New derivatives of 2,4-dioxopyrimidine and 2,4 - dioxotetrahydrofuran and medicines containing them as active ingredient

 

(57) Abstract:

The invention relates to new 1-(biphenyl-4-yl)methyl-1H-1, 2,4-triazole compounds and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole compounds, and each of them has as a substituent in the 2'-position (2,4-dioxopyrimidine-5-ilidene)methyl or (2,4-dioxotetrahydrofuran-5-ilidene)methyl, and their salts. Due to their strong antagonism to the receptor of angiotensin 11 and antihypotensive action can be used as a therapeutic agent for diseases of the circulatory system, such as hypertension, or for the treatment of heart failure. 3 S. and 6 C.p. f-crystals, 1 table.

The technical field

The invention relates to a new derivative of 2,4-dioxopyrimidine and a new derivative of 2,4-dioxo-tetrahydrofuran, which has an excellent pharmacological actions, their salts and medicines containing these compounds as active ingredients.

More specifically, the present invention relates to new 1-(biphenyl-4-yl)methyl-1H-1,2,4-triazole and 1-(biphenyl-4-yl)methyl-4H-1,2,4-triazole with (2,4-dioxopyrimidine-5-ilidene)methyl group or (2,4-dioxotetrahydrofuran-5-ilidene)methyl group at the 2'-position in the studies of the circulatory system, for example, hypertension, and/or diseases, such as heart disease and kidney failure, caused by the action of angiotensin II, thanks to their strong antagonism to the receptor of angiotensin II and antihypotensive action, and medicines containing these compounds as active ingredient.

Background of the invention

The renin-angiotensin system plays an important role in vivo in maintaining homeostasis of the circulatory system, humoral values and electrolytic balance.

The results of the study of receptor antagonists angiotensin II inhibitors angiotensin II converting enzyme and renin inhibitors allow us to suggest that the renin-angiotensin system included in the mechanism of manifestation of hypertension. Inhibitors angiotensin II converting enzyme (ACE inhibitors), such as captopril and enalapril, are effective in treating hypertension or heart failure and is already widely used.

The ACE inhibitors, however, have an adverse effect on the metabolic pathway of bradykinin or substance P, thus causing side effects such as dry cough or swelling that are associated with the accumulation of these peptides. With the suggests to minimize side effects. Peptide antagonist, such as saralasin, as antagonists of angiotensin II receptor stably binds to the receptor, but because of its short time of half-life from the human body is not suitable for oral administration. [M. A. Ondatti and D. W. Gushman, Annual Reports in Medical Chemistry 13, 82-91 (1978)].

In these conditions was developed ones receptor antagonist of angiotensin II, although its activity is not so strong (U.S. patent 4340598, U.S. patent 4355040). Described a number of biphenylmethanol compounds as antagonists of receptors of angiotensin II, which have ones nature, very effective, selective, and it has been described that they possess antihypertensive effect when administered orally [D. J. Carini et al., J. Med. Chem. 34, 2525-2548 (1991)] . It was also suggested that the presence of acid groups in the 2'-position biphenylenes group is important for binding to the receptor of angiotensin II. As the acid group was selected hydrophobic tetryzoline group, which is suitable for oral administration and has a high bioavailability, a DUP-753 known as biphenylmethane compound containing tetrazole group in the 2'-position.

Imidazopyridine [N. C. Mantlo et al. , J. Med. Che. the. Ashton et al., J. Med. Chem. 36, 3595-3650 (1993)], triazole [W. T. Ashton et al., J. Med. Chem. 36, 591-609 (1993), PCT/US91/02926] pyrimidine [K. S. Atwal et al., J. Med. Chem. 35, 4751-4763 (1993)] and pyridine [R. H. Bradbury et al., J. Med. Chem. 36, 1245-1254 (1993)] have been described as an alternative to the imidazole ring, a part of the structure of imidazole compounds. Of these compounds 1,2,4-triazole is preferred because it represents a heterocyclic ring, geometrically similar to the imidazole ring, and G. D. Searle & Co. the described connection SC-50560 with 1H-1,2,4-triazole as the best compound which has a strong antagonism to the receptor of angiotensin II (PCT/US91/02926).

2,4-Dioxopyrimidine (also called Ternovoi acid) and 2,4-dioxotetrahydrofuran (also known as tetronic acid) are known as the components of the chemical structure of certain physiologically active substances of natural origin [N. G. Henning and A. Gelbin, Advances in Heterocyclic Chemistry, Vol. 157, pp. 139 (1993), Academic Press. Inc., G. Pattenden, Progress in the Chemistry of Organic Natural Products Vol. 35, pp. 133 (1978)] . Such a heterocyclic group, as is easily proved, corresponds to the hydrophobic cavity in the connecting area of the body, which is necessary for the manifestation of the physiological activity of a substance having as a component hetero is the mechanism of angiotensin II receptor, that is quite possible as bio-isostere for tetrazole ring DUP-763.

Thus, the creators of the present invention were synthesized derivative of 2,4-dioxopyrimidine and a derivative of 2,4-dioxocyclopentene and studies of antagonism of angiotensin II receptors for the detection of compounds with significant effects as the ones antagonists of angiotensin II receptors, as described below.

Description of the invention

The present invention relates to a compound of the following formula (I) or its salt:

< / BR>
where X represents a group of the following formula (II) or (III):

< / BR>
< / BR>
Y represents a group of the following formula (IV) or (V):

< / BR>
< / BR>
R1and R2independently represent a hydrogen atom, alkyl group having from 1 to 6 carbon atoms, halogenation group having from 1 to 6 carbon atoms, cycloalkyl group having from 3 to 6 carbon atoms, aryl group, halogenated aryl group, aracelio group or a heterocyclic group containing at least one atom in the ring selected from oxygen atom, sulfur atom and nitrogen atom.

The compound of formula (I) pregroup formula (II) and Y is a group of formula (IV);

(2) a compound of the following formula (I-b) or its salt:

< / BR>
where X represents a group of formula (II) and Y is a group of the formula (V);

(3) the compound of the following formula (I-C) or its salt:

< / BR>
where X represents a group of formula (III) and Y represents a group of formula (IV);

(4) the compound of the following formula (I-d) or its salt:

< / BR>
where X represents a group of formula (III) and Y represents a group of formula (V).

An alkyl group having from 1 to 6 carbon atoms included in the definition of substituent may be unbranched or branched chain, and for example, as preferred may be mentioned methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, pencilina group or exilda group. Particularly preferred may be mentioned an alkyl group, such as n-sawn group, ISO-propyl group or n-bucilina group.

Halogenation group having from 1 to 6 carbon atoms, represents an alkyl group, mono - or polyamidine halogen atoms, and is, for example, permatile group, dipley group, 2,2,2-triptorelin group, 2-foretelling group, 2-chloraniline group, 2,2,2-trichlorethylene group, 1,1-deperately group, 1,1-deferrable group, 1,1-deformational group or 1,1-differentley group or similar.

Cycloalkyl group is, for example, cyclopropane group, cyclobutyl group, cyclopentyloxy group or tsiklogeksilnogo group or the like, cycloalkyl group is preferred.

As aryl and halogenosilanes groups, preferred are a phenyl group, 2-Fortunella group or 4-Fortunella group or the like, as aranceles group are preferred phenylmethylene group or 2-phenylethylene group or similar.

Heterocyclic group containing at least one atom in the ring selected from oxygen atom, sulfur atom or nitrogen atom, is pureley group, thienyl group or peredelnoj group or the like, and preferable heterocyclic group is furan-2-yl, group, thiophene-2-yl and the group, pyridine-4-yl.

As specific compounds belonging to the above formula (I-a), you can specify the following is dipropyl-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole;

3,5-aminobutiramida-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1-H-1,2,4-triazole;

5-butyl-3-cyclopropyl-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene) methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole;

3,5-dibutil-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-lH-l,2,4-triazole;

5-butyl-3-(1,1-deferror)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-phenyl-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1-H-1,2,4-triazole;

5-butyl-3-(2-phenylethyl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-lH-l,2,4-triazole;

5-butyl-3-(4-forfinal)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(2-forfinal)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(4-pyridyl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

3-butyl-3-(2-furyl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene) methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(thiophene-2-yl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole.

As specific compounds belonging to the above formula (I-b), you can specify the following group of compounds:
irreligion-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

3,5-aminobutiramida-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2, 4-triazole;

5-butyl-3-cyclopropyl-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene) methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

3,5-dibutil-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(1,1-deferror)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-phenyl-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-phenyl-(2-phenylethyl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(4-forfinal)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(2-forfinal)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(4-pyridyl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene) methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(2-furyl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene) methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(thiophene-2-yl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole.

As specific compounds belonging to the above formula (I-C), you can specify the following group SOU'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene) methyl] biphenyl-4-yl]methyl-3-H-1,2,4-triazole;

3,5-aminobutiramida-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene) methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-cyclopropyl-3-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

3,5-dibutil-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(1,1-deferror)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-phenyl-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene) methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(2-phenylethyl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(4-forfinal)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(2-forfinal)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(4-pyridyl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(2-furyl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole;

5-butyl-3-(thiophene-2-yl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole.

As specific compounds belonging to the above formula (I-d), you can specify sleduushuu-dipropyl-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene) methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

3,5-aminobutiramida-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene) methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-cyclopropyl-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

3,5-dibutil-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(1,1-deferror)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-phenyl-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene) methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(2-phenylethyl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(4-forfinal)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(2-forfinal)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(4-pyridyl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(2-furyl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole;

5-butyl-3-(thiophene-2-yl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole.

