.67; N, 12,37.

Found: C, 50,18; H, 2,66; N, 12,37.

Example 109

3-[[5-chloro-4-(2,3-dihydro-2-thio-1H-imidazol-1-yl)- 2-hydroxyphenyl] -methyl]-5-[4-(trifluoromethyl)phenyl]-1.3.4 - oxadiazol-2(3H)-he (XXI109: X = S)

So pl. 201-203oC.

Analysis, calculated: C19H12ClF3N4O3S: C, 48,68; H, 2,58; N, 11,95.

Found: C, 48,65; H, Of 2.54; N, 11,84.

Preparative example N 5

Source oxadiazoline floor>3 ethoxy-5-[4-(trifluoromethyl)phenyl]-4(H)-1.2.4 - thiazole (R1= R3= H, R2= CF3)

5-[4-(trifluoromethyl)phenyl)-1,3,4 - oxadiazol-2-amine (10.0 g, 44 mmol) and potassium hydroxide (7.4 g, 0,132 mol) dissolved in abs. ethanol (300 ml) and refluxed for 3 hours After cooling to 24oC the solution is neutralized with acetic acid and concentrated in a rotary evaporator. The residue is treated with ethyl acetate and washed with water and brine. Recrystallization from a mixture of acetonitrile / ether (2:1) to give 9 g (82%); so pl. 151-152oC. IR (KBr, = cm-1) 2996, 1534, 1460, 1330, 1162, 1130, 1070;1H NMR (300 MHz, CDCl3) : of 1.35 (3H, t, J = 7,1 Hz), to 4.38 (2H, q, J = 7.0 Hz), 7,82 (2H, d, J = 8,3 Hz), 8,10 (2H, d, J = 8.1 Hz), 13,64 (1H, br.s); MS(DCl)m/z: 258 (MH+).

Analysis, calculated: C11H10F3N3O: C, 51,37; H, TO 3.92; N, 16,34.

Found: C, 51,40; H, 3,74; N, 16.28 Per.

Example 111

3 ethoxy-5-[3.4-dichlorophenyl]-4(H)-1.2.4-thiazole (R1= R2= Cl, R3= H)

The above toxiciity obtained by the method similar to that described in Example 110.

So pl. 165-165,5oC.

Analysis, calculated: C10H9ClN3O: C, 46,54; H, 3,51; N, 16.28 PER.

Found: C, 46,49; H, 3,56: N, 16,34.

Examples 112-114

< / BR>
Example 112

N-[2-chloro-4-[5-ethoxy-3-[[4- (tripto )

3 ethoxy-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (1,76 g, 6.8 mmol) and N-[4-(methyl bromide)-2-chloro-5-methoxyphenyl] ndimethylacetamide [JP 49049929] (2.0 g, 6.8 mmol) was dissolved in anhydrous DMF under 24oC and add portions in a nitrogen atmosphere 2 EQ. (408 mg, 14 mmol) of sodium hydride (80%). The reaction mixture is stirred for 18 h, poured into water (2 volumes) and extracted with ethyl acetate, washed with brine and dried. Chromatography, elution with a mixture of 20% THF / benzene gives 1.2 g (34%) of the product and 1.1 g (33%) of regioisomer. IR (KBr, = cm-1) 3298, 1664, 1560, 1326, 1160, 1114;1H NMR (300 MHz, DMCO-d6/CDCl3) / : of 1.39 (3H, t, J = 7,1 Hz), of 2.08 (3H, s in), 3.75 (3H, s), a 4.53 (2H, q, J = 7,1 Hz), 5,07 (2H, s), to 7.15 (1H, s), 7,47 (1H, s), of 7.75 (2H, d, J = 8,3 Hz), 8,07 (2H, d, J = 8.1 Hz), 9,48 (1H, s); MS(ES)m/z: 469 (MH+).

Analysis, calculated: C21H20ClF3N4O3: C, 53,80: H, 4,30; N, 11,95.

Found: C, 53,93; H, Of 4.44; N, 11,85.

The following products obtained by the method similar to that described in Example 112.

Example 113

N-[2-chloro-4[5-ethoxy-3-[[3.4-dichlorophenyl] methyl]- 1H-1.2.4-triazole-1-yl] -methoxyphenyl]ndimethylacetamide (XXII113: Y = NHAc, R1= R2= Cl)

So pl. 197-198oC.

Analysis, calculated: C20H19Cl3N4O3: C, 51,14; H, 4,08; N, 11,93.

Found: C, 51,15; H, To 4.17; N, 12,15.

Example 114

SUP> = CF3)

So pl. 74-76oC.

Analysis, calculated: C19H17ClF3N3O2: FROM, TO 55.42; H, 4,16; N, 10,20.

Found: C, 55,80; H, 4,43; N, 9,65.

