Nitrocatechol derivatives as comp inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

 

This invention relates to new substituted nitrocatechol, their use in the treatment of some disorders of the Central and peripheral nervous system and pharmaceutical compositions containing them.

Despite the use in clinical practice for several decades, levodopa (L-DOPA, L-DOPA) remains the drug of the gold standard for symptomatic treatment of Parkinson's disease. This helped save a great interest in the development of inhibitors of the enzyme catechol-O-methyltransferase (COMT, COMT), based on the hypothesis that inhibition of this enzyme may provide clinical improvement in patients suffering from Parkinson's disease, in the treatment with L-DOPA and an inhibitor of peripheral amino acid decarboxylase (AADC). Explanation for use of COMT inhibitors as tools for L-DOPA/AADC therapy is based on their ability to reduce metabolic O-methylation of L-DOPA to 3-O-methyl-L-DOPA (3-OMD). Period caused by L-DOPA clinical improvement short as the time is short half-life in vitro L-DOPA in contrast to the long half-life of 3-OMD. In addition, 3-OMD competes with L-DOPA for transfer across the blood-brain barrier (BBB, blood-brain barrier), which means that only a very limited number of oral is conducted doses of L-DOPA actually reaches the place of action, i.e. the brain. Usually only a few years after the initial L-DOPA therapy with normal dosing caused by L-DOPA clinical improvement is reduced at the end of each cycle dosage, leading to the so-called state of "wear" motor fluctuations. Described is a direct relationship between the phenomenon of "wear and accumulation of 3-OMD (Tohgi H. et al., Neurosci. Letters, 132:19-22, 1992). It is assumed that this may be due to slow penetration of L-DOPA in the brain because of the competition for the transportation system through the BBB with 3-OMD (Reches A. et al., Neurology 32: 887-888, 1982) or, in other words, a small amount of L-DOPA is able to reach the brain (Nutt J.G., Fellman J.H., Clin. Neuropharmacol., 7: 35-49, 1984). In fact, inhibition of COMT protects L-DOPA from the metabolic breakdown in the periphery during O-methylation, so that with repeated doses of L-DOPA average concentrations of L-DOPA in plasma increases. In addition to reduced competition for transfer to the brain significantly greater percentage of injected dose oral L-DOPA is able to reach the scene. Thus, inhibition of COMT increases the bioavailability of L-DOPA, and the period of antiparkinsonian action is extended with single doses of L-DOPA (J.G. Nutt, Lancet, 351: 1221-1222, 1998).

The most effective inhibitors of COMT described to nastasemarian, are 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (tolkapon, Australian patent AU-B-69764/87), (E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide (entacapone, German patent DE 3740383 A1) and BIA 3-202 (American patent US 6512136), all of which are the inhibition constants in the low nanomolar range. Having essentially the same pharmacophore, tolkapon differs from entacapone and BIA 3-202 that easily penetrates into the Central nervous system (CNS) and is able to inhibit cerebral COMTE, and peripheral COMT. It can be assumed that the Central inhibition may be less significant if greater effect on inhibition of COMT is to prevent the destruction of L-DOPA in the periphery. Indeed, the use of COMT inhibitors, which do not penetrate into the brain at clinically relevant doses, can prevent possible unwanted side effects of these agents in the Central nervous system.

Another serious problem that appeared after these COMT inhibitors were introduced into clinical practice, refers to the ability of these based on nitrocatechol xenobiotics can cause severe liver damage (hepatotoxicity). Indeed, soon after its release, tolkapon was withdrawn from sale after it became aware of several cases of hepatotoxicity, including three sudden the death from fatal fulminant hepatitis. Today tolkapon can only be used for patients with Parkinson's disease who are not receptive to other treatments, and strictly only with constant monitoring of liver function, which is costly and inconvenient for the patient. Although the actual mechanistic causes of liver toxicity associated with tolkapon, not fully understood, in vitro study showed that tolkapon can be reduced metabolic to reactive intermediates, and it is assumed that they can form covalent adducts with proteins of the liver, causing hepatocellular damage (for K.S. Smith et al., Chem. Res. Toxicol., 16: 123-128, 2003).

Entakapon on the contrary, due to tolkapon the same nitrocatechols pharmacophor, not associated with liver toxicity and, generally regarded as a safe drug. Unfortunately, however, entacapone is much less effective inhibitor of COMT than tolkapon, and has a much shorter half-life in vivo. This means that entacapone has a very limited duration and, as a consequence, the medicinal substance should be introduced in very high doses, with each dose of L-DOPA, adopted by the patient. In this regard, the clinical efficacy of entacapone was questioned - indeed, a recent study (Parashos SA,et al.,Clin. Neuropharmacol., 27(3): 119-123, 2004) showed that the main reason for stopping treatment entacapone patients with Parkinson's disease is the perceived lack of effectiveness.

In the end, there is still a clear clinical need for safe and effective inhibitor of COMT for conjugate therapy in the treatment of symptoms of Parkinson's disease. Preferably, the inhibitor of COMT possessed greater efficiency and duration of inhibition of COMT than entacapone that would lead to greater clinical efficacy. More preferably, the inhibitor of COMT unlike tolcapone had limited access to the CNS, i.e. it should, it is preferable to inhibit peripheral COMT than the Central COMT. Even more preferably, the inhibitor of COMT were United by the above-mentioned features and, in addition, had the ability to cause hepatic toxicity, as determined by tolkapon.

We now unexpectedly been found that some nitrocatechol are very effective inhibitors of COMT, which also lack or have very reduced risk of toxicity. In addition, it has been unexpectedly found that the lack of toxic effects of these compounds is determined by the chemical functional group acatenango Deputy connected with gets rosiglitazon ring.

Today, in the prior art described is only one example nitrocatechols [1,2,4]-oxadiazole (example 75 Australian patent AU-B-69764/87), representing 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-nitrocatechol 1, which has the chemical structure shown below:

This substance is a 3,5-disubstituted-[1,2,4]-oxadiazol with a methyl group in a position C-3 of heterocyclic oxadiazole rings, and nitrocatechols pharmacophore attached at C-5.

We investigated oxadiazoline connection 1 mentioned above, and found that it is moderately active in the analysis of inhibition of COMT (59% of control, see experimental section). Unfortunately, however, the connection 1 shows a significant risk of toxicity (55% viability of the cells, see experimental section). In this regard, one cannot say that this particular connection 1 represents the right solution to this problem of creating an effective and clinically safe COMT inhibitor.

We unexpectedly found that if the Central ring substituted pyridinium ring in oxidized form (i.e. N-oxide of pyridine), then the resulting compound N-oxide of pyridine are greatly reduced toxicity or even devoid of the risk of toxicity, at the same the time is still able to maintain inhibition of COMT better entacapone. If the position of nitrocatechols of pharmacophore "switched" from C-5 to C-3 oxadiazoline ring, the resulting compounds are usually less active against inhibition of COMT. Regioisomeric 1,3,4-oxadiazole in which nitrocatechols pharmacophor attached to C-2 oxadiazolines Central rings are also usually less active against inhibition of COMT. For example, consider the regioisomers 2 and 3 oxadiazole 1 of the prior art, which we also synthesized and evaluated in vivo:

Despite the fact that 2 and 3 show a reduced risk of toxicity relative to 1, in relation to inhibition of COMT compound 2 showed only 79% of the control, and compound 3 was only slightly better at 64%. Thus, we can conclude that this combination of correct positional arrangement of the heteroatoms in the Central oxadiazole ring and the inclusion of functional groups N-oxide of pyridine unexpectedly is crucial for obtaining the synergy between high-inhibiting COMT activity and safety for this type COMT inhibitor.

Thus, the present invention relates to nitrocatechols COMT inhibitors that lack or have very reduced risk of toxicity. In addition, it has been unexpectedly found that on the value of nitrogen-containing heterocyclic group in the N-oxidized form, such as, for example, N-oxide of pyridine, determines the lack of toxic effects nitrocatechols compounds. Moreover, we unexpectedly found that compounds of General formula I are inhibitors of COMT, which have proportionate properties, bioactivity, bioavailability and safety features:

where R1and R2independently of one another represent hydrogen or a group which is hydrolyzed under physiological conditions, possibly substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents an oxygen atom, nitrogen or sulfur; n is a number 0, 1, 2 or 3, and m represents the number 0 or 1; R3represents the group N-oxide of pyridine according to the formula a, B or C, which is attached, as shown unmarked connectivity:

where R4, R5, R6and R7independently of one another represent hydrogen, C1-C6-alkyl, C1-C6-thioalkyl, C1-C6-alkoxy, C6-C12-aryloxy or6-C12-chiarello group, C1-C6-alkanoyl or7-C13-arilou group, amino, C1-C6-alkylamino,1-C6-dialkylamino,3-C12-cycloalkyl the Mino, With3-C12-heterocyclochain, C1-C6-alkylsulfonyl, C6-C12-arylsulfonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, cyano, nitro, or heteroaryl group; or two or more together residue R4, R5, R6and R7represent aliphatic or heteroaromatics rings or aromatic or heteroaromatic rings, and where P represents the Central part, which preferably is planar part and which is even more preferably selected from the regioisomers 1,3,4-oxadiazol-2,5-deila, 1,2,4-oxadiazol-3,5-deila, 4-methyl-4H-1,2,4-triazole-3,5-deila, 1,3,5-triazine-2,4-Diil, 1,2,4-triazine-3,5-deila, 2H-tetrazol-2,5-deila, 1,2,3-thiadiazole-4,5-deila, 1-alkyl-3(alkoxycarbonyl)-1H-pyrrole-2,5-deila, where the alkyl represented by stands, ethyl, n-propylene and n-bootrom, and where the alkoxy represented by methoxy, ethoxy, n-propoxy, isopropoxy, 1-alkyl-1H-pyrrole-2,5-deila, where the alkyl represented by stands, ethyl, n-propylene and n-bootrom, thiazol-2,4-Diil, 1H-pyrazole-1,5-deila, pyrimidine-2,4-Diil, oxazol-2,4-Diil, carbonyl, 1H-imidazole-1,5-deila, isoxazol-3,5-deila, furan-2,4-Diil, 3-alkoxycarbonyl-2,4-Diil, where the alkoxy represented by methoxy, ethoxy, n-propoxy, isopropoxy, benzene-1,3-deila and (Z)-1-cyanate-1,2-deila.

In the above definition of the regioisomers Central the Noah part include both regioisomer, implemented by the permutation nitrocatechols fragment -(X)n(Y)m-R3the fragment.