The above compounds of the present invention can be converted in the usual method hidrochloride, a sulfate or a nitrate; salts with organic acid such as acetate, oxalate, succinate or maleate; salt with alkaline metal such as sodium salt or potassium salt; or a salt with an alkaline earth metal, such as a salt of calcium.

General method for synthesis of

Compounds according to this invention can be synthesized, for example, in accordance with the following method shown in schemes 1 and 2 (see the end of the description). In the following description of non 1-19, data connections, refer respectively to each connection in schemes I and II with this number. In addition, indicate (a)-(k), data connections, refer respectively to the connections with these designations, the substituents R1and R2which is shown next.

R1- R2< / BR>
a: n-s3H7- n-C3H7< / BR>
b: ISO-C3H7- ISO-FROM3H7< / BR>
from: Cyclopropyl - n-C4H9< / BR>
d: n-C4H9- n-C4H9< / BR>
e: Phenyl - n-C4H9< / BR>
f: 2-Phenylethyl - n-C4H9< / BR>
g: 4-Forfinal - n-C4H9< / BR>
h: 2-Forfinal - n-C4H9< / BR>
i: Pyridine-4-yl - n-C4H9< / BR>
j: Furan-2-yl - n-C4H9< / BR>
k: Thiophene-2-yl - n-C4

Compound 7 is subjected to interaction with diisobutylaluminium to obtain the corresponding compound (9), which are used as intermediate compounds that are common to the target compounds 1 and 2.

A solution of compound (9) and 4-methoxy-2-pyrrolidone (compound 10) in ethanol is treated with alkali to obtain the compound (11). about the connection O-demetrious using NVG with obtaining the target compound 1, with (Z)-5-ridenow structure.

Compound 2, TetraSociology derived compound 1, obtained by interaction of the compound (9) with 4-methoxy-2-furanone (compound 12). However, in contrast to the interaction with the above pyrrolidone (compound 10) receive the product Algologie interaction (compound 13) by reaction of compounds 9 and 12. This compound is O-Mailroot and then treated with 1,8-diazabicyclo[5.4.0] undec-7-Yong (DBU) for dehydration. In most cases, this interaction leads to the formation of a mixture of compounds 14 and its (E)-isomer, but the stereoselectivity is very high (>90:10). The connection 14 and its (E)-isomer O-demetrious interaction with lithium 2-proportionator in N, N'-dimethylpropyleneurea (DMPI) at room temperature for obtaining the same (Z)-5-ridetherainbow acid (compound 2). According to IR and1H-NMR spectrum is determined that compound 2 has the structure of a 4-hydroxybutanone, which is shown in figure 1, the structure of 2,4-dioxy, which is tautomerism.

As for compounds 1d and 2d was observed various antagonism towards the receptor of angiotensin II, these 4H-1,2,4-triazole compounds 19a and 19b were also synthesized according to receive condensation of acylhydrazone (compound 15) and 4-Amin o-methyl 2'-cyanobiphenyl (compound 16). The target compounds 19a and 19b is produced from compound 17 using the above method for producing compounds 1 and 2 of compound 7.

Compounds of the present invention have low toxicity and high safety. Based on the antagonism of angiotensin II, they strongly inhibit the vasoconstrictor and anti-hypertensive effects of angiotensin II, thereby reducing blood pressure in animals, in particular mammals, such as humans, dogs, monkeys, rabbits and rats. Thus, these compounds are effective as therapeutic agents for hypertension and other diseases associated with angiotensin II, specifically with hypertension, such as simple, renal or renovaskulyarnoy hypertension, and diseases of the circulatory system, including heart failure.

Thus, this invention relates to a medical composition containing a therapeutically effective amount of the compounds of the receptor antagonist of angiotensin II and acceptable from a medical point of view, the carrier and/or diluent, where the compound is an antagonist of the angiotensin II receptor selected from the compounds of formula (I) or its acceptable from a medical point of view salts.

It is as hypertension and heart failure, containing the compound of formula (I) and its acceptable from a medical point of view of salt.

When the present compound is used as a drug, the present compound is administered orally or parenterally. The dosage depends on the disease, symptoms, recipient and the route of administration, but if the connection is introduced as a drug for acute simple hypertension, the introduction is preferably carried out once or three times a day, so that the total number of medications was about 1-1000 mg when administered orally, while for normal injection is a number from 0.1 to 100 mg/kg

If this drug can be prepared in the form of a preparation for oral administration, the basic feature add an appropriate pharmacologically acceptable carrier, and the carrier with reception of tablets, powder, granules or capsules, in accordance with customary methods. Media that can be used in this invention include lactose, sucrose, corn starch, glucose, cellulose, esters of cellulose, powders of starch, dextrin, pectin, gelatin, Arabic gum, polyethylene glycol, silicon dioxide, , polivinilpirrolidon, polyvinyl alcohol and propylene glycol. In addition, if required, can be used cocoa powder, peppermint oil, aromatic acid or cinnamon powder. In addition, as a component of controlling the release rate of the active substance, can be used hypromellose.

If an injection is prepared in the form of a preparation for parenteral administration, the above-mentioned carrier and a diluent or solvent may be added to the main component, as required to obtain intravenous, subcutaneous or intramuscular injection, using conventional methods. The diluent or solvent that can be used in this invention include water, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, saline solution and/or various buffers, Polysolvate 80, polyoxyethylenesorbitan and macrogol. Moreover, sodium sulfite, peroxybenzoate acid and its esters or sorbic acid may be added as a stabilizer.

A preferred method of carrying out the invention

The invention is described in detail in reference examples examples example the following examples, the melting point was measured using a Yanagimoto micro for measuring the melting point, and all the values of the melting points miscorrection. The boiling point was determined by distillation Kugelrohr apparatus.1H-HMP range was determined on the instruments nuclear magnetic resonance Varian Gemini-300, Varian Unity plus 500 as internal standard used Me4Si or l3(7,26). To denote the waveforms used the following abbreviations: s = singlet, d = doublet, t = triplet, q = Quartet, m = multiplet, Shir. = wide. Mass spectrometry bombardment by electrons (EI-MC) and mass spectrometry high resolution (VRMS) were performed using a Jeol JMS-AX505HAD. Spectra IR were measured using an infrared spectroscopic analyzer PERKIN ELMER 1600 Fourier transform (FT). Column chromatography was performed using silica gel Fuji Davison BW-200 (150-325 mesh) and silica gel 60 E. Merk 9385 (230-400 mesh mesh). Treated with a 1% KH2PO4silica gel is produced by immersing silica gel 60 E. Merk 9385 (230-400 mesh mesh) in an aqueous solution of 1% KN2RHO4and drying the solution. Plate for TLC analysis covered with silica gel E. Merk 60F-254 (0.25 mm). Acylhydrazone (compound 3) is produced by interaction of ester with hydrazine, ethylimino-carboxylate (compound 4) is obtained from hydrochloride of the compound 4, which is obtained by the interaction of nitrile with sibutril-1H-1,2,4-triazole

In the atmosphere of nitrogen compound 3d (4,00 g, 34.5 mmol) was added to a solution (50 ml) of compound 4d (4,45 g, 34.5 mmol) in absolute ethanol and the mixture was heated and boiled under reflux. Then after 5 hours the mixture was added of 4.45 g (34.5 mmol) of compound 4d, after 25 hours was added 1.12 g (8,7 mmol) of compound 4d and the mixture was heated for 28 hours. After this interaction by heating the reaction liquid was evaporated under reduced pressure and the residue was subjected to column chromatography (90 g silica gel, hexane/ethyl acetate = 3:2) to give white solid product 5d (5.53 g; yield: 85%).

So Kip. 112-115oWith /of 0.45 Torr (59,9949 PA), so pl. 42-43oC (lit. 50,5-51,5o(C) (after recrystallization from hexane/ISO-RG2O), Rf=0,35 (hexane/ethyl acetate= 1: 2),1H-NMR (300 MHz, Dl3) : 0,91 (6N, t, J=7,6 Hz, Me), to 1.37 (4H, sq t, J=7,6 Hz, CH2IU), 1,71 (4H, TT, J=7, 6 Hz, CH2Et), 2,73 (4H, t, J=7,6 Hz, CH2Pr).

Elemental analysis: C10H19N3. Calculated: 66,26; N 10,56; N 23,18. Found: 66,38; N Is 10.68; N 23,24.

Other 1H-1,2,4-triazole compounds 5A, 5b, 5C, 5e, 5f, 5g, 5h, 5i, 5j and 5k were obtained in the same manner as described above. Their exits and physical properties shown below.