Examples 115-117

< / BR>
Example 115

2-[(4-amino-5-chloro-2-methoxyphenyl)methyl]-2.4 - dihydro-5-[4-(trifluoromethyl)phenyl] -3H-1.2.4-triazole-3-one (XXIII115: Y = NH2, R1= H, R2= CF3)

N-[2-chloro-4-[5-ethoxy-3-[[4- (trifluoromethyl)phenyl]methyl]-1H-1,2.4-triazole-1-yl] - methoxyphenyl] ndimethylacetamide (1.5 g, 3.2 mmol) is treated with absolute ethanol (100 ml) and 10 ml of concentrated HCl and refluxed for 20 minutes After cooling, the formed precipitate is filtered off, suspended in ethyl acetate (dissolved add a little THF) and washed with a solution of NaHCO3, brine and dried (MgSO4). So pl. > 270oC (Sublim. ); IR (KBr, = cm-1) 3442, 3344, 1680, 1622, 1324, 1164, 1128, 1066;1H NMR (300 MHz, DMSO-d6) : 3,70 (3H, s), 4,74 (2H, s), are 5.36 (2H, s), 6,44 (1H, s), 6.89 in (1H, s), 7,83 (2H, d, J=8,4 Hz), 7,95 (2H, d, J = 8,2 Hz), 12,43 (1H, s); MS(ESI)m/z: 397 (MH+).

Analysis, calculated: C17H14ClF3N4O20,1 H2O: C, 50,95; H, TO 3.58; N, 13.98.

Found: C, 50,66; H, 3,71; N, 13,44.

The following triazolone obtained by the method similar to that described in Primal-3-one (XXIII116: Y = NH2, R1= R2= Cl)

So pl. 265-268oC.

Analysis, calculated: C16H13C13N4O2: C, 48,08: H, OR 3.28; N, 14,02.

Found: C, 48,71; H, To 3.58; N, 13,08.

Example 117

2-[(5-chloro-2-methoxyphenyl)methyl]-2.4 dihydro-5- [4-(trifluoromethyl)-phenyl] -3H-1.2.4-triazole-3-one (XXIII117: Y = H, R1= H, R2= CF3)

So pl. 245-246oC.

Analysis, calculated: C17H13ClF3N3O2: C, 53,21; H, 3,41; N, 10,95.

Found: C, 53,15; H, 3,39; N, Of 10.93.

The following phenols obtained by the method similar to that described in Example 78 using BBr3.

Examples 118-120

< / BR>
Example 118

2-[4-amino-5-chloro-2-hydroxyphenyl)methyl]- 2.4 dihydro-5-[4-(trifluoromethyl)phenyl] -3H-1.2.4-triazole-3-one (XXIII118: Y = NH2, R1= H, R2= CF3)

Analysis, calculated: C16H12ClF3N4O20.5 H2O: C, 48,81; H, TO 3.33; N, 14,23.

Found: C, 49,10; H, 3,42; N, 14,05.

Example 119

2-[(4-amino-5-chloro-2-hydroxyphenyl)methyl] -2.4 dihydro-5-[3,4-dichlorophenyl]-3H-1.2.4-triazole-3-one (XXIII119: Y = NH2, R1= R2= Cl)

So pl. 290-293oC.

Analysis, calculated: C15H11Cl3N4O20,1 Hl)methyl]-2.4 dihydro-5- [4-(trifluoromethyl)phenyl] -3H-1.2.4-triazole-3-one (XXIII120: Y = H, R1= H, R2= CF3)

So pl. > 280oC.

Analysis, calculated: C16H11ClF3N3O2: C 51,98; H, 3,00; N, 11,37.

Found: C, 52,01; H, 3.04 From; N, 11,35.

Preparative example N 6

Example 121

5-chloro-3-[2-oxo-2-[4-(trifluoromethyl)phenyl] ethyl] - 2(3H)-benzoxazolone (XXIV121)

< / BR>
Bromine (of 0.67 ml, 13 mmol) is added dropwise at room temperature to a solution of 4'-(trifluoromethyl)acetophenone (2.5 g, 13 mmol) in diethyl ether (20 ml) and 1,4-dioxane (10 ml). Chlorzoxazone (2,19 g, 13 mmol) is treated with sodium hydride (400 mg, 13 mmol) in DMF under nitrogen atmosphere for 15 min and applied with a syringe in a freshly prepared solution of bromide. The reaction mixture was stirred at 60oC for 3 h and poured into water (1 volume). The product is extracted with ethyl acetate, the organic layer washed with water and brine and dried. Concentration leads to solid substance 4.4 g (93%), which is recrystallized from acetonitrile; so pl. 188-189oC. IR (KBr, cm-1) 1776, 1704, 1330, 1226, 1122;1H NMR (300 MHz, DMSO-d6) : 5,64 (2H, s), 7,20 (1H, dd, J = 8.6 Hz, 2.1 Hz), 7,44 (1H, d, J = 8.5 Hz), EUR 7.57 (1H, d, J = 2.1 Hz), to 7.99 (2H, d, J = 8,3 Hz), of 8.27 (2H, d, J = 8.1 Hz); MS(DCl)m/z: 356 (MH+).