Preferably C1-C6-alkyl residues are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl. Preferably1-C6-thioalkyl residues are thiomethyl, thioethyl, thio-n-propyl, thio-isopropyl thio-n-butyl, thio-n-pentyl and thio-n-hexyl. Preferably C1-C6-alkoxy residues are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. Preferably6-C12-aryloxy residues represent phenoxy or naphthoxy, which may be substituted. Preferably6-C12-thiouridine residues are thiophenyl and Tinetti, which may be substituted. Preferably1-C6-alcoholnye residues are methanol, ethanol, propanol or butanol. Preferably7-C13-aroline balances represent the benzoyl and naphtol. Preferably C1-C6-alkylamino residues are methylamino, ethylamino, n-propylamino, isopropylamino and n-butylamine. Preferably1-C6-dialkylamino residues are dimethylamino, diethylamino, di-n-propylamino, di-n-butylamine is, di Isopropylamine, methylethylamine, methylpropylamine, ethylpropylamine. Preferably C3-C12-cyclooctylamino balances represent pyrrolidino, piperidino, cyclohexylamino, dicyclohexylamine. Preferably3-C12-heterocyclochain residues represent morpholino, 2,6-dimethylmorpholine, 3,5-dimethylmorpholine, piperazine derivatives, N-methylpiperazine and N-ethylpiperazine. Preferably1-C6-alkylsulfonyl or6-C12-arylsulfonyl balances represent the methylsulphonyl, ethylsulfonyl, phenylsulfonyl and tamilselvan. Preferably the remains of Halogens are chlorine, bromine, iodine and fluorine. Preferably C1-C6-haloalkaline residues are chloromethyl, vermeil, dichloromethyl, deformity, trichloromethyl and trifluoromethyl. Preferably heteroaryl residues are pyridyl, pyrimidyl, isoxazolyl, oxazolyl, isoxazole, oxadiazole, triazole and tetrazole. In cases when two or more together residue R4, R5, R6and R7represent aliphatic or heteroaromatics rings or aromatic or heteroaromatic rings, the preferred combined residues represent indolizinyl, isoindolyl, indolyl, indazoles, the purine is l, finalizing, naphthyridine, ethanolic and finalyl.

The Central part is preferably selected from five-membered heteroaromatic ring which contains from 1 to 4 heteroatoms N, O and S. More preferably, the Central portion R is selected from the regioisomers 1,3,4-oxadiazol-2,5-deila, 1,2,4-oxadiazol-3,5-deila, 4-methyl-4H-1,2,4-triazole-3,5-deila, 1,3,5-triazine-2,4-Diil, 1,2,4-triazine-3,5-deila, 2H-tetrazol-2,5-deila, 1,2,3-thiadiazole-4,5-deila, 1-alkyl-3-(alkoxycarbonyl)-1H-pyrrole-2,5-deila, where the alkyl represented by stands, ethyl, n-propylene and n-bootrom, and where the alkoxy represented by methoxy, ethoxy, n-propoxy, isopropoxy, 1-alkyl-1H-pyrrole-2,5-deila, where the alkyl represented by stands, ethyl, n-propylene and n-bootrom, thiazol-2,4-Diil, 1H-pyrazole-1,5-deila, oxazol-2,4-Diil, carbonyl, 1H-imidazol-1,5-deila, isoxazol-3,5-deila, furan-2,4-Diil, 3-alkoxycarbonyl-2,4-Diil, where the alkoxy represented by methoxy, ethoxy, n-propoxy, isopropoxy.

Most preferably the Central part R is selected from 1,3,4-oxadiazol-2,5-deila and 1,2,4-oxadiazol-3,5-deila.

Preferred compounds of the above General formula (I), with 1,2,4-oxadiazol-3,5-diyl as the Central part, include 5-[3-(3,5-dichloro-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-morpholine-4-yl-1-hydroxy-pyrid is n-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 3-nitro-5-[3-(1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, 5-[3-(4-bromo-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-6-methyl-1-hydroxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-morpholine-4-yl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 3-nitro-5-[3-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxidiazol-5-yl]-benzene-1,2-diol, 5-[3-(2-methyl-1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2,6-dimethyl-1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-methyl-1-hydroxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-hydroxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-6-methyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-4,5,6-trimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2-chloro-4,5,6-trimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2-br the m-5-chloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and 3-nitro-5-[3-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, 1-oxide 3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)pyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,5,6-trimethylpyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)pyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-herperidin, 1-oxide 4-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-2-herperidin, 1-oxide 2-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-forperiod is on, 1-oxide, 2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-5-yl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)having a 1,3,4-oxadiazol-2,5-diyl as the Central part, include 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,6-dimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,5,6-trimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-(trifluoromethyl peer is Dina, 1-oxide 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,6-dimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-herperidin, 1-oxide 4-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-2-herperidin, 1-oxide 2-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-6-herperidin, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,3,4-oxadiazol-2-yl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)with 4-methyl-4H-1,2,4-triazole-3,5-diyl as the Central part, include 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4,6-dimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2,6-dimethyl-4-(trifluoromethyl)PI is Idina, 1-oxide, 3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4,5,6-trimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4,6-dimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2-herperidin, 1-oxide 4-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2-herperidin, 1-oxide 2-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-6-herperidin, 1-oxide 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)with 1,3,5-triazine-2,4-diyl as the Central part, include 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-4(trifluoromethyl)pyridine, 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2-(trifluoromethyl)pyridine 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-5-(trifluoromethyl)pyridine.

Preferred compounds of the above General formula (I), with 1,2,4-triazine-3,5-diyl as the Central part, include 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-4-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1 oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-(trifluoromethyl)pyridine, 1-ACS is D. 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-5-(trifluoromethyl)pyridine, 1-oxide 4-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-herperidin and 1-oxide 2-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-6-herperidin.

Preferred compounds of the above General formula (I), with a fragment of (Z)-1-cyanate-1,2-diyl as the Central part, include 1-oxide, (Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4-(trifluoromethyl)pyridine, 1-oxide, (Z)-2-chloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,6-dimethylpyridine, 1-oxide (Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide, (Z)-5-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-(trifluoromethyl)pyridine, 1-oxide, (Z)-5-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide, (Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, (Z)for 3,5-dichloro-4-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)pyridine, 1-oxide, (Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, (Z)-2-bromo-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,5,6-trimethylpyridine, 1-oxide, (Z)-2-chloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,5,6-trimethylpyridine, 1-oxide, (Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-(trifluoromethyl)pyridine, 1-oxide, (Z)-2,5-dichloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,6-dimethylpyridine, 1-oxide, (Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-5-(t is iformity)pyridine, 1-oxide, (Z)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-herperidin, 1-oxide, (Z)-4-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-2-herperidin, 1-oxide, (Z)-2-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-6-herperidin, 1-oxide (Z)-2-chloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-6-methylpyridine, 1-oxide, (Z)-2-bromo-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-6-methylpyridine 1-oxide, (Z)-2-bromo-5-chloro-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)having as Central part of the fragment furan-2,4-diyl or 3-alkoxycarbonyl-2,4-diyl, where the alkoxy represented by methoxy, ethoxy, n-propoxy, isopropoxy include 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-4,6-dimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)wagon is-2-yl)pyridine, 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-4,6-dimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)furan-2-yl)-5-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-herperidin, 1-oxide 4-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-herperidin, 1-oxide 2-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-6-herperidin, 1-oxide 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)having as Central part of the fragment 1H-imidazol-1,5-diyl include 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-4,6-dimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-they shall Gasol-1-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-2-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-2-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-2-herperidin, 1-oxide 2-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-6-herperidin, 1-oxide 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-6-methylpyridine 1-oxide, 2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-6-methylpyridine.

Preferred compounds of the above General formula (I)having as Central part of the fragment is isoxazol-3,5-diyl include 1-oxide 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,6-dimethylpyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)pyridine, 1-oxide, 3-(3-(3,4-dihydrox the-5-nitrophenyl)isoxazol-5-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,5,6-trimethylpyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,6-dimethylpyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-5-(trifluoromethyl)pyridine, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-herperidin, 1-oxide 4-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-herperidin, 1-oxide 2-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-6-herperidin, 1-oxide, 2-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)having as Central part of the carbonyl fragment, include 1-oxide 3-(3,4-dihydroxy-5-nitrobenzoyl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,6-dimethylpyridine, 1-oxide, 3-(3,4-dihydroxy-5-nitrobenzoyl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(3,4-dihydroxy-5-nitrobenzoyl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(3,4-dihydroxy-5-nitrobenzoyl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide, 3-(3,4-dihydrox the-5-nitrobenzoyl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(3,4-dihydroxy-5-nitrobenzoyl)pyridine, 1-oxide, 3-(3,4-dihydroxy-5-nitrobenzoyl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,5,6-trimethylpyridine, 1-oxide, 3-(3,4-dihydroxy-5-nitrobenzoyl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,6-dimethylpyridine, 1-oxide, 3-(3,4-dihydroxy-5-nitrobenzoyl)-5-(trifluoromethyl)pyridine, 1-oxide, 3-(3,4-dihydroxy-5-nitrobenzoyl)-2-herperidin, 1-oxide 4-(3,4-dihydroxy-5-nitrobenzoyl)-2-herperidin, 1-oxide 2-(3,4-dihydroxy-5-nitrobenzoyl)-6-herperidin, 1-oxide, 2-chloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-6-methylpyridine, 1-oxide, 2-bromo-3-(3,4-dihydroxy-5-nitrobenzoyl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(3,4-dihydroxy-5-nitrobenzoyl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)having as Central part of the fragment oxazol-2,4-diyl include 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,6-dimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-methyl-4-(Tr is permitil)pyridine, 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,6-dimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-5-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-herperidin, 1-oxide 4-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-herperidin, 1-oxide 2-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-6-herperidin, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)having as Central part of a piece of benzene-1,3-diyl include 1-oxide 3-(3',4'-dihydroxy-5'-nitrobiphenyl-3-yl)-4-(trifluoromethyl)pyridine, 1-oxide 5-(3',4'-dihydroxy-5'-nitrobiphenyl-3-yl)-2-(trifluoromethyl)pyrid is on, 1-oxide, 3,5-dichloro-4-(3',4'-dihydroxy-5'-nitrobiphenyl-3-yl)pyridine, 1-oxide, 3-(3',4'-dihydroxy-5'-nitrobiphenyl-3-yl)-2-(trifluoromethyl)pyridine 1-oxide 3-(3',4'-dihydroxy-5'-nitrobiphenyl-3-yl)-5-(trifluoromethyl)pyridine.

Preferred compounds of the above General formula (I)having as Central part of the fragment 1H-pyrazole-1,5-diyl include 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazole-1-yl)-4-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazole-1-yl)-2-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazole-1-yl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazole-1-yl)-2-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyridine 1-oxide 4-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-pyrazole-1-yl)-2-herperidin.

Preferred compounds of the above General formula (I)having as Central part of the fragment pyrimidine-2,4-diyl include 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-4,6-dimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-2-methyl-4-(trifter ethyl)pyridine, 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-4,6-dimethylpyridine and 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)pyrimidine-2-yl)-5-(trifluoromethyl)pyridine.