Compound 5A: 3,5-dipropyl-1 is (300 MHz, CDCl3) : 0,96 (6N, t, J=7.5 Hz, Me), to 1.76 (4H, sq t, J=7.5 Hz, CH2Me), a 2.71 (4H, t, J=7.5 Hz, CH2Et)

Elemental analysis: C8H15N3. Calculated: 62,71; N 9,87; N 27,42. Found: 62,67; N BECOMES 9.97; N 27,72

Compound 5b: 3,5-aminobutiramida-1H-1,2,4-triazole

Yield: 82%, colorless needle crystals from ISO-RG2Oh, so Kip. 140oC,1H-NMR (300 MHz, Dl3) : 1,33 (N, d, J=7,1 Hz, Me), is 3.08 (2H, sq sq, J= 7,1 Hz, CH2Me)

Elemental analysis: C8H15N3. Calculated: 62,71; N 9,87; N 27,42. Found: 62,82; N 9,90; N 27,55

Compound 5C: 5-butyl-3-cyclopropyl-1H-1,2,4-triazole

Yield: 80%, colorless needle crystals from ISO-RG2O, so pl. 65oC,1H-NMR (300 MHz, CDCl3) : of 0.87 (3H, t, J=7,1 Hz, Me), 0,90-0,99 (4H, m, cyclopropane2), of 1.34 (2H, sq t, J=7,1 Hz, CH2IU) of 1.66 (2H, TT, J=7,1 Hz, CH2Et), to 1.98 (1H, m, cyclopropyl-N), 2,68 (2H, t, J=7,1 Hz, CH2WG)

Elemental analysis: C9H15N3. Calculated: 65.42 Per; N 9,15; N 25,43. Found: 65,25; N 9,07; N 25,35

Compound 5e: 5-butyl-3-phenyl-1H-1,2,4-triazole

Yield: 52%, colorless needle crystals from ISO-RG2Oh, so pl. 85-86oC,1H-NMR (300 MHz, CDCl3) : 0,86 (3H, t, J=7.5 Hz, Me), 1,31 (2H, sq t, J= 7.5 Hz, CH2IU), was 1.69 (2H, TT, J=7.5 Hz, CH2Et), a 2.75 (2H, t, J=7.5 Hz, CH2Pr), 7,37-to: 71,56; N 7,46; N 21,18

Compound 5f: 3-butyl-3-(2-phenylethyl)-1H-1,2,4-triazole

Yield: 97%, so Kip. 141-144oWith/0,47 Torr, so pl. 58-60oC,1H-NMR (300 MHz, CDCl3) : of 0.93 (3H, t, J=7.5 Hz, Me) to 1.38 (2H, sq t, J=7.5 Hz, CH3IU) of 1.73 (2H, TT, J=7.5 Hz, CH2Et), a 2.75 (2H, t, J=7.5 Hz, CH2Pr), was 3.05 (4H, s, phenylethyl), 7,17-7,30 (5H, m, AGN)

Elemental analysis: C14H19N3. Calculated: 73,33; N 8,35; N 18,32. Found: 73,27; N 8,43; N 18,54

Compound 5g: 5-butyl-3-(4-forfinal)-1H-1,2,4-triazole

Yield: 68%, colorless needle crystals from ISO-RG2Oh, so pl. 93-94oC,1H-NMR (300 MHz, Dl3) : to 0.92 (3H, t, J=7,6 Hz, Me), of 1.39 (2H, sq t, J=7,6 Hz, CH2IU) of 1.75 (2H, TT, J=7,6 Hz, CH2Et), of 2.81 (2H, t, J=7,6 Hz, CH2WG), 7,11 (2H, t, J=8,8 Hz, AGN), 8,02 (2H, DD, J=8,8, 5,5 Hz, AGN)

Elemental analysis: C12H14N3F. Calculated: 65,74; N 6,44; N 19,16. Found: 65,84; N 6,48; N 19,39

Compound 5h: 5-butyl-3-(2-forfinal)-1H-1,2,4-triazole

Yield: 79%, colorless oil, so Kip. 208-210oWith/of 0.9 Torr,1H-NMR (300 MHz, CDCl3) : of 0.94 (3H, t, J=7,6 Hz, Me), to 1.42 (2H, sq t, J=7,6 Hz, CH2IU) of 1.78 (2H, TT, J=7,6 Hz, CH2Et), and 2.83 (2H, t, J=7,6 Hz, CH2WG), 7,19 (1H, t, J= 7.7 Hz, AGN), 7,25 (1H, d, J=7,7 Hz, AGN), 7,41 (1H, t, J=7.7 Hz, AGN), 8,19 (1H, t, J=7.7 Hz, AGN)

Elemental analysis: C12H16N3F. Calculated: Tsvetnye needle crystals of ISO-RG2O, so pl. 108-109oC,1H-NMR (300 MHz, CDCl3) : of 0.94 (3H, t, J=7,6 Hz, Me), to 1.42 (2H, sq t, J=7,6 Hz, CH2IU) of 1.80 (2H, TT, J=7,6 Hz, CH2Et), 2,89 (2H, t, J=7,6 Hz, CH2WG), 8,03 (2H, DD, J= 4,5) and 1.7 Hz, AGN), 8,71 (2H, DD, J=4,5) and 1.7 Hz, AGN), 13,00 (1H, Shir.s, NH)

Elemental analysis: C11H14N4. Calculated: 65,32; N 6,98; N 27,70. Found: 65,03; N 6,84; N 27,91

Compound 5j: 3-butyl-3-(furan-2-yl)-1H-1,2,4-triazole

Yield: 95%, lamellar crystals of AcOEt, so pl. 73-74oC, 1H-NMR (300 MHz, Dl3) : of 0.91 (3H, t, J=7,6 Hz, Me) to 1.38 (2H, sq t, J=7,6 Hz, CH2IU) of 1.76 (2H, TT, J=7,6 Hz, CH2Et), and 2.83 (2H, t, J=7,6 Hz, CH2WG), 6,51 (1H, DD, J=3,4, 1.7 Hz, AGN), of 6.99 (1H, DD, J=3,4, 0.6 Hz, AGN), 7,49 (1H, DD, J=1,7, 0.6 Hz, AGN)

Elemental analysis: C10H13N3O. Calculated: 62,81; N 6,85; N 21,97. Found: 63,01; N 6,87; N 22,26

Compound 5k: 5-butyl-3-(thiophene-2-yl)-1H-1,2,4-triazole

Yield: 74%, lamellar crystals of ISO-RG2Oh, so pl. 60-61oC, 1H-NMR (300 MHz, Dl3) : of 0.90 (3H, t, J=7,6 Hz, Me), to 1.37 (2H, sq t, J=7,6 Hz, CH2IU) of 1.73 (2H, TT, J=7,6 Hz, CH2Et), and 2.79 (2H, t, J=7,6 Hz, CH2WG), was 7.08 (1H, DD, J=5,1, and 3.7 Hz, AGN), 7,34 (1H, DD, J=5,1, 1,1 Hz, AGN), of 7.64 (1H, DD, J=3,7, 1,1 Hz, AGN)

Elemental analysis: C10H13N3S. Calculated: 57,94; N 6,32; N 20,27. Found: 57,83; N, 6.42 PER; N 20,38

(Reference PR is R> To anhydrous DMF (5 ml) was added under nitrogen atmosphere NaH (60%) (96 mg, 2.4 mmol) and the mixture, which was cooled in a bath of ice water, was added dropwise a solution of compound 5d (of 0.43 g, 2 mmol) in anhydrous DMF (4 ml). Twenty minutes later, to the mixture was added a solution of 4-methyl bromide-2'-cyanobiphenyl (compound 6) (0,82 g, 3 mmol) in anhydrous DMF (4 ml) and bath with ice water was removed. The mixture was stirred at room temperature for 2 hours and added to the reaction liquid saturated aqueous solution of NH4Cl (10 ml) followed by extraction Et2O (60 ml 2). The organic phase was washed with saturated saline (30 ml 2) and dried over magnesium sulfate. And then phase was evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel 47 g, hexane/ethyl acetate = 1:1) to obtain colorless oily substance 7d (0,63 g, 85%).

Rf= 0,47 (hexane/ethyl acetate = 1:1), IR (pure): 2224 cm-1,1H-NMR (500 MHz, CDCl3) : 0,89, 0,93 (each 3H, t, J=7,6 Hz, Me), 1,35, 1,39 (each 2H, sq t, J= 7,6 Hz, CH2Et), 1,67, 1,73 (each 2H, TT, J=7,6 Hz, CH2Et), 2,96, 2,70 (each 2H, t, J=7,6 Hz, CH2WG), and 5.30 (2H, s, N1-CH2), from 7.24 (2H, d, J= 8,4 Hz, AGN-3, 5), 7,44 (1H, TD, J=7.7 Hz, ArH-4'), 7,47 (1H, DDD, J= 7,7, 1,2, 0.5 Hz, AGN-6'), 7,53 (2H, d, J=8,4, ArH-2, 6), to 7.64 (1H, TD, J= 7,7, 1
H28N4. Calculated: 77,38; N 7,58; N 15,04. Found: 77,12; N. OF 7.55; N 14,92

Other 1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole compounds 7a, 7b, 7C, 7E, 7f, 7g, 7h, 7i, 7j and 7k were obtained in the same manner as described above. Their output and the physical properties shown below. For isomers 8C and 8e-8k1H-NMR spectrum showed that the peak of CH2Pr is shifted in the region of weak magnetic field (<0,44 MD).

Compound 7a: 3,5-dipropyl-1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole

Yield: 94%, oil, elemental analysis: C22H24N4. Calculated: 76,71; N 7,02; N 16,27. Found: 76,76; N 7,06; N 16,23

Compound 7b: 3,5-aminobutiramida 1-[2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole

Yield: 99%, needle crystals obtained by recrystallization from ISO-RG2Oh, so pl. 71-72oC elemental analysis: C22H24N4. Calculated: 76,71; N 7,02; N 16,27. Found: 76,62; N. Of 7.25; N 16,13.

Compound 7C: 5-butyl-3-cyclopropyl-1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole

Yield: 49% (ratio of isomers of compounds 7C/connections 8C=60:40), oil, elemental analysis: C23H24N4. Calculated: 77,50; N 6,79; N 15,72. Found: 77,25; N 6,82; N 15,74.

Compound 7E: 5-butyl-3-phenyl-1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole

Yield: 58% (gr-RG2Oh, so pl. 74-75oC elemental analysis: C26H24N4. Calculated: 79,56; N 6,16; N 14,27. Found: 79,28; N 6,12; N 14/42.