Analysis, calculated: C16H9ClF3NO-1,3 dihydro-4-[4- (trifluoromethyl)phenyl]-2H-imidazol-2-he (XXV122)

< / BR>
5-chloro-3-[2-oxo-2-[4-(trifluoromethyl)phenyl] ethyl]-2(3H)- benzoxazolone (1 g, 2.8 mmol) and ammonium acetate (2.1 g, 28 mmol) is treated with acetic acid (100 ml) and heated at 100oC for 2 h the Solution was poured into water (2 volumes) and extracted with dichloromethane. Concentration leads to a solid substance which is recrystallized from a mixture of acetonitrile / AcOH (10: 1); so pl. 278-279oC. IR (KBr, = cm-1) 2980, 1668, 1624, 1498, 1328, 1170, 1136, 1066;1H NMR (300 MHz, DMSO-d6) : 7,01 (1H, d, J = 8.7 Hz), 7,26 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7,46 (1H, d, J = 2.6 Hz), 7,52 (1H, d, J = 1.6 Hz), 7,72 (2H, d, J = 8.6 Hz), 7,78 (2H, d, J = 8.5 Hz), 10,27 (1H, s), 11,27 (1H, s); MS(ESI)m/z: 355 (MH+).

Analysis, calculated: C16H10ClF3N2O2: C, 54,18; H, 2,84; N, 7,10.

Found: C, 53,98; H, 2,89; N, 7,92.

Preparative example N 7

Example 123

4-(trifluoromethyl)phenylhydrazine 4-(acetylamino)-5 - chloro-2-methoxy-benzoic acid (Y = NHAc, R1= CF3, R2= H)

< / BR>
ISO-butylchloroformate (1.6 ml, 16.4 mmol) is added dropwise at 0oC to a solution of 4-(acetylamino)-5-chloro-2 - methoxybenzoic acid (4 g, 16.4 mmol) and 4-methylmorpholine (1.8 ml, 16.4 mmol) in 400 ml of anhydrous THF and stirred for 0.5 h at room temperature, then add 4- (trifluoromethyl)familyalbum), washed with water, saturated solution of NaHCO3and brine. Concentration leads to a solid substance which is recrystallized from acetonitrile, 5.7 g (86%); so pl. 217-219oC. IR (KBr, cm-1) 3486, 3286, 1704, 1670, 1500, 1338, 1238, 1104;1H NMR (300 MHz, DMSO-d6) / : of 2.15 (3H, s), 3,88 (3H, s), to 6.88 (2H, d, J = 8.5 Hz), 7,49 (2H, d, J = 8.5 Hz), 7,68 (1H, s), 7,76 (1H, s), 8,61 (1H, br. s), 9,62 (1H, br.s), of 10.01 (1H, br.s), 11,27 (1H, s); MS(ESI)m/z: 400 (M-H-).

Analysis, calculated: C17H15ClF3N3O3: C, 50,82; H, 3,76; N, 10,46.

Found: C, 50,68; H, With 3.79; N, 10,45.

The following hydrazides obtained by the method similar to that described in Example 123.

Example 124

Phenylhydrazide 4-(acetylamino)-5-chloro-2 - methoxybenzoic acid (Y = NHAc, R1= R2= H)

So pl. 180-181oC.

Analysis, calculated: C16H16ClN3O3: C, 57,58; H,4,83; N, 12,59.

Found: C, 57,44; H, Of 4.77; N, 12,72.

Example 125

2-[4-(trifluoromethyl)phenylhydrazine] -5-chloro-2 - methoxybenzoic acid (Y = N, R1- CF3, R2= H)

So pl. 183,5-184,5oC.

Analysis, calculated: C15H12ClF3N2O2: C, 52,27; H, 3.51; N, 8,13.

Found: C, 52,17; H, Of 3.53; N, 8.08.

Examples 126-130

< / BR>
Example 126

N-[2-chloro-4-[4.5 = CF3, R2= H) 4-(trifluoromethyl] )phenylhydrazide 4-(acetylamino)-5-chloro-2-methoxy - benzoic acid (5.7 g, of 14.2 mmol) dissolved in THF (500 ml) under nitrogen atmosphere and add 1,1'-carbonyldiimidazole (2.3 g, of 14.2 mmol) and triethylamine (1.5 ml, of 14.2 mmol). The solution is stirred for 18 h at 24oC and then remove the solvent in a rotary evaporator. The residue is treated with ethyl acetate (400 ml) and washed with 0.1 N HCl solution (100 ml), water (100 ml), brine and then dried over MgSO4. Recrystallization from acetonitrile gives 3.3 g (55%); so pl. 235-236oC. IR (KBr, cm-1) 3348, 1772, 1690, 1334, 1234, 1116;1H NMR (300 MHz, DMSO-d6) : to 2.18 (3H, s), with 3.89 (3H, s), 7,51 (1H, s), 7,79-to 7.93 (3H, m), with 8.05 (2H, d, J = 8.5 Hz), 9,67 (1H, br.s); MS(ESI)m/z: 426 (M-H-).

Analysis, calculated: C18H13ClF3N3O4: C, 50,54; H, A 3.06; N, 9,82.

Found: C, 50,43; H, A 3.01; N, 9,88.

The following oxadiazole obtained by the method similar to that described in Example 126.