Preferred compounds of the above General formula (I)having as Central part of the fragment 1H-pyrrole-2,5-diyl include 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-3-(etoxycarbonyl)-1H-pyrrol-2-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)-1-methyl-1H-pyrrol-2-yl)-4,6-dimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-1-ethyl-3-(etoxycarbonyl)-1H-pyrrol-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-shall yrrol-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-4,5,6-trimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-4,6-dimethylpyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-5-(trifluoromethyl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-herperidin, 1-oxide 4-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-2-herperidin, 1-oxide 2-(5-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)-1-methyl-1H-pyrrol-2-yl)-6-herperidin, 1-oxide, 2-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-1H-pyrrol-2-yl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)having as Central part of the fragment 2H-tetrazol-2,5-diyl include 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)-4-(trifluoromethyl)pyridine, 1-hydroxy is 5-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)pyridine, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)-2-(trifluoromethyl)pyridine 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-2H-tetrazol-2-yl)-5-(trifluoromethyl)pyridine.

Preferred compounds of the above General formula (I)having as Central part of a piece of 1,2,3-thiadiazole-4,5-diyl include 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-4,6-dimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-4,5,6-trimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichlor-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-4,6-dimethylpyridine, 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-5-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-2-herperidin, 1-oxide 4-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-2-herperidin, 1-oxide 2-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-6-herperidin, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,2,3-thiadiazole-5-yl)-4,6-dimethylpyridine.

Preferred compounds of the above General formula (I)having as Central part of the fragment thiazole-2,4-diyl include 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4-(trifluoromethyl)pyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4,6-dimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-methyl-6-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 5-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-methyl-4-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2,6-dimethyl-4-(trifluoromethyl)pyridine, 1-oxide, 3,5-dichloro-4-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-6-methyl-2-phenyl-4-(trifluoromethyl)pyridine, 1-oxide, 2-bromo-3-(4-(3,4-is hydroxy-5-nitrophenyl)thiazol-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4,5,6-trimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-(trifluoromethyl)pyridine, 1-oxide 2,5-dichloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-4,6-dimethylpyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-5-(trifluoromethyl)pyridine, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-herperidin, 1-oxide 4-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-2-herperidin, 1-oxide 2-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-6-herperidin, 1-oxide, 2-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-6-methylpyridine, 1-oxide, 2-bromo-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-yl)-6-methylpyridine 1-oxide, 2-bromo-5-chloro-3-(4-(3,4-dihydroxy-5-nitrophenyl)thiazol-2-Il)-4,6-dimethylpyridine.

In one embodiment of compounds of General formula I, where the Central part consists of 1,2,4-oxadiazol-3,5-diyl-fragment can be obtained by a method in which the compound of General formula IIA, IIB or IIC,

where R4, R5, R6and R7defined as in General formula I, is subjected to a cyclization reaction involving the condensation and dehydration, with the compound of General formula III,

where R8and R9independently of one another represent hydrogen or a suitable protective group for an aromatic hydroxyl group, when y is s, suitable for oxadiazoline derivatives of the formula IVA, IV or IVB,

with the subsequent removal of protecting the hydroxyl group, to obtain compounds of General formula I, where the Central part consists of 1,2,4-oxadiazol-3,5-diyl-fragment.

In another embodiment of the compounds of General formula I, where the Central part consists of 1,2,4-oxadiazol-3,5-diyl-fragment can be obtained by a method in which the compound of General formula VA, V or VB,

where R4, R5, R6and R7defined as in General formula I, is subjected to a cyclization reaction involving the condensation and dehydration, with the compound of General formula III under conditions suitable for obtaining oxadiazoline derivatives of the formula VIA, VI or VIB,

with subsequent oxidation peredelnogo nitrogen atom that gives compound according to formula IVA, IV or IVB, as shown above, and finally, if necessary, removing the protecting the hydroxyl group, to obtain compounds of General formula I, where the Central part consists of 1,2,4-oxadiazol-3,5-diyl-fragment.

Suitable protective groups for aromatic hydroxyl groups are well known in this field. Examples of suitable protective groups for aromatic hydroxyl groups include methyl, ethyl, isopropyl, be the ZIL, 4-methoxybenzyl, methoxymethyl, benzoyloxymethyl, methoxyethoxymethyl, tetrahydropyranyl, phenacyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, benzyloxycarbonyl, tert-butoxycarbonyl, ester, sulphonate, urethane, phosphinate, acetylene and Catalunya derivatives.

In the preferred embodiment of one of the groups R8and R9represents hydrogen and the other represents methyl. In a particularly preferred embodiment R8represents methyl, and R9represents hydrogen.

In an alternative preferred embodiment of the protective group R8and R9substituted with hydrogen or a group which is hydrolyzable under physiological conditions. The protective group R8and R9can be removed independently of each separate reaction stages or they may be removed in a single reaction stage. Also enter group which is hydrolyzable under physiological conditions, can be carried out either in the same or in a subsequent reaction stage.

In the present invention, the conditions suitable for obtaining oxadiazoline derivatives include conditions that give oxadiazoline derived with high yield and purity. Preferably the output required oxadiazole derivative is at least 70%, more p is edocfile 75-99%, even more preferably 80-97% and most preferably 85-95%. Preferably the purity of the desired oxadiazole derivative is at least 90%, more preferably at least 95%, even more preferably at least 99% and most preferably at least 99.5%pure. Based on the object of the present invention by a qualified specialist can in the usual way to establish the most suitable reaction conditions to optimize the yield and purity of oxadiazole. The parameters that should be considered qualified, include, but are not limited to, reagents, carrying out the condensation, and dehydrating agents, the choice of protective groups R8and R9system , solvent, reaction temperature and reaction time, and the solubility of the reactants.

The compound of General formula III requires activation prior to condensation with the compound of the formula IIA-IIB or VA-VB. Suitable reagents for the activation of the compounds of formula III include 1,1-carbonyldiimidazole, thionyl chloride, sulphonylchloride, N,N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, phosgene, l3, l3, PCl3, anhydrides, trichlorotriazine and chlorodimethylsilane and the like. Especially preferred 1,1-carbonyldiimidazole and thionyl chloride. In some case the Yah those same reagents can be used to perform the cyclization stage, which consists of the condensation and dehydration. Alternative reagents for the implementation of condensation and/or dehydration include pyridine and tetrabutylammonium fluoride. Preferably the dehydration can be performed during thermal heating of the reaction mixture together with the above reagents.

The compound of General formula III can be activated with an excess of reagent, such as thionyl chloride, in a suitable solvent or without additional solvent. Preferably an excess of the reagent can then be removed, for example, by distillation and replaced by the solvent and the other reagent, such as pyridine, to perform phase condensation and dehydration. The preferred solvent system for activating compounds of General formula III and cyclization to compounds of General formulas IIA - IIB or VA - VB are dipolar aprotic solvents, including dimethylformamide, dimethylsulfoxide, dimethylacetamide and N-methylpyrrolidinone. Particularly preferred dimethylsulfoxide and dimethylacetamide.

A suitable reaction temperature and reaction time depend on the reactivity used to carry out the condensation and dehydration reagents. Preferably the reaction temperature is in the range from 0°C to the boiling point of the used solvent system, more pre is respectfully in the range 20-150°C. and most preferably in the range of 25-120°C. Preferably, the reaction time ranges from 30 minutes to 24 hours, more preferably in the range of from 1 hour to 18 hours, and most preferably 2-6 hours.

In an alternative preferred embodiment the reaction of condensation and dehydration is carried out in the presence of organic or inorganic bases. Suitable preferred bases include triethylamine, tributylamine, 2,6-lutidine, N-methylmorpholine, pyridine, imidazole, N-Mei and 4-dimethylaminopyridine. Particularly preferred bases include pyridine, N-Mei and 4-dimethylaminopyridine.

In the preferred embodiment of the present invention the condensation and dehydration is carried out in two separate reaction steps. In this particular embodiment different agents condensation and dehydration and solvents can be used to optimize the yield and purity of product.

In an alternative preferred embodiment of the present invention the condensation and dehydration carried out sequentially in the same vessel without isolating the O-acylated intermediates. In this particular embodiment, the reagents for carrying out the condensation and dehydration, may be the same or different but are preferably identical.

The number of reagents exercising condenses the Yu and dehydration, is not determinative. Normal amounts of reactants carrying out the condensation and dehydration include at least an amount of 1 mol, preferably 2.1 mol to 5 mol, more preferably 2.2 to 4 mol and most preferably of 2.3 mol to 3 mol per mol pyridine derivative. In cases where reagents carrying out the condensation and dehydration, also serve as solvent or co-solvent, the excess amount may be much greater.

As mentioned above, in preferred embodiments of the invention includes a step in which the nitrogen atom peredelnogo fragment VIA VI or VIB oxidized under suitable conditions, to the corresponding derived pyridyl-N-oxide of IVA, IV or IVB after the cyclization reaction.

In the present invention oxidative conditions suitable for obtaining pyridyl-N-oxide, include conditions that yield derived pyridyl-N-oxide with high yield and purity. Preferably the output of the desired derivative pyridyl-N-oxide is at least 90%, more preferably 92-99%, even more preferably 94-98% and most preferably 95 to 97%. Preferably the purity of the desired derivative pyridyl-N-oxide is at least 90%, more preferably at least 95%, even more preferably at least 99% and most preferred is sustained fashion at least 99.5%pure. Based on the object of the present invention by a qualified specialist can in the usual way to establish the most suitable reaction conditions to optimize the yield and purity of the pyridyl-N-oxide. The parameters that should be considered qualified, include, but are not limited to, the oxidant, the amount of oxidant, the choice of protective groups, solvents, reaction temperature and reaction time, and the solubility of the reactants.

Preferred oxidizing agents include hydrogen peroxide, Mno2, peracetic acid, cryptanalysis acid, tert-butylhydroperoxide, meta-chloroperoxybenzoic acid, nadseroy acid, Oxon®, a complex of urea with hydrogen peroxide and triperoxonane anhydride, chlorproma pyridinium and permanganate ions. Particularly preferred complex of urea with hydrogen peroxide and triperoxonane anhydride.

The preferred amount of oxidant is in the range of equimolar quantities of up to 20-fold excess relative to the pyridine derivative. Preferably the amount of oxidant is in the range from 1.2-fold to 10-fold excess, more preferably from 1.5-fold to 8-fold excess, and most preferably from 2-fold to 5-fold excess.

The preferred solvent system for carrying out OK the comprehension are solvents, which is inert to the oxidizing agent. Particularly preferred halogenated solvents such as dichloromethane, chloroform, chlorobenzene and carbon tetrachloride, aromatic solvents such as benzene and toluene, alkanes such as cyclohexane and hexane, ethers such as THF, 1,4-dioxane and tert-butyl methyl ether.