Compound 7f: 3-butyl-3-(2-phenylethyl)-1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole

Yield: 52% (ratio of isomers of compound 7f/connections 8f=53:46), oil, elemental analysis: C28H28N4. Calculated: 79,97; N. Of 6.71; N 13,32. Found: 79,88; N 6,72; N To 13.09.

Compound 7g: 5-butyl-3-(4-forfinal)-1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole

Yield: 91% (ratio of isomers of compound 7g/connections 8g=92:8), needle crystals obtained by recrystallization from ISO-RG2Oh, so pl. 109-110oC elemental analysis: C26H23N4F. Calculated: 76/08; N The 5.65; N 13,65. Found: 75,87; N Vs. 5.47; N 13,35.

Compound 7h: 5-butyl-3-(2-forfinal)-1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole

Yield: 69% (ratio of isomers of compound 7h/connections 8h=89:11), needle crystals obtained by recrystallization from ISO-RG2O, so pl. 81oC elemental analysis: C26H23N4F. Calculated: 76,08; N The 5.65; N 13,65. Found At 76.00; N. Of 5.48; N 13,39.

Connection 7i: 5-butyl-3-(pyridin-4-yl)-1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2, 4-triazole

Yield: 46%, needle crystals obtained peracre the 76,31; N OF 5.89; N 17,80. Found: 76,08; N. Of 5.83; N 17,74.

Connection 7j: 3-butyl-3-(furan-2-yl)-1-(2'-cyanobiphenyl-4-yl) methyl-1H-1,2,4-triazole

Yield: 62% (ratio of isomers of compounds 7j/connections 8j=70:30), lamellar crystals obtained by recrystallization from ISO-RG2Oh, so pl. of 77.5-78.5 peroC elemental analysis: C24H22N4O. Calculated: 75,37; N 5,80; N 14,65. Found: 75,35; N 5,59; N 14,72.

Connection 7k: 5-butyl-3-(thiophene-2-yl)-1-(2'-cyanobiphenyl-4-yl)methyl-1H-1,2,4-triazole

Yield: 86% (ratio of isomers of compounds 7k/connections 8k=88:12), needle crystals obtained by recrystallization from ISO-RG2Oh, so pl. 73-74oC elemental analysis: C24H22N4S. Calculated: 72,33; 5,56 N; N 14,06. Found: 72,09; N 5,32; N 14,06.

(Reference example 3)

Synthesis of intermediate compound 9d:

3,5-dibutil-1-(2'-formylphenyl-4-yl)methyl-1H-1,2,4-triazole

Compound 7d (4.1 g, 11 mmol) was dissolved in anhydrous CH2Cl2(80 ml) under nitrogen atmosphere. To the mixture, which is stirred and cooled to -80oC, was added dropwise 0,98 M hexane solution (28 ml, 27 mmol) in ISO-VI2lH and after 1 hour the reaction liquid was poured into a mixture of acetic acid (20 ml) and ice (20 g), to which was then added 1N. HCl (20 O3(50 2 ml) and then saturated brine (50 ml-1). After drying over magnesium sulfate the organic phase was evaporated under reduced pressure and the residue was subjected to column chromatography (90 g silica gel, hexane/ethyl acetate = 1:1) to obtain colorless oily compound 9d (3,84 g; yield: 93%).

Rf= 0,47 (hexane/ethyl acetate: 1:1), IR (pure): 1773, 1745 cm-1,1H-NMR (500 MHz, CDCl3) : 0,90, of 0.94 (each 3H, t, J=7,6 Hz, Me), 1,36, 1,40 (each 2H, sq t, J=7,6 Hz, CH2IU), 1,67, 1,74 (each 2H, TT, J=7,6 Hz, CH2Et), 2,69, 2,71 (each 2H, t, J=7,6 Hz, CH2Pr), 5,32 (2H, s, N1-CH2), of 7.23 (2H, d, J= 8,4 Hz, ArH-3, 5), of 7.36 (2H, d, J=8,3 Hz, ArH-2, 6), 7,41 (1H, d, J=7.9 Hz, AGN-6'), 7,51 (1H, DD, J=7,6, 7.5 Hz, ArH-4'), to 7.64 (1H, DD, J= 7,9, 7.5 Hz, AGN-5'), 8,02 (1H, d, J=7,6 Hz, ArH-3'), for 9.95 (1H, s, CRO), EI-MS m/z: 375 (M+), 346, 333 (main peaks), 195, 167, 165, HR-MSm/z. Calculated: C24H29N3O (M+): 375, 2311. Found: 375, 2306.

Other 1-(2'-formylphenyl-4-yl)methyl-1H-1,2,4-triazole compounds 9a-9c and 9e-9k received from the corresponding nitrile compounds, using the recovery method, such as those described above, and then subjected to column chromatography on silica gel for the next interaction.

(Example 1)

Synthesis of compound 1d:

3,5-dibutil-1-[2'-[(2,4-dio is 5H)-pyrrolidone (compound 10) (305 mg, 2,70 mmol) was dissolved in absolute ethanol (0.5 ml) and the mixture was added 1N. sodium hydroxide (4 ml). After 1 hour stirring at room temperature, the reaction liquid was dissolved in ethyl acetate (20 ml). After washing with water (10 ml) liquid was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel 47 g, hexane/ethyl acetate = 1:3) to obtain colorless oily substance (compound 11d). Physical properties of compound 11d shown below.

Rf= 0,24 (hexane/ethyl acetate = 1:3), IR (pure): of 3,649, 1684 cm-1,1H-NMR (500 MHz, CDCl3) : 0,88, 0,93 (each 3H, t, J=7,4 Hz, Me), 1,34, 1,40 (each 2H, sq t, J=7,4 Hz, CH2IU), 1,67, 1,73 (each 2H, TT, J=7,4 Hz, CH2Et), 2,67, 2,70 (each 2H, t, J=7,4 Hz, CH2Pr), 3,81 (3H, s, OMe), 5,16 (1H, s, H-3"), AND 5.30 (2H, s, N1-CH2), 6,13 (1H, s/ 5" =CH), 7,16 (2H, d, J= 8.0 Hz, ArH-3, 5), 7,31 (2H, d, J=8.0 Hz, ArH-2, 6), 7,34-7,41 (3H, m, AGN-4', 5', 6'), 7,51(1H, d, J = 7,3 Hz, ArH-3')

Compound 11d (0.95 g, 2.02 mmol) was dissolved in methanol (7 ml) and the mixture was added 47% Nug (10 ml). After 1 hour stirring at room temperature, the reaction liquid was evaporated under reduced pressure. To the residue was added l3(40 ml 3) for extraction, and the organic phase washed with water (40 night chromatography (silica gel, treated with a 1% KN2RHO4, 47 g, hexane/ethyl acetate = 1:3) to give compound 1d (0.21 g, 23%), which is a crystalline solid product. The compound was recrystallized from ethyl acetate to obtain colorless, like sand crystals with so pl. 179-180oC.

Rf= 0,19 (hexane/ethyl acetate = 1: 2), IR (KBR): 3437, 1674, 1587 cm-1; (l3): 1758, 1726, 1645 cm-1,1H-NMR (500 MHz, Dl3) : 0,90, of 0.94 (each 3H, t, J= 7.5 Hz, Me), 1,37, 1,40 (each 2H, sq t, J=7.5 Hz, CH2IU), 1,69, 1,73 (each 2H, TT, J=7.5 Hz, CH2Et), 2,69, 2,70 (each 2H, t, J=7.5 Hz, CH2WG), of 3.13 (2H, s, CH2-3"), from 5.29 (2H, s, N1-CH2), to 6.43 (1H, s, 5"=CH), 7,17 (2H, d, J=8,1 Hz, AGN-3, 5), 7,30 (2H, d, J=8,1 Hz, AGN-2, 6), 7,39-7,45 (4H, m, AGN-3', 4', 5', 6'), 8,01 (1H, s, NH).

Elemental analysis: C28H32N4O2. Calculated: 73,66; N 7,06; N 12,27. Found: 73,51; N 7,05; N 12,30.

Other 1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole compounds 1a, 1b, 1C,1e, 1f, 1g, 1h, 1i, 1j and 1k were obtained in the same manner as described above. Their output and the physical properties shown below.

Compound 1A: 3,5-dipropyl-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2, 4-triazole

Exit 24% (from compound 9), so pl. 179-180

Data1H-NMR (500 MHz, Dl3)

3.5 Deputy triazole as 0.96, and 0.98 (each 3H, t, J=7,6 Hz), 1,75, 1,77 (each 2H, sq t, J=7,6 Hz), 2,67, 2,68 (each 2H, t, J=7,6 Hz).

Biphenylmethane group: and 5.30 (2H, s), 7,17 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,2 Hz), 7,37-of 7.48 (4H, m).

Dioxopyrimidine group: 3,12 (2H, s), to 6.43 (1H, s), 8,10 (1H, s).

Compound 1b: 3,5-aminobutiramida-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 24% (from compound 9), so pl. 141-142oWith such sand crystals (from ethyl acetate), elemental analysis: C26H28N4O2. Calculated: To 72.87; H 6,59; N 13,07. Found: 72,70; N 6,30; N 12,88.

Data1H-NMR (500 MHz, Dl3)

3.5 Deputy triazole: 1,27, 1,35 (each 6N, d, J=6.9 Hz), 3,01, 3,07 (each 1H, sq sq, J=6,9 Hz).

Biphenylmethane group: 5,33 (2H, s), to 7.15 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,2 Hz), 7,37-7,46 (4H, m).