Example 127

N-[2-chloro-4-[4.5-dihydro-5-oxo-4-phenyl]-1.3.4 - oxadiazol-2-yl]-5-methoxyphenyl]ndimethylacetamide (XXVI127: Y = NHAc, R1= R2= H)

So pl. 216-217oC.

Analysis, calculated: C17H14ClN3O4: C, 56,76; H, TO 3.92; N, 11,68.

Found: C, 56,52; H, 3,76; N, 11,81.

Example 128
2
= H)

So pl. 126-128oC.

Analysis, calculated: C16H10ClF3N2O3: C, 51,84; H, 2,72; N, 7,56.

Found: C, 51,69; H, 2,77; N, 7,53.

The following anilines by hydrolyzing the acetate group in accordance with the procedure described in Example 68.

Example 129

5-(4-amino-5-chloro-2-methoxyphenyl)-3-phenyl-1,3,4 - oxadiazol-2(3H)-he (XXVI129: Y = NH2, R1= R2= H)

So pl. 193-195oC.

Analysis, calculated: C15H12ClN3O3: C, 56,70; H 3,81; N, 13,23.

Found: C, 56,44: H, 3,91; N, 12,30.

Example 130

5-(4-amino-5-chloro-2-methoxyphenyl)-3-[3.4 - dichlorophenyl] -1.3.4-oxadiazol-2(3H)-he (XXVI130: Y = NH2, R1= R2= Cl)

So pl. 220-221oC.

Analysis, calculated: C15H10Cl3N3O3: C, 46,60: H, 2,61; N, 10,87.

Found: C, 46,31; H, 2.57 M; N, 10,65.

The following phenols obtained by the method similar to that described in Example 123 using BBr3.

Examples 131-134

< / BR>
Example 131

5-(4-amino-5-chloro-2-hydroxyphenyl)- 3-[4-(trifluoromethyl)phenyl] -1.3.4-oxadiazol-2(3H)-he (XXVI131: Y = NH2, R1= CF3, R2= H)

So pl. 266-268oC.

Analysis, calculated: C15H9ClF132: Y = NH2, R1= R2= H)

So pl. 280-282oC.

Analysis, calculated: C14H10ClN3O3: C, 55,37; H, 3,32; N, AT 13.84.

Found: C, 55,13; H, To 3.38; N, 13,74.

Example 133

5-(5-chloro-2-hydroxyphenyl)-3[4- (trifluoromethyl)phenyl]-1.3.4-oxadiazol-2(3H)-he (XXVI133: Y = H, R1= CF3, R2= H)

So pl. 214-215oC.

Analysis, calculated: C15H8ClF3N2O3: C, 50,51; H, AND 2.26; N, A 7.85.

Found: C, 50,07; H, 2,11; N, Of 7.96.

Example 134

5-(4-amino-5-chloro-2-hydroxyphenyl)-3-[3.4-dichlorophenyl]-1.3.4 - oxadiazol-2(3H)-he (XXVI134: Y = NH2, R1= R2= Cl)

So pl. > 300oC.

Analysis, calculated: C14H8Cl3N3O3: C, 45,13; H, 2,16; N, 11,28.

Found: C, 45,26; H, 2,12; N, 11,13.

Preparative example N 8

Example 135

2-(5-chloro-2 - methoxyphenyl)hydrazone-oxo-4-(trifluoromethyl)-phenylacetic acid (XXVII135: R1= R3= R4= H, R2= CF3)

< / BR>
A solution of 4-brominated (22,5 g of 0.1 mol) in anhydrous diethyl ether (30 ml) is added dropwise within 30 min to a stirred suspension of magnesium turnings (3.65 g of 0.15 mol), activated catalytic amount Deeb is added dropwise within 30 min to a cooled (-78oC) stir the solution dry diethyloxalate (14.6 g, 0,1 mol) in 50 ml of the same solvent. The resulting mixture was adjusted to -20oC for 1 h and incubated at -20oC for 1 h, and then acidified by slow addition of 1 N HCl. The organic layer was washed with a saturated solution of NaHCO3, brine and dried over Na2S04. Concentration, followed by distillation under vacuum gives the liquid, 22.1 g (90%); so bales. 88-90oC/of 0.75 torr.

Oxalate (12.3 g, 0,05 mol) hydrolyzing, stirring with 3 N NaOH (50 ml) in THF (50 ml), boiling under reflux for 6 hours THF evaporated in a rotary evaporator and the aqueous residue cooled (0oC) and acidified with 6 N HCl. Extraction with EtOAC, washing with brine and drying (Na2SO4) leads to [4- (trifluoromethyl)-phenyl] glyoxalase acid in the form of a Golden oil, which after curing in a vacuum solidifies to a light yellow solid (10.2 g, 93%); so pl. 63-65oC.