A suitable reaction temperature and reaction times depend on the reactivity of the used oxidant. Preferably the reaction temperature is in the range from 0°C to the boiling point of the used solvent system, more preferably in the range of 20-100°C. and most preferably in the range of 40-80°C. Preferably, the reaction time ranges from 30 minutes to 24 hours, more preferably in the range of from 1 hour to 18 hours, and most preferably 2-6 hours.

Oxidation peredelnogo nitrogen atom can be performed at any stage of the process of producing compounds according to the General formula I. Preferably the oxidation is carried out before the formation of compounds of formulas IIA-IIC or alternative after the formation of oxadiazole ring in the compounds of formulae VIA-VIB.

In another aspect of the invention the compounds of formula IIA, IIB or IIB receive during interaction of the compounds of General formula VIIA, VII or VIIB,

with hydroxylamine in the presence of Hel is Obrajuelo agent under suitable reaction conditions.

In another aspect of the invention the compounds of formula VA, V or VB obtained in the course of interaction of the compounds of General formula VIIIA, VIII or VIIIB,

with hydroxylamine in the presence of chelat forming agent under suitable reaction conditions.

In the present invention is suitable reaction conditions for the above reactions include conditions that yield derived amidoxime with high yield and purity. Preferably the output of the desired derivative amidoxime is at least 70%, more preferably 72-95%, even more preferably 75-90%, and most preferably 78-85%. Preferably the purity of the desired derivative amidoxime is at least 90%, more preferably at least 95%, even more preferably at least 96% and most preferably at least 97%. Based on the object of the present invention by a qualified specialist can in the usual way to establish the most suitable reaction conditions to optimize the yield and purity amidoxime. The parameters that should be considered qualified, include, but are not limited to, the amount of hydroxylamine, the choice of catalyst, the nature of the substituents R4-R7system , solvent, reaction temperature and reaction time, and the solubility is of agentov.

The preferred amount of hydroxylamine is in the range of equimolar quantities of up to 50-fold excess relative to the pyridine derivative. Preferably the amount of hydroxylamine is in the range from 1.2-fold to 20-fold excess, more preferably from 1.5-fold to 10-fold excess, and most preferably from 3-fold to 5-fold excess.

The preferred hepatoblastoma agents include 8-hydroxyquinoline, ortho-phenanthroline and their hydrates and derivatives. The preferred amount of chelat forming agent is in the range of 0.1 to 10 molar %, more preferably 0.5 to 5 molar %, more preferably 0.75 to 3 molar%, and most preferably about 1-1 .5 molar %.

The solvent system is not particularly limited and includes water, alcohols such as methanol, ethanol or isopropanol, ethers, such as THF or 1,4-dioxane, and dipolar aprotic solvents such as dimethylsulfoxide and the like or mixtures of these solvents.

Preferably the reaction temperature is in the range from 0°C to the boiling point of the used solvent system, more preferably in the range of 20-100°C. and most preferably in the range of 40-80°C. Preferably, the reaction time ranges from 30 minutes to 24 hours, more preferably in the range of from 1 hour to 8 hours and most preferably 2-8 hours.

To obtain pharmaceutical compositions of the General formula (I) inert pharmaceutically acceptable carriers are mixed with the active compounds. Pharmaceutically acceptable carriers can be either solid or liquid. The solid form preparations include powders, tablets, dispersible granules, and capsules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, soljubilizatory, lubricants, suspendresume agents, binders or dezintegriruetsja agents for tablets; it may also be a kapsulirujushchej material.

Preferably, the pharmaceutical preparation is in the standard dosage form, such as a packaged preparation, the package contains a specific quantity of the drug, such as packaged tablets, capsules, and powders in vials or ampoules.

The dosage can vary depending on the needs of the patient, the severity of the disease and specific applicable connection. For convenience, the total daily dosage may be divided and enter the parts during the day. The proper dosage in a particular situation is determined by the qualification of a specialist in the medical field.

Materials and methods

Analysis of the activity of COMT mice

Samples of liver NMRI mice at the age of 0 days and weighing 20-30 g (Harlan-Interfauna Ibérica, Barcelona, Spain)contained ten in the cell under controlled environmental conditions (12-hour day/night cycle and room temperature 24°C)was used in all experiments. Perfoirmance saline tissue obtained from a shot by pentobarbitone (60 mg/kg) mice used in all experiments. Tissues were immediately removed and homogenized in 5 mm phosphate buffer, pH 7,8, and stored at -80°C.

The activity of COMT was assessed by the ability to metilirovanie adrenaline to metanephrine, as before described (Vieira-Coelho M.A., Soares-da-Silva P., Brain Res, 1999, 821, 69-78). Aliquots of 0.5 ml of the homogenates of the liver pre-incubated for 20 minutes with 0.4 ml of phosphate buffer (5 mm); then the reaction mixture was incubated for 10 minutes with epinephrine (500 μm; 0.1 ml) in the presence of saturated concentration of S-adenosyl-L-methionine, a methyl donor (250 μm). The incubation medium also contained pargyline (100 μm), MgCl2(100 μm) and EGTA (1 mm). Pre-incubation and incubation was carried out at 37°C in conditions protect from light with continuous shaking and without oxygen saturation. At the end of the incubation period, the test tube was transferred to ice and the reaction was stopped by adding 200 ál of 2 M perchloro acid. Then the samples were centrifuged (200×g, 4 min, 4°C) and 500 ál aliquot of the supernatant, filtered through filter t the skirts Spin-X with a pore size of 0.22 μm (Costar), used for metanephrine analysis using high-performance liquid chromatography with electrochemical detection.

In experiments designed to assess the effects of these compounds on COMTE liver, the compounds (5% carboxymethylcellulose) by gastric probe was administered in the evening hungry mice. Then at certain intervals of time, the liver was removed and used for determining the activity of COMT, as described above.

Analysis of the activity of COMT rats

The liver of male rats of Wistar at 60 days of age and weighing 240-260 g (Harlan-Interfauna Ibérica, Barcelona, Spain), contained two in a cage with controlled environmental conditions (12-hour day / night cycle and room temperature 24°C)was used in all experiments. After decapitate bodies were immediately removed and homogenized in 5 mm phosphate buffer with a pH of 7.8. The activity of COMT was assessed by the ability to metilirovanie adrenaline to metanephrine. Aliquots of 0.5 ml of the homogenates of the liver pre-incubated for 20 minutes with 0.4 ml of phosphate buffer (5 mm); then the reaction mixture is incubated for 5 minutes with epinephrine (1000 microns; 0.1 ml) in the presence of saturated concentration of S-adenosyl-L-methionine (500 μm), a methyl donor; the incubation medium also contained pargyline (100 μm), MgCl2(100 μm) and EGTA (1 mm). Pre is sustained fashion incubation and incubation was carried out at 37°C in conditions protect from light with continuous shaking and without oxygen saturation.

In experiments designed to assess the bioavailability of these compounds when administered orally, the compounds on gastric probe was introduced to the hungry in the evening rats. Then at certain intervals, animals were killed by decapitation, the liver was removed and used for determining the activity of COMT, as described above. At the end of the incubation period (5 minutes) the test tube was transferred to ice and the reaction was stopped by adding 200 ál of 2 M perchloro acid. Then the samples were centrifuged (200×g, 4 min, 4°C) and 500 ál aliquot of the supernatant, filtered through filter tube Spin-X with a pore size of 0.22 μm (Costar)was used for analysis of metanephrine. The metanephrine analysis was performed by high-performance liquid chromatography with electrochemical detection. Lower limits of detection metanephrine ranged from 350 to 500 fmol (0.5-1.0 pmol/mg protein/h).

Levels of L-DOPA and 3-O-methyl-L-DOPA in plasma

Hungry in the evening rats were administered oral tolkapon, entacapone and compounds of General formula I (all 3 mg/kg) or the filler (in 0.5% carboxymethylcellulose, 4 ml/kg). After 1, 6, or 23 hours rats were administered oral L-DOPA (12 mg/kg) plus benserazide (3 mg/kg) or the filler (in 0.5% carboxymethylcellulose, 4 ml/kg). After one hour the rats did anesthesia with pentobarbitone sodium (60 mg/kg, entrape fonearena), the blood was collected from the Vena cava and the whole brain was rapidly removed. Blood samples were centrifuged for 15 minutes at 3000 g (4°C) and plasma samples were stored at -80°C until analysis of L-DOPA and 3-O-methyl-L-DOPA. All experiments with animals were carried out according to the European Directive number 86/609 and the rules of the "Guide for the care and use of laboratory animals (Guide for the Care and Use of Laboratory Animals, 7th edition, 1996, Institute for Laboratory Animal Research (ILAR), Washington, DC.

Analysis of L-DOPA and catechol derivative

L-DOPA and 3-O-methyl-L-DOPA in the blood samples were analyzed using HPLC with electrochemical detection as described before (Soares-da-Silva et al., Brain Res. 2000; 863: 293-297). Briefly, aliquots of 20 µl were injected into the chromatograph. The chromatographic system consisted of a pump (Gilson 307) and 5 μm ODS2 column stainless steel (Biophase; Bioanalytical Systems, West Lafayette, IN) with a length of 25 cm and a diameter of 4.6 mm; samples were injected by an automatic sample dispenser (Gilson 231)connected to dilatory Gilson (Gilson 401). The mobile phase was a degassed solution of citric acid 0.1 mm; octisalate sodium 0.5 mm; sodium acetate 0.1 M; PA2EDTA 0.17 mm; dibutylamine 1 mm and methanol (10% vol./vol.), brought to pH 3.5 with 2M SAR (pyrrolidonecarboxylic acid) and pumped at a speed of 1.0 ml min-1. Detection was performed electrochemically with a glassy carbon electrode the reference electrode Ag/AgCl and amperometric detector (Gilson 142); cell detector operated at 0,75 Century Created the current was processed using the software for HPLC Gilson Unipoint.

Cellular toxicity

The method, which identifies the cellular toxicity of the investigated substances are described from Pedrosa and Soares-da-Silva (Br.J.Pharmacol., 137, 1 1305-1313, 2002). Briefly, cells of mice neuroblastoma Neuro 2A were cultivated in 96-well plates in 200 μl per well of culture medium to attach cells (MCA, calcium magnesium acetate) in a humid atmosphere WITH2/air (5%/95%) at 37°C. the Control for the test system prior to incubation was in the morphological control (optical microscopy) for cultured cells: consolidation, distribution and density. Five days after sowing (after 24 hours the cells became fused) the compounds were incubated for 24 hours with cultured cells. Cultivation without the test sample or with ethanol was performed in parallel as negative and positive control. All incubation contained the same percentage of solvent required for the compounds.