Dioxopyrimidine group: 3,11 (2H, s), 6.42 per (1H, s), 8,08 (1H, s).

Compound 1C: 5-butyl-3-cyclopropyl-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 23% (from compound 9), so pl. 166-168oWith the plate-like crystals (from ethyl acetate), elemental analysis: C27H28N3)

3.5 Deputy triazole: of 0.90, and 0.98 (7H, m) to 1.38 (2H, sq t, J=7.5 Hz), 1,62 (TT, J=7.5 Hz), 1,97 is 2.00 (1H, m) to 2.66 (2H, t, J=7,5).

Biphenylmethane group of 5.26 (2H, s), 7,18 (2H, d, J=8,2 Hz), 7,29 (2H, d, J=8,2 Hz), 7,37-of 7.48 (4H, m).

Dioxopyrimidine group: 3,12 (2H, s), to 6.43 (1H, s), 8,10 (1H, s).

Compound 1: 5-butyl-3-phenyl-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Output 15% (from compound 9), so pl. 180-181oWith, amorphous solid (from ethyl acetate), elemental analysis: C30H28N4O2. Calculated: 75,61; N. Of 5.92; N 11,76. Found: 75,50; N. Of 5.75; N 11, 65.

The data of 1H-NMR (500 MHz, Dl3)

3.5 Deputy triazole: to 0.92 (3H, t, J=7,6 Hz) of 1.41 (2H, sq t, J=7,6 Hz) of 1.73 (2H, TT, J=7,6 Hz), 2,77 (2H, t, J=7,6 Hz), 7,37-7,46 (3H, m), 8,11 (2H, d, J=8,2).

Biphenylmethane group: 5,41 (2H, s), from 7.24 (2H, d, J=8,2 Hz), 7,30 (2H, d, J=8,2 Hz), 7,37-7,46 (4H, m).

Dioxopyrimidine group: 3,12 (2H, s), to 6.43 (1H, s), to 7.99 (1H, Shir. C).

Compound 1f: 3-butyl-3-(2-phenylethyl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 32% (from compound 9), so pl. 188-189oWith such sand crystals (from ethanol), elemental analysis: C32H32N4O2. Calculated: 76,17; N To 6.39; N 11,10. Found: 76,27; N 6,sq t, J=7,6 Hz), 1.69 in (2H, TT, J= 7,6 Hz), 2,70 (2H, t, J=7,6), 2,99-OF 3.12 (4H, m), 7,14-7,47 (5H, m).

Biphenylmethane group: 5,28 (2H, s), 7,14-7,47 (8H, m).

Dioxopyrimidine group: 3,12 (2H, s), to 6.43 (1H, s), 8,16 (1H, s).

Compound 1g: 5-butyl-3-(4-forfinal)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 33% (from compound 9), so pl. 188-190oWith needle crystals (from ethyl acetate/hexane) elemental analysis: C30H27N4O2F. Calculated: 72,86; N. Of 5.50; N 11,33. Found: 72,77; N To 5.35; N 11,36.

Data1H-NMR (500 MHz, Dl3)

3.5 Deputy triazole: to 0.92 (3H, t, J=7,6 Hz) of 1.41 (2H, sq t, J=7,6 Hz) of 1.73 (2H, TT, J=7,6 Hz), was 2.76 (2H, t, J=7,6 Hz), 7,11 (2H, t, J=8.7 Hz), of 8.09 (2H, DD, J=8,7, 5,5 Hz).

Biphenylmethane group of 5.39 (2H, s), from 7.24 (2H, d, J=8,2 Hz), 7,31 (2H, d, J=8,2 Hz), 7,39-7,44 (4H, m).

Dioxopyrimidine group: 3,12 (2H, s), to 6.43 (1H, s), 8,10 (1H, s).

Compound 1h: 5-butyl-3-(2-forfinal)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Yield 22% (from compound 9), so pl. 169-170oWith such sand crystals (from ethyl acetate/hexane) elemental analysis: C30H27N4O2F. Calculated: 72,86; N. Of 5.50; N 11,33. Found: 72,75; N Vs. 5.47; N 11,34.

Data1H-NMR (500 MG 7,13-7,47 (3H, m), of 8.06 (1H, TD, J=7,6, 2,0).

Biphenylmethane group: 5,44 (2H, s), 7,13-7,47 (8H, m).

Dioxopyrimidine group: 3,11 (2H, s), 6.42 per (1H, s), 8,10 (1H, s).

Compound 1i: 5-butyl-3-(pyridin-4-yl)1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 13% (from compound 9), so pl. 144-145oWith needle crystals (from ethyl acetate/hexane) elemental analysis: C29H27N5O2. Calculated: 72,94; N 5,70; N 14,66. Found: 72,65; N 5,80; N 14,41.

Data1H-NMR (500 MHz, Dl3)

3.5 Deputy triazole: to 0.92 (3H, t, J=7,7 Hz), 1,40 (2H, sq t, J=7,7 Hz), 1,72 (2H, TT, J=7,7 Hz), 2,78 (2H, t, J=7,7 Hz), to 7.99 (2H, d, J=5.3 Hz), 8,68 (2H, d, J=5.3 Hz).

Biphenylmethane group: 5,44 (2H, s), 7,26 (2H, d, J=7.9 Hz), 7,35-7,42 (5H, m), 7,53 (1H, d, J=7,3 Hz).

Dioxopyrimidine group of 3.80 (2H, s), 6,14 (1H, s).

Compound 1j: 3-butyl-3-(furan-2-yl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

The output 30% (from compound 9), so pl. 169-170oWith such sand crystals (from ethyl acetate/hexane) elemental analysis: C28H26N4O3. Calculated: 72,08; N 5,62; N 12,01. Found: 72,07; N To 5.57; N 12,13.

Data1H-NMR (500 MHz, Dl3)

3.5 Deputy triazole: of 0.91 (3H, t, J=7,6).

Biphenylmethane group of 5.40 (2H, s), from 7.24 (2H, d, J=8.1 Hz), 7,30 (2H, d, J=8.1 Hz), 7,37-of 7.48 (4H, m).

Dioxopyrimidine group: 3,12 (2H, s), 6.42 per (1H, s), with 8.33 (1H, s).

Compound 1k: 5-butyl-3-(thiophene-2-yl)-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 37% (from compound 9), so pl. 186-187oWith such sand crystals (from ethyl acetate), elemental analysis: C28H26N4O2S. Calculated: 69,69; N 5,43; N Of 11.61. Found: At 69,39; N. Of 5.40; N 11,68.

Data1H-NMR (500 MHz, Dl3)

3.5 Deputy triazole: of 0.91 (3H, t, J=7.4 Hz), 1.39 in (2N, sq t, J=7.4 Hz), 1,71 (2H, TT, J=7.4 Hz), a 2.75 (2H, t, J=7.4 Hz), to 7.09 (1H, DD, J=5,2, 3.5 Hz), 7,22 was 7.45 (1H, m), 7,68 (1H, DD, J=3,5, 1,1 Hz).

Biphenylmethane group: 5,38 (2H, s), 7,22 was 7.45 (8H, m).

Dioxopyrimidine group: 3,12 (2H, s), 6.42 per (1H, s) to 8.12 (1H, s).

(Example 2) Synthesis of compound 2d:

3,5-dibutil-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-1H-1,2,4-triazole

Compound 9d (1.55 g, 4,13 mmol) and 4-methoxy-2(5H)-furanone (compound 12) (0.52 g, 4,56 mmol) was dissolved in absolute ethyl alcohol (6.5 ml) and the solution was added 0.1 G. LiOH (4 ml). Then the solution was stirred at room temperature for three hours, it was removed with ethyl alcohol at below were dried over magnesium sulfate. The solid product was then evaporated under reduced pressure to get the product Algologie communication (connection 13d), which was a white solid. Compound 13d was dissolved in anhydrous CH2CL2(80 ml). SO2CL (0.33 ml, 4.3 mmol), dimethylaminopyridine (0,47 g, 3.9 mmol) and triethylamine (1,10 ml, 7,89 mmol) was added to the solution while stirring and cooling to -50oAnd the temperature is gradually raised to -10oC for 1 hour. Then, the reaction liquid was added water (40 ml) to separate the organic phase was washed with saturated saline solution (50 ml of 2) and the mixture was dried over magnesium sulfate and evaporated under reduced pressure to obtain On-metilirovannah forms of compound 13d. On-mebilirovannuyu form was dissolved in anhydrous CH2CL2(80 ml) was added DBU (1.20 ml, 8,02 mmol) in a solution which was then heated and boiled under reflux for 20 minutes. After cooling to separate the organic phase was added water (40 ml) solution, which was then washed with saturated saline (50 ml) and water (30 ml), dried over magnesium sulfate and evaporated under reduced pressure.

Result1H-NMR showed that the ratio of compound 14d to the/ethyl acetate = 2:3) to give white solid product 14d (1/59 g; 82% of 9d). The ethyl acetate-hexane was used for recrystallization to obtain colorless plate crystals with a melting point of from 89,5 to 90,5oC. Physical properties of the compound 14d shown below.