Pure 5-chloro-2-methoxyphenylhydrazine (1.73 g, 10 mmol) is added in portions to a stirred solution of [4- (trifluoromethyl)phenyl]-Glyoxylic acid (2,18 g, 10 mmol) in absolute ethanol and the resulting bright yellow suspension was stirred at room temperature for 30 mile and the product is recrystallized from a mixture of EtOAc-hexane, which leads to the above hydrazone carboxylic acid (3.57 g, 96%); so pl. 210-212oC. IR (KBr , = cm-1) 3300- 2300, 1660, 1230, 1160, 1116;1H NMR (300 MHz, DMSO-d6) : 3,91 (3H, s), 6,98 (1H, m), 7,10 (1H, d, J = 8.7 Hz), 7,44 (1H, d, J = 2.5 Hz), of 7.75 (2H, d, J = 8.1 Hz), 7,92 (2H, d, J = 8.1 Hz), br12.62 (1H, br.s); MS m/e 371 (M-H-).

Examples 136-138

< / BR>
Example 136

1-(5-chloro-2-methoxyphenyl)-3-[4- (trifluoromethyl)phenyl] -1.2.4(4H)-triazole-5-he (XXVIII136: R1= R3= R4= H, R2= CF3)

Diphenylphosphoryl azide (1.51 g, 5.5 mmol) is added to a mixed solution of alpha-oxo-4- (trifluoromethyl)phenyloxazol acid, 2-(5-chloro-2 - methoxyphenyl)hydrazone (1.86 g, 5 mmol) and triethylamine (of 0.77 ml, 5.5 mmol) in dry toluene (60 ml). The obtained yellow solution is refluxed for 3 h, diluted with ethyl acetate and poured with vigorous stirring into a saturated solution of NaHCO3(100 ml). After separation of the organic layer the aqueous phase is additionally extracted with ethyl acetate and the combined organic extracts washed with water, brine and dried (Na2SO4). Evaporation of the solvent and subsequent rubbing with warm ether leads to a white solid substance, 1,69 g (91%): so pl. 251-253oC. IR (KBr, = cm-1) 2900, 1770, 1330, 1290, 1130; 1 (1H, br.s); MS (DCl) m/z: 370 (MH+).

Analysis, calculated: C16H11ClF3N3O20,17 H2O: C, 51,55; H, A 3.06; N, 11,27.

Found: C, 51,54: H, To 2.94; N, 11,07.

Compounds of the following Examples obtained by the method similar to that described in Example 136.

Example 137

1-(5-chloro-2-methoxyphenyl)-3[3- (trifluoromethyl)phenyl]-1.2.4(4H)-triazole-5-he (XXVIII137: R1= CF3, R2= R3= R4= H)

So pl. 240-243oC.

Analysis, calculated: C16H11ClF3N3O2: C 51,98; H, 3,00; N, 11,37.

Found: C, 51.89ˆ; H, 3,02: N, 11,43.

Example 138

1-(5-chloro-2-methoxyphenyl)-3-[3.5 - bis(trifluoromethyl)phenyl] -1.2.4(4H)-triazole-5-he (XXVIII138: R1= R3= CF3, R2= R4= H)

So pl. 227-230oC.

Analysis, calculated: C17H10ClF6N3O2: C, 46,65: H, 2,30; N, 9,60.

Found: C, 46,82; H, 2,23; N, Of 9.55.

Example 139

5-[5-chloro-2-methoxyphenyl] -2.4-dihydro-2-[4- (trifluoromethyl)phenyl] -1.2.4(3H)-triazole-3-one (XXIX139)

< / BR>
So pl. 265,5-267,5oC.

Analysis, calculated: C16H11ClF3N3O2: C, 51,97; H, 3,00; N, 11,37.

Found: C, Better Than Anticipated At 51.90; H, 2,96; N, 11,43. The following phenols are obtained in a manner similar to picnometer)-3-[4- (trifluoromethyl)phenyl] -1.2.4(4H)-triazole-5-he (XXVIII140: R1= R3= R4= H, R2= CF3)

So pl. 252-255oC.

Analysis, calculated: C15H9ClF3N3O20,1 H2O: C, 50,40; H, 2,59; N, 11,75.

Found: C, 50,39; H, 2,46; N, 11,63.

Example 141

1-(5-chloro-2-hydroxyphenyl)-3-[3- (trifluoromethyl)phenyl] -1.2.4(4H)-triazole-5-he (XXVIII141: R1= CF3, R2= R3= R4= H)

So pl. 240-245oC.

Analysis, calculated: C15H9ClF3N3O2: C, 50,65; H, TO 2.55; N, 11,81.

Found: C, 50,21; H, 2,50; N, Are 11.62.

Example 142

1-(5-chloro-2-hydroxyphenyl)-3-[2- (trifluoromethyl)phenyl] -1.2.4(4H)-triazole-5-he (XXVIII142: R4= CF3, R1= R2= R3= H)

So pl. 167-170oC.

Analysis, calculated: C15H9ClF3N3O20,78 H2O: C, 48,72; H, 2,87; N, 11,36.

Found: C, 48,73; H, Of 2.51; N, 11,32.

Example 143

1-(5-chloro-2-hydroxyphenyl)-3-[3.5 - bis(trifluoromethyl)phenyl] -1,2,4(4H)-triazole-5-he (XXVIII143: R1= R3= CF3, R2= R4= H)

So pl. 250-253oC.

Analysis, calculated: C16H8ClF6N3O20.5 H2O: C, 44,41; H, 2,10; N, 9,71.

Found: C, 44,62; H, 2,04; N, Being 9.61.