Cell viability was measured using calcein-AM (Molecular Probes, Eugene, OR, USA). Penetrating into the membrane calcein-AM, afluorescent dye, absorbed and transformed under the action of intracellular esterases to non-penetrating into the membrane feces is Zein, which emits green fluorescence. After treatment with the test sample or the filler within 24 hours, the cells were twice washed with environment Hanks (medium composition, in mm: NaCl 137; KCl 5; gSO40,8; Na2HPO40,33; KH2RHO40,44; CaCl20,25; MgCl21,0; Tris HCl 0.15 and sodium butyrate 1,0, pH=7,4) and put 2 microns kalayna-AM on Wednesday Hanks at room temperature for 30 minutes. Fluorescence was measured at excitation wavelengths of 485 nm and emission 530 nm on the device for reading tablets. To determine the minimum coloring for calcein-AM (calceinmin), eight wells were treated with ethanol for 30 minutes before adding calcein AM. The percentage viability was then calculated as [(calceinsample-calceinmin)]/[(calceincontrol-calceinmin)]×100.

Results

Table 1 shows the impact of the standard COMT inhibitors, tolcapone and entacapone, and compounds of General formula I on the activity of COMT liver of mice 3 hours after oral administration (3 mg/kg). Table 1 shows the cell viability after 24 hours of exposure tolcapone, entacapone and compounds of General formula I (all 30 μm) on cell Neuro 2A.

Table 1
Activity COMT mouse liver (% of control) after administration of 3 mg/kg (oral) listed compounds and cell viability Neuro 2A (% viable cells)
No.(X)n (Y)nR3the activity of COMT (% of control)% viable cells
Tolkapon13,927,2
Entakapon79,881,4
1n=m=0-CH359,955,1
2n=m=0-CH378,892,5
3n=m=0-CH363,6100,5
4 n=m=042,198,3
5n=m=058,493,8
6n=m=0101,0107,1
7n=m=014,256,9
8n=m=055,4106,7
9n=m=080,679,7
10n=m=0for 95.269,3
n=m=063,9105,7
12n=m=092,991,7
13n=m=0to 102.3
14n=m=0of 76.8to 83.5
15n=m=079,2to 97.1
16n=m=085,964,6
17n=m=0to 89.996,0
18n=m=0of 21.2for 93.4
19n=m=045,2100,1
20n=m=056,6
21n=m=095,6
22n=m=0111,6
23n=m=04341,1
24n=m=071,893,7
25n=m=023,1100,2
26n=m=035,5110,9
27n=m=047,595,7
28n=m=011,3of 87.0
29n=m=010,962,2
30n=m=08,881,8
31n=m=00,837,2
32n=m=0the 9.726,6
33n=m=039,845,0
34n=m=088,689,0
35n=m=081,288,0
36n=m=022,976,3
37n=m=042,592,3
38n=m=016,386,0
39X=CH2,
n=1, m=0
53,894,9
40n=m=055,269,1
41n=m=01495,1
42n=m=09,496,4
43X=CH2,
n=1, m=0
27,2of 101.5
44X=CH2,
n=1,
Y=0,
m=1
24,5
45n=m=0 30,486,6
46n=m=0to 43.153,0
47n=m=025,281,2
Note: * indicates the place of attachment of the Deputy of the N-oxide of pyridine to the molecule

Also it was found that compounds of General formula I are effective inhibitors of COMT rat liver, the greatest inhibitory effect is achieved within 1-3 hours after oral administration (table 2). The maximum inhibitory effect of entacapone (ENT) and tolcapone (Sense) was observed within 1 hour after administration (table 2). After nine hours after the introduction of entacapone has no inhibiting COMT effects and tolkapon shows the minimum inhibiting effects (~16% inhibition), whereas compounds of General formula I continue to inhibit the activity of COMT 22%-90% of the control levels (table 2).

Table 3 shows the percentage changes in the levels of L-DOPA and 3-O-methyl-L-DOPA (3-OMD) in p is the AZM rats treated with L-DOPA plus benserazide, 2 hours after the introduction of entacapone, tolcapone and compounds of General formula I (3 mg/kg). L-DOPA plus benserazide was administered one hour before collection of plasma samples. This time was chosen because it is a tmaxfor L-DOPA. As you can see, the compounds of General formula I caused a significant increase in L-DOPA in plasma, followed by reduction of 3-O-methyl-L-DOPA in plasma.

Table 3
The impact of these compounds (3 mg/kg; oral administration) change (% of control) levels of L-DOPA and 3-O-methyl-L-DOPA (3-OMD) in the plasma of rats treated with L-DOPA plus benserazide
ConnectionL-DOPA
% increase
3-OMD
% reduction
L-DOPA/3-OMD
Entakapon68,5-55,6the 3.8
Tolkapon202,4-89,027,6
1861,4-63,94,5
29105,1-80,710,6
30103,5-75,08,1
41for 95.2-72,37,1
4230,7-43,42,3
4374,9-48,33,4
45100,8-54,34,4
47102,9-58,5a 4.9

Conclusion

Compounds of General formula I are very effective inhibitors of catechol-O-methyltransferase (COMT) with significantly reduced toxicity. Compounds of General formula I possess potentially valuable pharmaceutical properties in the treatment of some disorders of the Central and peripheral nervous system, when the inhibition of O-methylation of catecholamines can bring therapeutic benefits, such to the to affective disorders, Parkinson's disease and parkinsonism disorders, tired leg syndrome, gastrointestinal diseases, formation of edema and hypertension. The ability to apply effective inhibitor of long-term action with an improved safety profile opens new perspectives in the treatment of Parkinson's disease and parkinsonism disorders, gastrointestinal diseases, conditions of formation of edema and hypertension, improving security nitrocatechols inhibitors COMT and at the same time improving or maintaining the duration and selectivity of inhibition of COMT. This is particularly important having in mind the treatment of patients suffering from Parkinson's disease who take L-DOPA plus inhibitor peripheral AADC, due to the fact that it is a long treatment.

Open here the invention is illustrated by the following examples of the preparation, which, as should be considered, do not limit the scope of the invention. Alternative methods and similar structures may be obvious to a qualified specialist in this field.

Example 1

3-Nitro-5-[3-(1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol (compound 4, table 1)

a) To a stirred solution of 3,4-dimensions-5-nitrobenzoic acid (0.5 g, of 1.32 mmol) in dimethylformamide (5 ml) at room temperature was added 1,1-carb is soldierization (0,246 g, of 1.52 mmol) at once. After stirring for one hour at a time was added N'-hydroxypyridine-4-carboxamide (0,208 g of 1.52 mmol) and the resulting mixture was stirred at room temperature overnight. Then the mixture was stirred at 110°C for three hours and then cooled to room temperature. The mixture was poured into ice water (100 ml) and was extracted with 20% isopropanol/dichloromethane. The organic extracts were washed with water and brine, then dried (Na2SO4), filtered and evaporated before the formation of the solid residue, which was recrystallized from ethanol. 4-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridine was obtained as a beige solid (0,395 g, 62%).

b) Mixed solution of the above pyridine compounds (0,331 g, 0,689 mmol) in dichloromethane (15 ml) was cooled in a bath of ice water, and the parts added meta-chloroperoxybenzoic acid (0,179 g of 1.03 mmol). The resulting mixture was stirred in the cold for thirty minutes and then at room temperature for thirty minutes, then again cooled in a bath of ice water. Added more meta-chloroperoxybenzoic acid (0.17 g, of 1.03 mmol) and the mixture is then stirred at room temperature for an hour and a half. Water (20 ml) was added and the organic phase division is whether and washed with saturated aqueous sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated to obtain a yellow oil. The addition of diethyl ether resulted in the formation of a precipitate, which was filtered and recrystallized from a mixture of dichloromethane/isopropanol. 1-Oxide 4-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridine was obtained as white crystals (0,239 g, 70%).

C) a Solution of the above dimensional ether (0,232 g, 0,468 mmol) in dichloromethane (5 ml) was cooled to -78°C With stirring in an argon atmosphere and treated with tribromide boron (0,586 g, 2.34 mmol) dropwise. The resulting dark purple suspension was then stirred at room temperature for one hour before re-cooling to -78°C.

The mixture is extinguished, carefully adding methanol. After stirring at room temperature for one hour, and the volatile components evaporated and the residue was treated with ethanol/toluene and again evaporated. The yellow residue was washed with boiling ethanol and filtered warm, getting listed in title product as a yellow solid (is 0.102 g, 69%), TPL 280-282°C.

Example 2

3-Nitro-5-[3-(1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol (compound 5, table 1)

a) To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (0,232 g 1,022 mmol) in dimetilan amide (5 ml) at room temperature was added 1,1-carbonyldiimidazole (0,174 g, 1,073 mmol) at once. The resulting mixture was stirred for ninety minutes, after which 1-oxide-N'-hydroxypyridine-3-carboxamidine (0.156 g, 1,022 mmol) was added at once. The resulting mixture was stirred at room temperature for two hours, and then at 75°C overnight. After cooling to room temperature the mixture was poured into water (100 ml) and the precipitate was filtered, washed with water, then dried in air and recrystallized from diethyl ether. 1-Oxide 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridine was obtained as a white solid (rate £ 0.162 g, 46%).

b) To a stirred solution of the above dimethyl ether (0,153 g, 0,445 mmol) in dichloromethane (10 ml) at -78°C in an atmosphere of argon was added tribromide dropwise boron (0,445 g 1,779 mmol). The reaction mixture was heated to room temperature and was stirred for ninety minutes before carefully pouring into water (100 ml). After stirring for twenty minutes, the mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated. 2-Methoxy-3-nitro-5-[3-(1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-phenol was obtained as a yellow solid (0.12 g, 82%).

C) Stirring a suspension of the above metrolog the ether (to 0.108 g, 0,327 mmol) in 1,2-dichloroethane (10 ml) at room temperature in an argon atmosphere was treated with aluminum chloride (0,087 g, 0,654 mmol), then pyridine (0,207 g, 2,62 mmol) dropwise. Then the mixture was heated under reflux for seven hours, after which was added aluminium chloride (0,087 g, 0,654 mmol) and pyridine (0,207 g, 2,62 mmol) and the mixture was stirred at reflux for an additional seven hours. The mixture was then cooled to room temperature and poured into cold 1 n hydrochloric acid (30 ml). The resulting precipitate was filtered, washed with water and dried at 50°C under vacuum. The desired product was obtained as an orange solid (0.075 g, 72%), TPL-280°C.