Rf=0,17 (hexane/ethyl acetate = 2:3), IR (KBR): 1759 cm-1;1H-NMR (500 MHz, Dl3) : 0,88, of 0.94 (each 3H, t, J=7,6 Hz, Me), 1,35, 1,40 (each 2H, sq t, J=7,6 Hz, CH2IU), 1,66, 1,74 (each 2H, TT, J=7,6 Hz, CH2Et), 2,70, 2,72 (each 2H, t, J=7,6 Hz, CH2WG), 3,88 (3H, s, OMe), of 5.24 (1H, s, H-3"), 5,32 (2H, s, N1-CH2), 6,18 (1H, s, 5"=CH), 7,18 (2H, d, J=8.1 Hz, ArH-3,5), 7,28 (1H, DD, J= 7,6, and 1.6 Hz, ArH-6'), 7,31 (2H, d, J=8,1 Hz, AGN-2, 6), was 7.36 (1H, DDD, J=7,6, to 7.6 and 1.4 Hz, ArH-5'), 7,41 (1H, DDD, J=7,7, 7,6, the 1.6 Hz, ArH-4'), 8,23 (1H, DD, J=7,7, and 1.4 Hz, ArH-3').

(E)-isomers of compound 14d was exit 7% and Rf=0,27 (hexane/ethyl acetate = 2: 3), and1H-NMR showed that the peaks ilidene-N are shifted into the region of low magnetic field (0,4 MD). The ratio of E/z other compounds 14a and 14C and 14 and 14k was obtained by dehydrogenation product Algologie interaction (compound 13) in two stages, as shown below: compound 14a=94:6, connection 14b=94:6, connection 14C= 100:0 connection 14=93:7, compound 14f=98:2, connection 14g= 97: 3, connection 14h=94:6, connection 14i=94:6, connection 14j=89:11, connection 14k=94:6.

In nitrogen atmosphere coed,36 M DMPU solution of n-PrSLi (15 ml, 5.40 mmol). The reaction liquid was stirred at room temperature for 0.5 hours and cooled with ice was added water (100 ml), then the liquid was washed with ethyl acetate (50 ml). The aqueous phase was acidified (pH=2) 10% hydrochloric acid and then with ethyl acetate (50 ml of 2) carried out the extraction. The extract was washed with water (50 ml 3) and dried over sodium sulfate. The solid product had slipped away under reduced pressure to obtain compound (Z) 2d (0,92 g, 77%) as a white solid product. The ethyl acetate was used for recrystallization to obtain colorless plate crystals with a melting point of 168-169oC. Physical properties of the compound 2d is shown below.

IR (KBR): 3411, 1767, 1601 cm-1; (l3): 1752, 1598 cm-1;1H-NMR (300 MHz, CDCl3) : 0,70, 0,90 (each 3H, t, J=7.5 Hz, Me), 1,20, 1,35, (each 2H, sq t, J=7.5 Hz, Snme), 1,47, 1,67, (each 2H, TT, J=7.5 Hz, CH2Et), 2,64, 2,68 (each 4H, m, CH2WG), to 4.98 (1H, s, H-3"), 5,33 (2H, s, N1-CH2), 6,24 (1H, s, 5"=CH), 7,25-7,47 (7H, m, AGN-2,3,5,6,4',5',6'), 8,33 (1H, DD, J=7,7, 1,1 Hz, AGN-3').

Elemental analysis: C28H31N3O3. Calculated: 73,50; N 6,83; N 9,18. Found: 73,43; N. Of 6.73; N 9,27.

In addition, when the compound (E)-14d were demetilirovania, as described above, it isol] biphenyl-4-yl] methyl-lH-l, 2,4-triazole compounds 2A, 2b, 2C, 2E, 2f, 2g, 2h, 2j and 2k were obtained in the same manner as described above. Their output and the physical properties shown below.

Compound 2A: 3,5-dipropyl-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 40% (from compound 9), so pl. 160-161oWith the plate-like crystals (from ethyl acetate), elemental analysis: C26H27N3O3. Calculated: 72,71; N 6,34; N 9,78. Found: 72,65; N 6,21; N 9,52.

Data 1H-NMR (300 MHz, Dl3)

3.5 Deputy triazole: 0,74, 0,93 (each 3H, t, J=7.5 Hz), 1,51, 1,72 (each 2H, sq t, J=7.5 Hz), 2,64, 2,65 (each 2H, t, J=7.5 Hz)

Biphenylmethane group of 5.34 (2H, s), 7,28-7,47 (7H, m), with 8.33 (1H, d, J=8,2 Hz)

The group of tetronic acid: 4,96 (1H, s), 6,21 (1H, s)

Compound 2b: 3,5-aminobutiramida-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

A yield of 20% (from compound 9), so pl. 191-193oWith the plate-like crystals (from ethanol), elemental analysis: C26H27N3O3. Calculated: 72,71; N 6,34; N 9,78. Found: 72,63; N 6,27; N 9,73.

Data 1H-NMR (500 MHz, Dl3)

3.5 Deputy triazole with 1.07, 1.28 (in each 6N, d, J=6.9 Hz), 2,98, 3,05 (each 1H, sq sq, J=6,9 Hz)

Biphenylmethane group: the Association 2C: 5-butyl-3-cyclopropyl-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Yield 31% (from compound 9), so pl. 168-170oWith the plate-like crystals (from ethyl acetate), elemental analysis: C27H27N3O3. Calculated: 73,45; N 6,16; N 9,52. Found: 73,35; N. Of 6.26; N 9,41.

Data 1H-NMR (300 MHz, Dl3)

3.5 Deputy triazole: 0,71 (3H, J=7.4 Hz), of 0.95 (2H, m) of 1.23 (2H, sq t, J=7.4 Hz), of 1.46 (2H, TT, J=7.4 Hz), 1,90-of 1.97 (1H, m), 2.63 in (2H, t, J= 7,4 Hz).

Biphenylmethane group: from 5.29 (2H, s), 7,25-7,47 (7H, m), 8,32 (1H, d, J=7,1 Hz).

The group of tetronic acid: to 5.03 (1H, s), 6,23 (1H, s).

Compound 2E: 5-butyl-3-phenyl-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Yield 22% (from compound 9), so pl. 188-189oWith needle crystals (from ethyl acetate), elemental analysis: C30H27N3ABOUT3. Calculated: 75,45; N 5,70; N 8,80. Found: 75,18; N 5,78; N 8,96.

Data 1H-NMR (300 MHz, Dl3)

3.5 Deputy triazole: to 0.68 (3H, t, J=7.4 Hz), 1,24 (2H, sq t, J=7.4 Hz), 1,49 (2H, TT, J=7.4 Hz), 2,70 (2H, t, J=7.4 Hz), 7,30-7,47 (3H, m), to $ 7.91-of 7.95 (2H, m).

Biphenylmethane group: 5,44 (2H, s), 7,30-7,47 (7H, m), with 8.33 (1H, d, J=8,2 Hz).

The group of tetronic acid: 4,91 (1H, s), 6,27 (1H, s).

Compound 2f: 3-butyl-3-(2-phenylethyl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]matunty analysis: WITH32H31N3ABOUT3. Calculated: 76,02; N 6,18; N 8,31. Found: 75,88; N THE 6.06; N 8,33,

Data 1H-NMR (300 MHz, Dl3)

3.5 Deputy triazole: to 0.89 (3H, t, J=7.5 Hz), of 1.35 (2H, sq t, J=7.5 Hz), of 1.66 (2H, TT, J=7.5 Hz), a 2.71 (2H, t, J=7.5 Hz), 2,96-3,11 (4H, m), 7,12-7,44 (5H, m)

Biphenylmethane group: 5,33 (2H, s), 7,12-7,44 (7H, m), to 8.20 (1H, DD, J=8,5, 1,4 Hz).

The group of tetronic acid: 5,14 (1H, s), 6,24 (1H, s).

Compound 2g: 5-butyl-3-(4-forfinal)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 21% (from compound 9), so pl. 175-176oWith the plate-like crystals (from ethyl acetate/hexane) elemental analysis: C30H26N3O3F. Calculated: 72,71; N. Of 5.29; N 8,48. Found: 72,84; N. Of 5.29; N 8,53.

Data 1H-NMR (300 MHz, Dl3)

3.5 Deputy triazole: 0,70 (3H, t, J=7.5 Hz), 1,22 (2H, sq t, J=7.5 Hz), 1,50 (2H, TT, J=7.5 Hz), a 2.71 (2H, t, J=7.5 Hz), was 7.08 (2H, t, J=8.7 Hz), 7,92 (2H, DD, J=8,7, 5,6 Hz)

Biphenylmethane group: 5,43 (2H, s), 7,47 (7H, m), 8,31 (1H, DD, J= 7,1, 1,1 Hz).

The group of tetronic acid: to 4.92 (1H, s), of 6.26 (1H, s).

Compound 2h: 5-butyl-3-(2-forfinal)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 23% (from compound 9), so pl. 184-185oWith needle crystals (from ethyl,56.

Data 1H-NMR (300 MHz, Dl3)

3.5 Deputy triazole: 0,70 (3H, t, J=7,6 Hz) of 1.23 (2H, sq t, J=7,6 Hz), of 1.52 (2H, TT, J=7,6 Hz), 2,73 (2H, t, J=7,6 Hz), 7,13-7,46 (3H, m), a 7.85 (1H, TD, J=7,4, 1.5 Hz).

Biphenylmethane group: vs. 5.47 (2H, s), 7,13-7,46 (7H, m), 8,31 (1H, DD, J=7,1, 1,1 Hz).

The group of tetronic acid: 4,88 (1H, s), 6,24 (1H, s).

Compound 2j: 3-butyl-3-(furan-2-yl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Output 10% (from compound 9), so pl. 172-173oWith such sand crystals (from ethanol), elemental analysis: C28H25N3O4. Calculated: 71,93; N. Of 5.39; N 8,99. Found: 71,79; N Are 5.36; N 9,03.