Example 144
2
= R4= CF3)

T. pl. 270-275oC.

Analysis, calculated: C16H8ClF6N3O21 H2O0,25CH2Cl2: C, 42,16; H, 2,28; N, THE REMAINING 9.08.

Found: C, 41,82; H, 2,18; N, 8,91.

Example 145

1-(5-chloro-2-hydroxyphenyl)-3[3-chloro-4- (trifluoromethyl)phenyl]-1.2.4(4H)-triazole-5-he (XXVIII145: R1= Cl, R2= CF3, R3= R4= H)

So pl. 220-224oC.

Analysis, calculated: C15H8Cl2F3N3O2: C, 46,18; H, 2,07; N, 10,77.

Found: C, 45.99 Per; H, 2,07; N, 10,54.

Example 146

5-(5-chloro-2-hydroxyphenyl)-2.4-dihydro-2[4- (trifluoromethyl)phenyl] -1.2.4(3H-triazole-3-one (XXIX146)

< / BR>
So pl. > 305oC.

Analysis, calculated: C15H9ClF6N3O2: C, 50,65; H, TO 2.55; N, 11,81.

Found: C, 50,66; H, To 2.67; N, 11,73.

Reasonable modifications, obvious to the person skilled in the art, are included in the scope of this invention.

1. Diphenylene heterocyclic compounds of General formula I

< / BR>
where Het represents a fragment selected from the group consisting of (A)-(H):

< / BR>
< / BR>
< / BR>
< / BR>
where z is independently for each case selected from O or S; Ra, Rband Rceach nezavisim> is not hydrogen; and Raand Rbdenote hydrogen; Rcmay be a heterocycle selected from the group comprising imidazol-1-yl, morpholinomethyl, N-methylimidazol-2-yl and pyridin-2-yl;

Rband Rceach independently selected from hydrogen, halogen, CF3or imidazol-2-yl;

m and n each independently selected from 0 or 1;

p = 1;

Rfand Rgeach independently represents hydrogen, C1-4alkyl; or Rfand Rgtaken together with the nitrogen atom to which they are attached, form a heterocycle selected from the group consisting of N-methylpiperazine, research, thiomorpholine, N-benzylpiperazine and imidazolinone,

or its non-toxic pharmaceutically acceptable salt or MES.

2. Connection on p. 1, wherein Het represents triazolinones fragment group (C) or (F) and m=n=0.

3. Connection on p. 2, selected from the group including:

1-(5-chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl] -1,2,4(4H)-triazole-5-he;

1-(4-amino-5-chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]-1,2,4(4H)-triazole-5-he;

1-(5-chloro-2-hydroxyphenyl)-3-[3-(trifluoromethyl)phenyl] -1,2,4(4H)-triazole-5-he;

1-(5-chloro-2-hydroxyphenyl)-3-[2-(trifluoromethyl)phenyl] -1,2,4(4H)-triazole-5-he;
1-(5-chloro-2-hydroxyphenyl)-3-[3-chloro-4-(trifluoromethyl)phenyl] -1,2,4(4H)-triazole-5-he;

5-[5-chloro-hydroxyphenyl] -2,4-dihydro-4-[4-(trifluoromethyl)phenyl] -1,2,4(3H)-triazole-3-one;

4-(5-chloro-2-hydroxyphenyl)-5-[3,5-bis(trifluoromethyl)phenyl] -2,4-dihydro 3H-1,2,4-triazole-3-one;

4-(5-chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl] -2,4-dihydro-3H-1,2,4-triazole-3-one;

4-(5-chloro-2-hydroxyphenyl)-5-[3-(trifluoromethyl)phenyl] -2,4-dihydro-3H-1,2,4-triazole-3-one;

4-(5-chloro-2-hydroxyphenyl)-5-(4-forfinal)-2,4-dihydro-3H-1,2,4-triazole-3-one; and

[2-hydroxy-5-(trifluoromethyl)phenyl] -5-[4-(trifluoromethyl)phenyl] -2,4-dihydro-4(3H)-1,2,4-triazole-3-one.

4. Connection on p. 1, wherein Het represents triazolinones fragment group (C) or (F) and m = 1 and n = 0 or m = 0 and n =1.

5. Connection on p. 4, selected from the group including:

5-(5-chloro-2-hydroxyphenyl)-4-[[4-(trifluoromethyl)phenyl]methyl]-2,4-dihydro-3H -1,2,4-triazole-3-one;

2-[(4-amino-5-chloro-2-hydroxyphenyl)methyl]-2,4-dihydro-5-[4-(trifluoromethyl)phenyl]-3H-1,2,4-triazole-3-one;

2-[(4-amino-5-chloro-2-hydroxyphenyl)methyl] -2,4-dihydro-5-[3,4-dichlorophenyl]-3H-1,2,4-triazole-3-one;

2-[(5-chloro-2-hydroxyphenyl)methyl] -2,4-dihydro-5-[4-trifluoromethyl)-phenyl]- 3H-1,2,4-triazole-3-one; and

4-(5-chloro-2-hydroxyphenyl)] -5-[[(trifluoromethyl] phenyl]metholodogy fragment groups (a) and m = n = 0.