Example 3

3-Nitro-5-[3-(1-oxy-pyridine-2-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol (compound 6, table 1)

a) To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (1.0 g, 4.40 mmol) in dimethylformamide (10 ml) at room temperature was added 1,1-carbonyldiimidazole (0,821 g of 5.06 mmol) at once. The resulting yellow mixture stirring within ninety minutes, after which 1-oxide-N'-hydroxypyridine-2-carboxamidine (0,775 g of 5.06 mmol) was added at once. The resulting mixture was stirred at room temperature overnight and then poured into water (100 ml). The resulting OS the dock was filtered, washed with water and then transferred in dichloromethane (30 ml). The organic layer was washed with water and brine, dried (Na2SO4), filtered and evaporated to a white solid (1,37 g, 86%).

b) To a stirred suspension of the above solid (1,365 g of 3.77 mmol) in tetrahydrofuran (14 ml) at room temperature in an argon atmosphere was added 1 n solution of tetrabutylammonium fluoride in tetrahydrofuran (3.8 ml, 3.8 mmol). The resulting clear yellow solution was stirred at room temperature for seven hours, during this time he formed a new precipitate. The mixture was filtered and the solid is washed with several portions of cold tetrahydrofuran. 1-Oxide 2-[5-[3,4-dimethoxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridine was obtained as a white solid (0.97 g, 75%).

C) To a stirred suspension obtained above dimethyl ether (0,961 g, and 2.79 mmol) in dichloromethane (15 ml) at -78°C in an atmosphere of argon was added tribromide boron (3.5 g, of 13.97 mmol) dropwise. The resulting purple suspension was then stirred at room temperature for seven hours, before cooling in a bath of ice water. The mixture was carefully suppressed by adding methanol. The resulting yellow mixture was stirred at room temperature for one hour, after which the wasp is OK was filtered and washed with methanol. The solid is triturated with boiling ethanol and filtered warm. After drying, the desired compound was obtained as an orange solid (0,712 g, 81%), TPL 168°C.

Example 4

5-(5-Methyl-[1,2,4]oxadiazol-3-yl)-3-nitro-benzene-1,2-diol (compound 2, table 1)

a) To a stirred solution of 3,4-bis-benzyloxy-N'-hydroxy-5-nitro-benzamidine (1.0 g, 2.54 mmol) in dimethylformamide (5 ml) at room temperature was added 1,1-carbonyldiimidazole (0,494 g 3,048 mmol) and the mixture was stirred at room temperature for ninety minutes. Then acetic acid (0,184 g 3,067 mmol) was added dropwise and the mixture was stirred for two hours at room temperature, then at 155°C for three hours. The mixture was cooled to room temperature and poured into ice-cold water (100 ml). Saline (10 ml) was added and the resulting precipitate was removed during filtration, washed with water and dried in air. Then the solid was dissolved in dichloromethane (20 ml) was added activated carbon on the tip of a spatula. After stirring for twenty minutes, the suspension was filtered through celite and the filtrate evaporated, receiving a yellow oil, which was hardened on the substrate. After recrystallization from dichloromethane/petroleum ether 3-(3,4-bis-benzyloxy-5-nitrophenyl)-5-methyl-[1,2,4]oxadiazol who was lucali in the form of a pale yellow solid (0,537 g, 51%).

b) To mix the solution obtained above solids (0,128 g, 0,307 mmol) in dichloromethane (15 ml) at -78°C in an atmosphere of argon was added tribromide boron (0,318 g 1,269 mmol) dropwise. The resulting purple suspension was stirred at room temperature for one hour, then was cooled to -78°C. the Mixture was suppressed, carefully adding methanol and after stirring at room temperature for one hour, the solvents evaporated. The yellow residue was washed with diethyl ether, filtered and dried. The desired compound was obtained as a yellow solid (0,070 g, 96%), TPL 169,8-172°C.

Example 5

5-(5-Methyl-[1,3,4]oxadiazol-2-yl)-3-nitro-benzene-1,2-diol (compound 3, table 1)

a) To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (0,438 g of 1.93 mmol) in tetrahydrofuran (10 ml) at room temperature was added 1,1-carbonyldiimidazole (0,343 g, 2,12 mmol) and the mixture was stirred at room temperature for one hour, then at 70°C for two hours, after which was added acetic acid hydrazide (of) 0.157 g, 2,12 mmol). The resulting mixture was stirred at room temperature for thirty minutes, then at 70°C for two hours. After cooling to room temperature the mixture was poured into ice water (100 ml), the precipitate tfilter ivali and washed with water. N'-acetyl-hydrazide of 3,4-dimethoxy-5-nitro-benzoic acid was obtained as a white solid (0,296 g, 54%).

b) the Suspension obtained above solids (in 0.288 g, 1,017 mmol) in phosphorus oxychloride (7 ml) was stirred at 120°C for two hours, then cooled to room temperature. Then the solution was poured into ice water (200 ml), causing the formation of a white precipitate. Was extracted with dichloromethane and the organic extracts were washed with water and brine, then dried, filtered and evaporated, getting a white solid. Recrystallization from dichloromethane/petroleum ether gave 2-(3,4-dimethoxy-5-nitro-phenyl)-5-methyl-[1,3,4]oxadiazol in the form of white crystals (0,151 g, 56%).

in) To the mixed solution obtained above solids (0,145 g, 0,547 mmol) in dichloromethane (10 ml) at -78°C in an atmosphere of argon was added tribromide boron (0,685 g, is 2.74 mmol) dropwise. The resulting purple suspension was stirred at room temperature overnight, then was cooled to -78°C. the Reaction was suppressed by adding methanol and after stirring at room temperature for one hour, and the volatile components evaporated. Toluene (20 ml) was added to the residue and again evaporated. The residue is triturated with boiling ethanol and filtered warm, obtaining the desired product as an orange solid substances is a (0,107 g, 82%), TPL 245-246°C.

Example 6

5-[3-(3,5-Dichloro-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol (compound 7, table 1)

a) To a stirred solution of 3,4-dimensions-5-nitrobenzoic acid (0.50 g, of 1.32 mmol) in dimethylformamide (5 ml) at room temperature was added 1,1-carbonyldiimidazole (0,246 g of 1.52 mmol) and the mixture was stirred for ninety minutes, then 3,5-dichloro-N'-hydroxy-1-axisofrotation (of 0.337 g of 1.52 mmol) was added at once. The resulting mixture was stirred at room temperature overnight and then poured into ice-cold water (100 ml). Saline (10 ml) was added and the precipitate was filtered, washed with water and dissolved in 30% isopropanol/dichloromethane. Then dichloromethane drove and the resulting isopropanol the suspension was left at 0°C for one hour. The solid was then filtered off, washed with cold isopropanol and dried, obtaining white solid (0,756 g, 98%).

b) a Portion of this solid (0,664 g to 1.14 mmol) and 1,1-carbonyldiimidazole (0,185 g to 1.14 mmol) was dissolved in dimethylformamide (10 ml) and stirred at 100°C for nine hours, then at room temperature overnight. The resulting mixture was poured into ice water (100 ml) and then acidified to pH 1-2, dropwise adding 2 n hydrochloric acid. Yellow precipitate, to the which was formed, was filtered, washed with water and dissolved in 10% isopropanol/dichloromethane (50 ml). The organic phase was dried, filtered and evaporated to dryness. The residue was chromatographically on silica gel using a solvent mixture ethyl acetate/petroleum ether (1:1). Homogeneous fractions were combined and evaporated and the residue was recrystallized from dichloromethane/isopropanol, receiving 2-benzyloxy-4-[3-(3,5-dichloro-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-6-nitro-phenol as a yellow solid (to 0.263 g, 49%).

C) To a stirred suspension of the above solid (0.24 g, worn : 0.505 mmol) in dichloromethane (5 ml) at -78°C in an atmosphere of argon was added tribromide boron (0,371 g, 1.5 mmol) dropwise. The resulting purple suspension was stirred at room temperature for one hour, then was cooled to -78°C and was suppressed by adding methanol. After stirring at room temperature for one hour the solvent was removed by evaporation. The resulting yellow foam was recrystallized from dichloromethane/isopropanol, obtaining the desired product as a yellow solid (0,153 g, 79%), TPL 252-253°C.

Example 7

5-[3-(2-Chloro-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol

(compound 8, table 1)

a) To a stirred solution of 3,4-dimensions-5-nitrobenzoic acid (0.50 g, 1.3 mmol) in dimethylformamide (5 ml) at room temperature was added 1,1-carbonyldiimidazole (0,246 g, of 1.52 mmol) and the mixture was stirred for one hour, after which 2-chloro-N'-hydroxy-1-hydroxy-isonicotinamide (0,284 g of 1.52 mmol) was added at once. The resulting mixture was stirred at room temperature for thirty minutes and then at 140°C for four hours. After cooling to room temperature the mixture was poured into water (100 ml) and acidified to pH 1-2, dropwise adding 2 n hydrochloric acid. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine, then dried, filtered and evaporated to an orange solid, which was recrystallized from dichloromethane/isopropanol, getting 1-oxide 4-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-chloro-pyridine as pale orange crystals (0,265 g, 38%).

b) To mix the solution obtained above solid (0.25 g, 0,471 mmol) in dichloromethane (5 ml) at -78°C in an atmosphere of argon was added tribromide boron (0,59 g, 2.36 mmol) dropwise. The resulting dark purple suspension was stirred at room temperature for one hour, then was cooled to -78°C. the Reaction was suppressed by adding methanol and after stirring at room temperature for one hour the solvent was removed by evaporation. Ethanol (5 ml) and toluene (20 ml) was added to the residue and the secondary is evaporated. The residue is triturated with boiling ethanol and filtered warm, obtaining the desired product as yellow crystals (0.12 g, 72%), which decomposed above 300°C.

Example 8

1-Oxide 2,5-dichloro-3-(5-(3,4-dihydroxy-2-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine

a) To a stirred suspension of 3-hydroxy-4-methoxy-2-nitrobenzoic acid (to 0.900 g, 4,22 mmol) in N,N-dimethylacetamide (10,35 ml) at room temperature was added dropwise 1,1-carbonyldiimidazole (1,540 g 9,506 mmol) in 7.65 ml of N,N-dimethylacetamide. After stirring for three hours (Z)-2,5-dichloro-N'-hydroxy-4,6-diethylnicotinamide (1.19 g, 5,107 mmol) was added 2.7 ml of N,N-dimethylacetamide at a time. The resulting mixture was stirred for one hour and forty-five minutes, then was heated at 135°C for one hour. The reaction mixture was poured into a mixture of ice and 2 n HCl. The precipitate was filtered, washed with water and dried under vacuum, obtaining a yellow solid. Recrystallization from dichloromethane/isopropanol gave 3-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-6-methoxy-2-NITROPHENOL as a yellow solid (MX 0.317 g, 18%).

b) To a stirred suspension of the above solid (0,315 g, 0,766 mmol) in dichloromethane (4.3 ml) at room temperature was added a complex joining of urea and hydrogen peroxide (0,231 g ,451 mmol). The resulting suspension was cooled to 0°C and triperoxonane anhydride (0,483 g of 2.30 mmol) was added dropwise. The mixture was stirred at room temperature for twenty-four hours, then added water and was stirred for one hour. The precipitate was filtered, washed with water and dried. The crude product was chromatographically in a mixture of dichloromethane/methanol (99:1). Evaporation of the pure fractions gave 1-oxide 2,5-dichloro-3-(5-(3-hydroxy-4-methoxy-2-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine in the form of yellow crystals (of € 0.195 g, 59%).