Data 1H-NMR (300 MHz, Dl3)

3.5 Deputy triazole: from 0.90 (3H, t, J=7,6 Hz) to 1.38 (2H, sq t, J=7,6 Hz), 1,71 (2H, TT, J=7,6 Hz), and 2.79 (2H, t, J=7,6 Hz), 6,53 (1H, DD, J=3,5, and 1.6 Hz), 6,94 (1H, d, J=3.5 Hz), 7,53 (1H, d, J=1.6 Hz).

Biphenylmethane group: the 5.45 (2H, s), 7,28-the 7.43 (7H, m), to 8.20 (1H, DD, J=7,7, 1,7 Hz).

The group of tetronic acid: 5,14 (1H, s), 6,23 (1H, s), 12,01 (1H, s).

Compound 2k: 5-butyl-3-(thiophene-2-yl)-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole

Exit 27% (from compound 9), so pl. 179-180oWith such sand crystals (from ethanol), elemental analysis: C28H25N3
3.5 Deputy triazole: from 0.90 (3H, t, J=7,6 Hz) of 1.39 (2H, sq t, J=7,6 Hz), 1.69 in (2N, sq t, J=7,6 Hz), 2,77 (2H, t, J=7,6 Hz), 7,10 (1H, DD, J=5,2, 3.6 Hz), 7,27-the 7.43 (1H, m), 7,66 (1H, DD, J=3,6, 1,1 Hz).

Biphenylmethane group: 5,42 (2H, s), 7,27-the 7.43 (7H, m), by 8.22 (1H, DD, J=7,4, 1,4 Hz).

The group of tetronic acid: 5,14 (1H, s), 6,24 (1H, s), 11,90 (1H, s).

(Reference example 4)

Synthesis of intermediate compound 17:

3,5-dibutil-1-(2'-cyanobiphenyl-4-yl)methyl-4H-1,2,4-triazole

In nitrogen atmosphere hydrochloride of compound 4d (2,99 g of 18.1 mmol) was dissolved in absolute ethanol (30 ml). To the solution was added dropwise within 15 minutes with stirring and cooling at -10oTo a solution of compound 3d (2.16 g, to 18.6 mmol) in absolute ethanol (70 ml) and then the temperature was raised to 0oC. the Solution was placed in a flask with a stopper and kept at the 5oWith in 3 days. The precipitate was filtered and was evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel, 80 g; ethyl acetate) to give the white solid product compound 15 (2,90 g, 70%). Rf=0,21 (ethyl acetate).

In the atmosphere of nitrogen compound 15 (2,01 g, 8,81 mmol) was dissolved in absolute ethanol (20 ml) was added connection 16 to a solution of 1.41 g of 6.78 mmol), which is then Nali under reduced pressure and the residue was subjected to column chromatography (silica gel 80 g; the ethyl acetate/methanol = 10:1) to give compound 17 (2.20 g, 87%) which was colorless and oily.

Rf=0,23 (ethyl acetate/methanol = 10:1), IR (pure): 2224 cm-1,1H-NMR (500 MHz, CDCl3) : 0,89 (6N, t, J=7,6 Hz, Me) to 1.38 (4H, sq t, J=7,6 Hz, CH2IU) to 1.70 (4H, TT, J=7,6 Hz, CH2Et), to 2.65 (4H, t, J=7,6 Hz, CH2WG), 5,11 (2H, s, N1-CH2), of 7.00 (2H, d, J= 8,3 Hz, AGN-3,5), 7,47 (1H, TD, J=7,6, 1.2 Hz, AGN-4'), of 7.48 (1H, DD, J=7,6, 1.2 Hz, AGN-6'), at 7.55 (2H, d, J=8,3 Hz, ArH-2, 6), 7,66 (1H, TD, J= 7,6, 1.5 Hz, ArH-5'), of 7.70 (1H, DD, J=7, 6, 1.5 Hz, ArH-3').

Elemental analysis: C24H28N4. Calculated: 77,38; N 7,58; N 15,04. Found: 77,44; N 7,87; N 15,28.

(Example 3)

Synthesis of compound 19a:

3,5-dibutil-1-[2'-[(2,4-dioxopyrimidine-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole

In nitrogen atmosphere, the compound 17 (480 mg, 1,29 mmol) was dissolved in anhydrous CH2Cl2. Then to this mixture, which was stirred and cooled at -80oC, was added dropwise 0,98 M hexane solution of ISO-Bu2AlH (of 3.46 ml, up 3.22 mmol) and 1 hour later, the reaction liquid was poured into a mixture of acetic acid (2.5 ml) and ice (3.4 g), to which then was added 1N. HCl (4,2 ml). After stirring the mixture for 4 hours, the organic phase was separated, washed with saturated solution of aqueous NaHCO

Rf=0,39 (ethyl acetate/methanol = 10:1), IR (pure): 1693 cm-1,1H-NMR (500 MHz, CDCl3) : 0,87 (6N, J=7,6 Hz, Me), to 1.37 (4H, sq t, J=7,6 Hz, CH2IU) to 1.70 (4H, TT, J=7,6 Hz, CH2Et), to 2.65 (4H, t, J=7, 6 Hz, CH2WG), 5,12 (2H, s, N1-CH2), 7,05 (2H, d, J=7.9 Hz, AGN-3, 5), of 7.36 (2H, d, J=7.9 Hz, AGN-2, 6), 7,39 (1H, DD, J=7,5, 0.5 Hz, ArH-6'), 7,51 (1H, TD, J=7,5, 0.5 Hz, ArH-4'), to 7.64 (1H, t, J=7.5 Hz, ArH-5'), 8,01 (1H, d, J=7.5 Hz, ArH-3'), to 9.93 (1H, s, Cho)

For O-demethylation product of aldol reaction, obtained by the interaction of compound 18 (570 mg, 1.54 mmol) with compound 10 (440 mg, of 3.85 mmol) was used NVG, as in the reaction, whereby the compound 1d was obtained from compound 9d. Compound 19a was obtained by recrystallization from AcOEt/ISO-RG2About in the form of light yellow needle-shaped crystals with a yield of 33%. So pl. 185-186oS, Rf=0,15 (ethyl acetate/methanol = 10:1), IR (KBR): 3206, 1682 cm-1;1H-NMR (500 MHz, Dl3) : 0,87 (6N, t, J=7,6 Hz, Me), of 1.39 (4H, sq t, J=7,6 Hz, CH2Me) 1,71 (4H, TT, J=7,6 Hz, CH2Et), to 2.65 (4H, t, J= 7,6 Hz, CH2WG), of 3.13 (2H, s, CH2-3"), 5,10 (2H, s, N1-CH2), 6: C28H32N4O2. Calculated: 73,66; N 7,06; N 12,27. Found: 73,79; N 6,98; N 12,23.

(Example 4)

Synthesis of compound 19b:

3,5-dibutil-1-[2'-[(4-hydroxy-2(5H)-furanone-5(Z)-ilidene)methyl] biphenyl-4-yl]methyl-4H-1,2,4-triazole

Compound 19b was obtained by the reaction of compound 18 with the connection 12 with a yield of 20%, using the reaction, which was the compound obtained from 2d compound 9d. White crystals were obtained by recrystallization from AcOEt/CH2Cl2. So pl. 166-168oC, IR (KBR): 1760 cm-1;1H-NMR (300 MHz, CDCl3) : 0,83 (6N, t, J=7.5 Hz, Me), of 1.34 (4H, sq t, J=7.5 Hz, CH2IU) of 1.65 (4H, TT, J= 7.5 Hz, CH2Et), 2,69 (4H, t, J=7.5 Hz, CH2WG), to 5.13 (2H, s, N1-CH2), from 5.29 (1H, s, H-3"), 6,17 (1H, s, 5"=CH), was 7.08 (2H, d, J=8,2 Hz, AGN-3, 5), 7,30 (1H, DD, J=7,5, and 1.4 Hz, ArH-6'), was 7.36 (1H, TD, J=7,5, and 1.4 Hz, ArH-4"), 7,41 (2H, d, J=8,2 Hz, AGN-2, 6), the 7.43 (1H, TD, J=7,5, 1.5 Hz, AGN-5'), 8,32 (1H, DD, J=7,5, 1.5 Hz, ArH-3'), elemental analysis: C28H31N3O3. Calculated: 73,50; N 6,83; N 9,18. Found: 73,54; N 6,76; N 9,98.

(Examples of study drug)

A case study 1: the Effect of inhibiting the binding of angiotensin II to the receptor of angiotensin II.

Method SOH et al. (Biochemical Pharmacology, 33, 4057-4064 (1984) was modified to implement the experimental is>9M) and 3H-labeled angiotensin II (10-9M) was added to the membrane fraction of the receptor of angiotensin II (0,57 mg/ml) prepared from adrenal rabbit, and the mixture was left to interact in 20 mm Tris buffer model HC1 (pH: 7,0) containing 120 mm NaCl, 5 mm EDTA, 0.1 mm PMSF and 0.2% BSA, 30oC for 20 minutes so that the final volume was 540 μl. Then, the reaction mixture was rapidly passed through a filter (Whatman GF/B) and the filter was rinsed three times with 4 ml of chilled on ice buffer. Then use the liquid acquired scintillation counter measured the radioactivity retained on the filter 3H-labeled angiotensin II is associated with the receptor. The activity of inhibiting the binding of angiotensin II receptor compound of the present invention was evaluated on the basis of concentration (IC 50) needed to displace 50% of the total amount of specifically bound 3H-labeled angiotensin II. The results are shown in the table.

Example study 2: the Inhibitory activity of the compounds at the vasoconstriction induced by angiotensin II, using the aorta of Guinea pigs.