7. Connection under item 6, selected from the group including:

5-(4-amino-5-chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl] -1,3,4-oxadiazol-2(3H)-he;

5-(4-amino-5-chloro-2-hydroxyphenyl)-3-phenyl-1,3,4-oxadiazol-2(3H)-he;

5-(5-chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl] -1,3,4-oxadiazol-2(3H)-he;

5-(4-amino-5-chloro-2-hydroxyphenyl)-3-[3,4-dichlorophenyl] -1,3,4-oxadiazol-2(3H)-he;

8. Connection on p. 1, characterized in that t is oxadiazolones fragment group (A); and m = 1 and n = 0.

9. Connection on p. 8, selected from the group including:

3-[(4-amino-5-chloro-2-hydroxyphenyl)methyl] -5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[4-(amino)-5-chloro-2-hydroxyphenyl)methyl] -5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[(4-amino-5-chloro-2-hydroxyphenyl)methyl] -5-[4-(trifluoromethyl)-phenyl] -1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxyphenyl)methyl] -5-[3,5-bis(trifluoromethyl)-phenyl] -1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxyphenyl)methyl] -5-[4-fluoro-3-(trifluoromethyl)-phenyl] -1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxyphenyl)methyl] -5-[2-chloro-5-(trifluoromethyl)-phenyl] -1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxyphenyl)methyl] -5-[3,5-dichlorophenyl] -1,

3-[(4-amino-3,5-dichloro-2-hydroxyphenyl)methyl] -5-[3,4-dichlorophenyl] -1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[2-hydroxy-5-(4-morpholinylmethyl)phenyl]methyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[5-chloro-4-[(ethylmethylamino)-2-hydroxyphenyl]methyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he,

3-[[2-hydroxy-5-(2-pyridinyl)phenyl] methyl-5-[4-(trifluoromethyl)-phenyl] -1,3,4-oxadiazol-2(3H)-he;

3-[[5-(1-methyl-1H-imidazol-2-yl)-2-hydroxyphenyl)methyl] -5-[2-(4-trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[2-hydroxy-5-(1-methyl-1H-imidazol-2-yl)phenyl)methyl] -5-[2-(3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he

3-[[2-hydroxy-5-(1H-imidazol-1-yl)phenyl)methyl]-5-[(4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[2-hydroxy-5-(1H-imidazol-1-yl)phenyl)methyl]-5[2-(3,5-bis(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

N-[2-chloro-4-[[1,5-dihydro-5-oxo-3-[4-(trifluoromethyl)phenyl] -1,2,4-oxadiazol-1-yl]-methyl]-5-hydroxyphenyl]-4-morpholinoethyl;

N-[2-chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl] -1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-thiomorpholine the Il-1-piperazineethanol;

N-[2-chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl] -1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-phenyl-1-piperazineethanol;

N-[2-chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl] -1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-4-benzyl-1-piperazineethanol;

N-[2-chloro-4-[[2,3-dihydro-2-oxo-5-[4-(trifluoromethyl)phenyl] -1,3,4-oxadiazol-3-yl]methyl]-5-hydroxyphenyl]-2-(dimethylamino)ndimethylacetamide;

N-[2-chloro-4-[[2,3-dihydro-2-oxo-5-[1,1'-biphenyl)-1,3,4-oxadiazol-3-yl] methyl]-5-hydroxyphenyl]-4-methyl-1-piperazineethanol;

N-[2-chloro-4-[[2,3-dihydro-2-oxo-5-[naphthas-2-yl] -1,3,4-oxadiazol-3-yl] methyl]-5-hydroxyphenyl]-4-morpholinoethyl;

3-[[5-chloro-4-(2,3-dihydro-2-oxo-1H-imidazol-1-yl)-2-hydroxyphenyl] methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he;

3-[[5-chloro-4-(2,3-dihydro-2-thio-1H-imidazol-1-yl)-2-hydroxyphenyl] -methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he.

10. Connection on p. 1, wherein Het represents imidazolinones fragment group (D) or (E) and m = n = 0.

11. Connection on p. 10, selected from the group including:

4-chloro-2-[2-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl]phenol;

4-chloro-2-[1-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]phenol;

4-chloro-2-[1-phenyl-1H-imidazol-2-yl]phenol; and

1-(5-chloro-2-R> 4-chloro-2-[3-amino-[5-[4-(trifluoromethyl)phenyl] -1,2,4-triazole-4(4H)-yl] ] phenol;

1-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-5-phenyl-2H-imidazole-2-he;

3-[(5-chloro-2-hydroxyphenyl)methyl] -5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-tion;

4-(5-chloro-2-hydroxyphenyl)-5-[4-(trifluoromethyl)phenyl] -2,4-dihydro-(3H)-1,2,4-triazole-3-tion.

13. Connection on p. 1, representing 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he.

14. Connection on p. 1, representing 1-(5-chloro-2-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]-1,2,4(4H)-triazole-5-he.

15. Connection on p. 1, representing 3-[(4-amino-5-chloro-2-hydroxyphenyl)methyl]-5-[3,5-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-he.