C) To a stirred suspension of the above solid (0,143 g, 0,335 mmol) in N-organic (2.5 ml) at 0°C in an atmosphere of argon was added aluminium chloride (0,056 g, 0.42 mmol) at one time, after which was added pyridine (0,106 g of 1.34 mmol). The resulting solution was heated at 60°C for twenty-five minutes, then cooled to room temperature and was poured into a mixture of ice and 2 n HCl. After stirring at room temperature for forty-five minutes the precipitate was filtered, washed with water and dried under vacuum. The crude product is recrystallized from a mixture of dichloromethane/isopropanol. After drying, the desired compound was obtained as yellow crystals (0,101 g, 73%), TPL 230°C (decomp.).

Example 9-17

Applying the above methods of payment related procedures, known qualified specialist in this field, and using the corresponding N-hydroxy-1-hydroxy-isonicotinamide received the following connections:

3-nitro-5-[3-(1-hydroxy-2-phenyl-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 264-264,8°C (compound 9, table 1);

5-[3-(2-furan-3-yl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 304-305°C (compound 10, table 1);

5-[3-(2-morpholine-4-yl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 277-280°C (compound 11, table 1);

3-nitro-5-[3-(1-hydroxy-2-thiomorpholine-4-yl-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 260-262°C (compound 12, table 1);

3-nitro-5-[3-(1-hydroxy-2-phenylsulfanyl-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 299-301°C (compound 13, table 1);

3-nitro-5-[3-(1-hydroxy-2-phenoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 245-246°C (compound 14, table 1);

5-[3-(2,6-dimethyl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 280-282°C (compound 15, table 1);

5-[3-(2-methanesulfonyl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 282-285°C (compound 16, table 1);

5-[3-(2-methylsulfanyl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 239-240°C (compound 17, table 1).

Example 18

3-Nitro-5-[3-(1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol (soy is inania 18, Table 1)

a) To a stirred solution of 3,4-dimensions-5-nitrobenzoic acid (0,291 g, 0,769 mmol) in dimethylformamide (5 ml) at room temperature was added 1,1-carbonyldiimidazole (0,131 g, 0,808 mmol) at once. After stirring for ninety minutes N'-hydroxy-1-hydroxy-4-trifluoromethyl-nicotinamide (0.17 g, 0,769 mmol) was added at once. The resulting mixture was stirred for two hours and then poured into ice-cold water (100 ml). The precipitate was filtered, washed with water and dried in the air, getting a white solid (0,192 g, 43%).

b) To mix the solution obtained above solids (0,192 g, 0.33 mmol) in tetrahydrofuran (10 ml) at room temperature in an argon atmosphere was added dropwise 1 n solution of tetrabutylammonium fluoride in tetrahydrofuran (1.2 ml, 1.2 mmol). After stirring at room temperature overnight the mixture was poured into water (100 ml) and was extracted with dichloromethane. The organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated. The residue was chromatographically on silica gel using a solvent mixture dichloromethane/methanol (99:1) as eluent. Homogeneous fractions were combined and evaporated and the residue is then recrystallized from dichloromethane/isopropanol. 1-Oxide 3-[5-(3,4-bis-benzyloxy-5-nitro-dryer is l)-[1,2,4]oxadiazol-3-yl]-4-trifluoromethyl-pyridine was obtained as a white solid (0,092 g, 49%).

in) To the mixed solution obtained above solid (0.09 g, 0.16 mmol) in dichloromethane (5 ml) at -78°C in an atmosphere of argon was added tribromide boron (0.16 g, 0.64 mmol) dropwise. The resulting purple suspension was stirred at room temperature for one hour, then was cooled to -78°C and carefully extinguished by adding methanol. After stirring at room temperature for one hour the precipitate was filtered, washed with water and dried at 50°C under vacuum, obtaining the desired compound as yellow crystals (0,048 g, 79%), TPL 239-240°C.

Example 19-35

Using the above method and related procedures known to a qualified specialist in this field, and using the corresponding N'-hydroxy-1-hydroxy-isonicotinamide received the following connections:

5-[3-(5-bromo-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 258-260°C (compound 19, table 1);

5-[3-(6-methyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 325-326°C (compound 20, table 1);

5-[3-(4-methyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 297°C (compound 21, table 1);

3-nitro-5-[3-(1-hydroxy-5-phenyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 288-289°C (compound 22, table 1);

5-[3-(6-chloro-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-neath the o-benzene-1,2-diol, TPL 268-270°C (compound 23, table 1);

5-[3-(2-chloro-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 265-267°C (compound 24, table 1);

5-[3-(2-chloro-6-methyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 218-220°C. (compound 25, table 1);

5-[3-(2-morpholine-4-yl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 175-177°C. (compound 26, table 1);

5-[3-(6-methylsulfanyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 264-266°C. (compound 27, table 1);

3-nitro-5-[3-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 269,5-271,3°C (compound 28, table 1);

5-[3-(2-methyl-1-oxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 240-242°C. (compound 29, table 1);

5-[3-(6-methyl-1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 250-252 .5°C (compound 30, table 1);

5-[3-(2,6-dimethyl-1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 252-253°C (compound 31, table 1);

5-[3-(2-methyl-1-hydroxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 256 -256,5°C (compound 32, table 1);

5-[3-(6-methyl-1-hydroxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 237-239°C (compound 33, table 1);

3-nitro-5-[3-(1-hydroxy-quinoline-4-yl)-[1,2,4]ACS is diazol-5-yl]-benzene-1,2-diol, TPL 306-307°C (compound 34, table 1);

3-nitro-5-[3-(1-hydroxy-quinoline-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 276-277°C (compound 35, table 1);

3-nitro-5-[3-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 253-254°C (compound 42, table 1).

Example 36

5-[3-(2-Bromo-6-methyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol (compound 36, table 1)

a) To a stirred solution of 3,4-dimensions-5-nitrobenzoic acid (1,355 g 3,576 mmol) in dimethylformamide (10 ml) at room temperature was added 1,1-carbonyldiimidazole (0,667 g 4,113 mmol) at once. After stirring for ninety minutes, 2-bromo-N'-hydroxy-6-methylnicotinamide (0,946 g 4,113 mmol) was added and the mixture was stirred overnight, then poured into water (100 ml). Added salt solution (10 ml) and the precipitate was filtered, washed with water and dissolved in dichloromethane (50 ml). The organic layer was washed with water and brine, then dried (PA2SO4), filtered and evaporated to education white foam (1,91 g, 90%).

b) To the solution obtained above solids (1,91 g of 3.23 mmol) in dimethylformamide (30 ml) was added 1,1-carbonyldiimidazole (0,576 g, 3,55 mmol) and the resulting mixture was stirred at 120°C for three hours, then cooled to room temperature. Was poured into ice water (150 ml) and p is kislali to pH 1-2, dropwise adding 2 n hydrochloric acid. The mixture was extracted with dichloromethane and the organic extracts were washed with water and brine, then dried (Na2SO4), filtered and evaporated to an orange solid. Recrystallization from dichloromethane/ethanol gave 3-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-bromo-6-methyl-pyridine as an orange solid (0,702 g, 38%).

in) To the mixed solution obtained above solids (0,609 g 1,063 mmol) in dichloromethane (15 ml) at room temperature was added a complex joining of urea and hydrogen peroxide (0,525 g 5,579 mmol). The resulting suspension was cooled to 0°C and triperoxonane anhydride (1.12 g, 5,314 mmol) was added dropwise. The mixture was stirred at room temperature for five hours, and then the insoluble product was filtered and washed with a small volume of dichloromethane. The combined filtrate was stirred with 10% aqueous solution of sodium metabisulfite (10 ml) for about fifteen minutes before the destruction of excess peroxide, and then the phases were separated. The organic phase is washed with water, saturated aqueous sodium bicarbonate, again with water and brine, then dried (Na2SO4), filtered and evaporated to a white solid. Recrystallization of the active ingredient is GDI from dichloromethane/ethanol gave 1-oxide 3-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-bromo-6-methyl-pyridine in the form of white crystals (0,344 g, 55%).

g) To the mixed solution obtained above solids (of 0.337 g, 0,572 mmol) in dichloromethane (10 ml) at -78°C in an atmosphere of argon was added tribromide boron (0,717 g of 2.86 mmol) dropwise. The resulting purple suspension was stirred at room temperature for one hour, then was cooled to -78°C and was suppressed by adding methanol. After stirring at room temperature for one hour, the solvents evaporated. Ethanol (5 ml) and toluene (20 ml) was added to the residue and again evaporated. The residue was stirred in boiling ethanol and filtered warm. After drying, the desired compound was obtained as orange crystals (0.187 g, 80%), TPL 246-247°C.

Example 37-41

Using the above method and related procedures known to a qualified specialist in this field, and using the corresponding N'-hydroxy-nicotinamide received the following connections:

5-[3-(2-chloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 234-235°C. (compound 37, table 1);

5-[3-(2-bromo-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, TPL 205-207°C (compound 38, table 1);

3-nitro-5-[3-(1'-hydroxy-pyridine-3-ylmethyl)-[1,2,4]oxadiazol-5-yl]-benzodia, TPL 232°C (compound 39, table 1);

3-nitro-5-[3-(1'-hydroxy-6-trifluoromethyl-pyridine-3-ylmethyl)-[1,2,4]oxides is l-5-yl]-benzene-1,2-diol, TPL 195,2°C (compound 43, table 1);

3-nitro-5-[3-(1'-hydroxy-5-trifluoromethyl-pyridine-2-intoximeter)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 222°C (compound 44, table 1).