Male Hartly Guinea pigs (350 to 400 g) were stunned and killed, allowing blood to flow from the common carotid artery. Immediately after smart,5 ml of Krebs-Henseleit (K-N) (120 mm NaCl, the 4.7 mm KCl, 4,7 mm MgSO4, 1.2 mm KH2PO4, 2.5 mm CaCl2, 25 mm Panso3and 10 mm glucose) in a vessel Magnus (Magnus). The solution To the-N in the vessel Magnus (Magnus) was kept at 37oWith and gaseous mixture containing 95% O2and 5% CO2continuously have barbotirovany through the solution. First, the sample was applied to 1 g initial tension, then it was left for 30 minutes and the solution was added 45 μl of 4M KCl solution to induce contraction. After the reduction has stabilized, carried out the washing procedure is for replacement of the solution To-N. Then, after the sample was left for 30 minutes, was added 45 μl of the solvent DMSO for incubation of the sample for 15 minutes to induce a reduction was added to 45 μl of a solution of angiotensin II (3 of 10-8M). This operation was repeated three times, and 100% reduction was used as the average. The sample was then stabilized by flushing. Further samples with a volume of 45 ál for each tested compound, prepared using DMSO as solvent for each concentration (3 to 10-5M-10-7M), used to monitor inhibitory effect of angiotensin II on vascular contraction performed using the same operations that opalene with equivalent-scale (TV-T, Japan Photoelectronics). Effects of inhibition of angiotensin II investigated compounds was evaluated by IC50 values. The results are shown in the table.

A case study 3: Inhibitory effect of compounds in hypertension caused by angiotensin II in rats.

Used male SD rats (age 11 weeks; 310-330 g), which under anesthesia by inaction in the femoral artery and Vena cava were placed permanent cannula. The arterial cannula is connected with transduction pressure to record blood pressure through the amplifier carrier frequency (AP-601G, Japan Photoelectronics), using a polygraph system (RM-6000 Japan Photoelectronics). Before the test, using the test compounds using constantly pulsating cannula was introduced 100 ng/kg equivalent of angiotensin II (50 ál of serum diluent rats) to verify the hypertensive actions. After 30 minutes using a constantly pulsating cannula was administered 1 mg/kg equivalent of the investigated compounds (50 μl of a solution of serum of rats) and is similar to the introduction of angiotensin II was performed after 5 and 60 minutes to check the corresponding hypertensive action. Hypertensive effect, manifested in the introduction only of angiotensin II, it was taken as a reference mn.

A case study 4: toxicity Study using male ICR mice

Studies of acute toxicity was performed for compounds 1d and 2d described in the table. Five-week mice (weight 24-32 g, 5 per group) were administered orally with 250 mg/kg 500 mg/kg and 1000 mg/kg of the compounds in the suspension containing 0.1% carboxymethylcellulose, and after injection, the mice were observed for 21 days. As a result, in each group, which were subjected to treatment at any concentration did not enter the compound, mice were killed. In addition, all mice, which was observed physiological transition weight, were at the end of the observation period opened to establish the absence of any pathology.

(Preparative example form)

Capsules

100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of microcrystalline cellulose and 10 mg of magnesium stearate were mixed and the mixture was granulated and placed in standard gelatin capsules to obtain capsules of each active ingredient.

Tablets

100 mg of powdered active ingredient, 100 mg of lactose, 50 mg of starch powder, 140 mg microcrystalline cellulose and 10 mg of magnesium stearate were mixed and the mixture was granulated. The usual method gotowka ingredient, 10% vol. propylene glycol and a corresponding number of parenteral composition was dissolved in distilled water for injection and the solution was sealed in a vial for the preparation of the injection for each active ingredient. All surgery was performed under aseptic conditions.

The toxicity of the compounds of the present invention is low, and their security is high. Based on the antagonism of angiotensin II, they inhibit the effects of the narrowing of the arteries and hypertension caused by angiotensin II, thus reducing blood pressure in animals, in particular mammals, such as humans, dogs, monkeys, rabbits and rats. Thus, the compounds of the present invention are effective as therapeutic agents for hypertension and other diseases caused by angiotensin II, specifically, in case of hypertension, such as simple, renal or renovaskulyarnoy hypertension, and diseases of the circulatory system, including heart failure.

1. Derivatives of 2,4-dioxopyrimidine and 2,4-dioxotetrahydrofuran General formula (I) or their salts

< / BR>
where X is a group of General formula (II) or (III)

< / BR>
< / BR>
Y represents a group of General formula (IV) or (V)

< / BR>
< / BR>
R1

2. The compound or its salt under item 1, where in the formula (I), X represents a group of formula (II)

< / BR>
and Y represents a group of formula (IV)

< / BR>
3. The compound or its salt under item 1, where in the formula (I), X represents a group of formula (II)

< / BR>
and Y represents a group of formula (V)

< / BR>
4. The compound or its salt under item 1, where in the formula (I), X represents a group of formula (III)

< / BR>
and Y represents a group of formula (IV)

< / BR>
5. The compound or its salt under item 1, where in the formula (I), X represents a group of formula III

< / BR>
and Y represents a group of formula (V)

< / BR>
6. Pharmaceutical composition having antagonistic activity against angiotensin II receptor containing the active agent and acceptable from the point of view of medicine, carrier and/or diluent, characterized in that the active agent is selected from compounds of formulas is th the binding of angiotensin II to the receptor of angiotensin II, containing the active ingredient, characterized in that it contains as active ingredient a compound of the formula (I) under item 1 or acceptable from the point of view of medicine, salt.

8. therapeutic agent according to p. 7 for the treatment of hypertension.

9. therapeutic agent according to p. 7 for the treatment of heart failure.

 

Same patents:

The invention relates to a derivative of a simple ester, application and intermediate compounds used for their production

The invention relates to new benzododecinium the compounds containing pharmaceutical compositions, method of production thereof, and to a method for producing an intermediate product

The invention relates to new derivatives of 3-phenylpyrazole, to methods for their preparation, to compositions containing them and to a method of protecting plants from fungal diseases

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to a method for producing compounds of formula (I) consists in the fact that the compound of formula (IX):

< / BR>
in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):

< / BR>
in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):

< / BR>
in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):

< / BR>
in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>
in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):

O=C=N-R6' (XV)

in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):

< / BR>
in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):

< / BR>
in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):

< / BR>
in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):

< / BR>
in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:

a) esterification of the acid function,

(b) saponification functions of ester to acid functions,

C) transforming functions of ester function acyl,

d) transforming Sinopoli in an acid function,

e) conversion of the acid function to an alcohol function,

g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,

h) oxidation of the alcohol function to the aldehyde, acid or keto-function

i) the conversion of the formyl radical in the radical carbarnoyl,

j) turning radical carbarnoyl in the nitrile radical,

k) converting the nitrile radical in tetrazolyl,

l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,

m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,

n) the transformation function oxo function of thioxo,

a) transforming radical

< / BR>
in radical

< / BR>
p) conversion of the acid function in function

< / BR>
q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,

r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

s) removal of protective groups, which can protect the reaction functions,

t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers

The invention relates to new sulfonamidnuyu derivatives or their pharmaceutically acceptable salts, which have the properties of inhibitor action of endothelin receptors and can find application in the treatment of diseases associated with disorders in the circulatory system, such as hypertension, ischemia, angina, spasms of the blood vessels as well as to pharmaceutical drugs based on them

The invention relates to new pyrimidine compounds or their salts with pharmaceutically acceptable acids and pharmaceutical compositions based on them

The invention relates to derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to novel triazole compounds of the General formula (1), where a denotes a linear or branched C1-C18-alkylenes group which may comprise at least one group which is selected from O, S, CONH, COO,3-C6-cycloalkene or double or triple bond; In denotes the radical of formula (a), (b) or (C); R1denotes H, NH2WITH3-C6-cycloalkyl or1-C8-alkyl, which is not substituted or substituted OS1-C8-alkyl; R2denotes H, HE, C1-C8-alkyl, C3-6-cycloalkyl, CF3, CN, NR3R4, SR3or CO2R3where R3denotes N or C1-C8-alkyl, a R4denotes H, C1-C8-alkyl, or COR3where R3stands WITH1-C8-alkyl; Ar represents naphthyl, phenyl with 1-2 substituent selected from C1-C8-alkyl, CF3, CHF2, NO2, SR3, SO2R3where R3means1-C8-alkyl; and pyridyl, pyrimidyl or triazinyl, which have from 1 to 3 substituents selected from C1-C8-alkyl, C2-C6-alkenyl, C2-C6-quinil, halogen, CN, CF3, OR4where R43-C6-lalouche possibly condensed, phenylalkylamine or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms, which may be condensed with a benzene ring

The invention relates to arylalkylamines formula I, where In - unsubstituted pyridyl, pyrazinyl, isoxazolyl or thienyl; Q - CH2; X - CH2or S; R1and R2each - H; and R3- OR5; R4OA; R5- Or cycloalkyl with 4-6 C atoms; And the alkyl with 1-6 C-atoms, and their physiologically acceptable salts

The invention relates to new Amida condensed terracarbon acid of General formula I, where G is Q(C)k-W-(C)m-Z, Q is phenyl, 2-, 3-, 4-pyridyl, which may be substituted; T is halogen, hydrogen, hydroxyl, amino, C1-C6alkoxy; W is-O-, -N-, -S-, CR7R8where R7and R8the same or different and represent H, C1-C6alkyl; X is hydrogen; Z is hydroxyl, C1-C6alkoxy, C3-C7cycloalkylation, NH2and other, NR9COR10where R9and R10the same or different represent H, C1-C6alkyl, etc
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