16. Connection on p. 1, representing 3-[(4-amino-5-chloro-2-hydroxyphenyl)methyl]-5-[3,4-dichlorophenyl]-1,3,4-oxadiazol-2(3H)-he.

17. Connection on p. 1, representing 5-[(4-amino-5-chloro-2-hydroxyphenyl)methyl]-3-[4-trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-he.

18. Pharmaceutical composition having the ability to open activated calcium potassium channels with large conductance, characterized in that it contains a therapeutically effective amount of the compounds under item 1 in combination with a headlamp is the opening of activated calcium potassium channels with large conductance representing cerebral ischemia or traumatic brain injury in a mammal in need of such treatment, wherein the specified mammal is administered a therapeutically effective amount of the compounds on p. 1.

 

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The invention relates to 2-[1',2',4'-triazole-3'-roximation] anilides formula I

< / BR>
in which the index and the substituents have the following meanings:

n means 0, 1, 2, 3 or 4, where the substituents R1may be different if n is greater than 1;

X represents a direct bond, O, or NRa;

Rameans hydrogen, alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl;

R1means nitro, cyano, halogen, optionally substituted alkyl, alkenyl, quinil, alkoxy, alkenylacyl, alkyloxy or

if n is 2, additionally represents associated with two adjacent ring atoms optionally substituted by a bridge containing three or four members from the group containing 3 or 4 carbon atoms, 1-3 carbon atoms and 1 or 2 nitrogen atom, oxygen and/or sulphur, and this bridge together with the ring to which it is linked, may form a partially unsaturated or aromatic radical;

R2means hydrogen, nitro, cyano, halogen, C1-C4alkyl, C1-C4halogenated, C1-C4alkoxy, C1-C4alkylthio or C1-C4alkoxycarbonyl; R3means optionally substituted is which, together with the carbon atoms may contain one to three heteroatoms as members of a cycle of the following: oxygen, sulfur and nitrogen, or an optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms or one or two nitrogen atom and one oxygen atom or sulfur or one oxygen atom or sulfur;

R4means hydrogen, optionally substituted alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, alkylaryl or alkoxycarbonyl;

R5means alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl or if X is NRaadditionally represents a hydrogen

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The invention relates to novel 3,5-dihydroimidazo[2,1-b] hinzelin-2 (1H)-it is a derivative of the formula I

O

(I) where R is a hydrogen atom, a C1-6-alkyl, phenyl, possibly substituted by 1-3 substituents, independently from each other selected from halogen atoms, hydroxy - C1-6-alkyloxy-FROM1-6is an alkyl or triptorelin groups, pyridinyl, or thienyl, unsubstituted or substituted with halogen or1-6by alkyl;

R1the atom of hydrogen or C1-6-alkyl;

R2a hydrogen atom, a C1-6-alkyl, hydroxy-C1-6alkyl or phenyl, or R1and R2together can form WITH1-5-alcander;

X is the radical of the formula

0 (a)

N-O-R3(b) or

SN-R4(c);

R3a hydrogen atom, three (C1-6-alkyl)-silyl or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, СОNR5R6or SOON2-CONR7R8;

R4COOH, COOC1-4-alkyl, СОNR5R6, COOCH2CONR7R8or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, CONR5R6or COOCH2CONR7R8;

RIS-C1-4-alkyl, C1-4-algological - Nile-C1-4-alkyl;

R6a hydrogen atom, a C1-5-alkyl, hydroxy-C1-4-alkyl or C3-7-cycloalkyl, or R5and R6together with the nitrogen atom to which they are bound, can form pyrrolidinyl, morpholinyl or piperazinil, which can be substituted at the nitrogen atom WITH1-4-alkyl or hydroxy-C1-4-alkyl;

R7and R8independently from each other mean a hydrogen atom, a C1-4-alkyl or hydroxy-C1-4-alkyl, and their pharmaceutically acceptable salts and stereoisomers

The invention relates to new derivatives of 1-phenyl-3-azabicycloalkanes-2-ones, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

Ar denotes phenyl or naphthyl, unsubstituted or one-, two - or three-fold substituted with H, Gal, Q, alkenyl with the number of C-atoms up to 6, Ph, OPh, NO2, NR4R5, NHCOR4, CF3, OCF3CN, OR4, COOR4, (CH2)nCOOR4, (CH2)nNR4R5, -N=C=O or NHCONR4R5phenyl or naphthyl;

R1, R2, R3each independently from each other, are absent or represent H, Gal, Q, CF3, NO2, NR4R5, CN, COOR4or CHCOR4;

R4, R5each independently of one another denote H or Q, or together also denote-CH2-(CH2)N-CH2-;

Q denotes alkyl with 1-6 C-atoms;

Ph denotes phenyl;

X denotes O or S;

Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

and their salts, except 4-methyl-N-(2,1,3-benzothiadiazole - 5-yl)benzosulfimide, 4-nitro-N-(2,1,3-benzothiadiazole-5-yl)- benzosulfimide and 4-amino-N-(2,1,3-benzothiadiazole-5-yl)- benzolsulfonat
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