Example 42

5-[3-(2-Bromo-4,5,6-trimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol (compound 40, table 1)

a) To a stirred solution of 3,4-dimensions-5-nitrobenzoic acid (0,945 g, 2.49 mmol) in dimethylformamide (10 ml) at room temperature was added 1,1-carbonyldiimidazole (0,465 g, 2,87 mmol) and the resulting mixture was stirred for two hours, after which 2-bromo-N'-hydroxy-4,5,6-trimethyl-nicotinamide (0.74 g, 2,87 mmol) was added at once. The resulting mixture was stirred at room temperature overnight and then poured into water (150 ml). Added salt solution (10 ml) and the resulting precipitate was filtered and washed with water. The solid is then dissolved in dichloromethane (50 ml) and the organic phase is washed with water and brine, then dried, filtered and evaporated to education off-white solid (1.40 g, 91%).

b) To mix the solution obtained above solid (1.39 g, 2,245 mmol) in tetrahydrofuran (20 ml) at room temperature in an argon atmosphere was added 1 n solution of tetrabutylammonium fluoride in tetrahydrofuran (2,47 ml, 2,47 mmol)After stirring at room temperature overnight, almost black reaction mixture was poured into water (150 ml) and was extracted with dichloromethane. The organic extracts were washed with water and brine, then dried, filtered and evaporated to education brown oil. Add dichloromethane (4 ml) and diethyl ether (4 ml) resulted in the formation of a precipitate, which was filtered and recrystallized from isopropanol. 3-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-bromo-4,5,6-trimethyl-pyridine was obtained as a beige solid (0,879 g, 65%).

in) To the mixed solution obtained above pyridine (0,621 g, 1,033 mmol) in dichloromethane (20 ml) at room temperature was added a complex of urea and hydrogen peroxide (1,018 grams, was 10.82 mmol) at once. The resulting suspension was cooled in a bath of ice water, and triperoxonane anhydride (2,23 g to 10.62 mmol) was added dropwise. The resulting suspension was stirred in the cold for fifteen minutes and then stirred at room temperature overnight. The insoluble product was then filtered and washed with a small volume of dichloromethane. The combined filtrate was stirred with 10% aqueous solution of sodium metabisulfite in about fifteen minutes and then the phases were separated. The organic phase is washed with water, saturated aqueous sodium bicarbonate, again with water and brine, then dried, filtered and evaporated before the formation of foam is brasego a pale orange solid. This solid was chromatographically on silica gel using a mixture of petroleum ether/ethyl acetate (1:1) as eluent. Homogeneous containing the product fractions were combined and evaporated. 1-Oxide 3-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-2-bromo-4,5,6-trimethyl-pyridine was obtained as foamy pale yellow solid (0,342 g, 54%).

g) To the mixed solution obtained above solids (0,325 g, 0,527 mmol) in dichloromethane (10 ml) at -78°C in an atmosphere of argon was added tribromide boron (0.66 g, 2,633 mmol) dropwise. The resulting dark purple suspension was stirred at room temperature for one hour, then was cooled to -78°C and carefully extinguished, adding dropwise methanol. After stirring at room temperature for one hour the solvent was removed by evaporation. Toluene (20 ml) and ethanol (5 ml) was added to the residue and again evaporated. The resulting yellow solid is triturated with boiling ethanol (15 ml) and filtered warm. The desired product was obtained as yellow solid (0.172 g, 75%), TPL 242-243°C.

Example 43-46

Using the above method and related procedures known to a qualified specialist in this field, and using the corresponding N'-hydroxy-nicotinamide received following is soedineniya:

5-[3-(2-chloro-4,5,6-trimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, TPL 246-247,3°C (compound 41, table 1);

5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, TPL 237-240°C (compound 45, table 1);

3-nitro-5-[3-(4,5,6-trimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, TPL 255-256°C (compound 46, table 1);

5-[3-(2-bromo-5-chloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, TPL 227-228°C (compound 47, table 1).

Example 47

As an example, compounds of General formula (I)with 2H-pyrazole-1,5-diyl fragment as the Central part, 3-nitro-5-[2-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-2H-pyrazole-3-yl]-benzene-1,2-diol was obtained by the following procedure:

a) To a stirred solution of 1-(3,4-dimethoxy-5-nitro-phenyl)-3-dimethylamino-prop-2-EN-1-she (0.5 g, to 1.79 mmol) and (2-trifluoromethyl-pyridine-3-yl)-hydrazine (0.33 g, of 1.87 mmol) in ethanol (10 ml) was added 10 drops of concentrated hydrochloric acid and the mixture was heated under reflux for two hours. The mixture was cooled to room temperature and the resulting precipitate was filtered, washed with ethanol and dried, obtaining 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazole-1-yl]-2-trifluoromethyl-pyridine, of 0.58 g (82%).

b) To a solution of 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazole-1-yl]-2-trifluoromethyl-pyridine (0,50g, of 1.27 mmol) in dichloromethane (10 ml), cooled in a bath of ice water was added to the complex of urea and hydrogen peroxide (0.26 g, was 2.76 mmol) at once, then triperoxonane anhydride (0,53 g, 2,52 mmol) dropwise. The resulting mixture was stirred at room temperature overnight and then the insoluble product was filtered. The filtrate was washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated to education off-white solid. Recrystallization from ethanol gave 1-oxide 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazole-1-yl]-2-trifluoromethyl-pyridine, 0.34 g (65%).

C) a Suspension of 1-oxide 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazole-1-yl]-2-trifluoromethyl-pyridine (0.3 g, 0.73 mmol) in 48% aqueous Hydrobromic acid (10 ml) was stirred at 140°C for one hour and then cooled to room temperature. Then the mixture was poured into ice water (100 ml) and the resulting yellow precipitate was filtered, washed with water and dried, obtaining 3-nitro-5-[2-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-2H-pyrazole-3-yl]-benzene-1,2-diol, 0.16 g (57%).

Example 48

As an example, compounds of General formula (I)having a 1,3,4-oxadiazol-2,5-diyl fragment as the Central part, 3-nitro-5-[5-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diol was obtained on the trail of the overall procedure:

a) a Mixture of 3,4-dimethoxy-5-nitrobenzoic acid (0,53 g, 2.34 mmol) and 1,1-carbonyldiimidazole (0,42 g at 2.59 mmol) was heated in tetrahydrofuran (10 ml) under reflux for three hours and then cooled to room temperature. Hydrazide 2-trifluoromethyl-nicotinic acid (0,53 g, 2.57 mmol) was added and the yellow mixture was stirred at reflux overnight and then cooled to room temperature. The mixture was poured into cold water (100 ml) and abundant precipitate was filtered, washed with water and dried, obtaining N'-(3,4-dimethoxy-5-nitro-benzoyl)-hydrazide 2-trifluoromethyl-nicotinic acid, 0.71 g (73%).

b) a Suspension of N'-3,4-dimethoxy-5-nitro-benzoyl)-hydrazide 2-trifluoromethyl-nicotinic acid (0,60 g, 1.44 mmol) in phosphorus oxychloride (10 ml) was stirred at 130°C for three hours, getting pale yellow solution. The mixture was cooled to room temperature and then poured into ice water (200 ml). The white precipitate was filtered, washed with water and dried, obtaining 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine, of 0.48 g (84%).

C) To a stirred solution of 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine (0.45 g, 1.13 mmol) in dichloromethane (10 ml), cooled in a bath of ice water was added to the complex of urea and hydrogen peroxide (0,23 g, 245 mmol) at one time, then triperoxonane anhydride (0,47 g, 2,24 mmol) dropwise. The resulting mixture was stirred at room temperature overnight and then the insoluble product was filtered. The filtrate was washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated to education off-white solid. Recrystallization from ethanol gave 1-oxide 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine, 0.39 g (83%).

g) a Suspension of 1-oxide 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine (0,30 g, 0.73 mmol) in a mixture of 48% Hydrobromic acid (5 ml) and 30% of bromovalerate in acetic acid (5 ml) was heated at 140°C. overnight and then cooled to room temperature. After evaporation to dryness under reduced pressure, toluene (10 ml) was added to the residue and re-evaporated under reduced pressure. The resulting solid is recrystallized from isopropanol, getting 3-nitro-5-[5-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diol as a yellow solid, 0,19 g (68%).

Example 49

As an example, compounds of General formula (I)having pyrimidine-2,4-diyl fragment as the Central part, 3-nitro-5-[2-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-pyrimidine-4-yl]-benzene-1,2-diol was obtained by the following procedure:

a) Stirring a suspension of 1-(3,4-dimethoxy-5-nitro-phenyl)-3-dimethylamino-prop-2-EN-1-she (0.28 g, 1.0 mmol), 1-hydroxy-2-trifluoromethyl-nicotinamide (0.31 g, 1.5 mmol) and tert-butoxide potassium (0.17 g, 1.5 mmol) in absolute ethanol (5 ml) was heated at 80°C in a sealed tube for one hour and then cooled to room temperature. The mixture was poured into cold water (100 ml) and the resulting precipitate was filtered, washed with water and dried, obtaining 4-(3,4-dimethoxy-5-nitro-phenyl)-2-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-pyrimidine, 0.31 g (73%).

b) a Suspension of 4-(3,4-dimethoxy-5-nitro-phenyl)-2-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-pyrimidine (0.25 g, 0.59 mmol) in 48% Hydrobromic acid (5 ml) was stirred at 140°C for four hours and then cooled to room temperature. The mixture was poured into ice water (100 ml) and the resulting filtrate was filtered, washed with water and dried, obtaining 3-nitro-5-[2-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-pyrimidine-4-yl]-benzene-1,2-diol, 0.21 g (90%).

Example 50

As an example, compounds of General formula (I)with benzene-1,3-diyl fragment as a Central part 5-nitro-3'-(1-hydroxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-3,4-diol was obtained by the following procedure:

a) To a stirred solution of 4-benzyloxy-3-methoxyphenylacetic acid (1.0 g, a 3.87 mmol) and 1-oxide 2-(3-bromo-phenyl)-6-t is iformity-pyridine (1.12 g, to 3.52 mmol) in toluene (10 ml) and ethanol (1 ml) at room temperature in an argon atmosphere was added 2 n aqueous solution of sodium carbonate (5,41 ml, was 10.82 mmol)and then tetrakis(triphenylphosphine)palladium (0,22 g, 0,19 mmol). The resulting mixture was stirred at 90°C for two hours and then cooled to room temperature. The phases were separated and the aqueous phase was extracted with toluene (5 ml). The combined organic phases are washed with water and brine, then dried over anhydrous sodium sulfate and filtered. Evaporation of solvent gave a brown oil, which was chromatographically on silica gel (petroleum ether/ethyl acetate, 9:1)to give 1-oxide 2-(4'-benzyloxy-3'-methoxybiphenyl-3-yl)-6-trifluoromethyl-pyridine in the form of a clear oil of 1.11 g (70%).

b) To a solution of 1-oxide 2-(4'-benzyloxy-3'-methoxybiphenyl-3-yl)-6-trifluoromethyl-pyridine (1.10 g, of 2.44 mmol) in dichloromethane (20 ml), cooled in a bath of ice water, was added a 30% solution of bromovalerate in acetic acid (4 ml, 20 mmol) dropwise. The resulting solution was stirred at room temperature for six hours, then poured into ice-cold water (100 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (10 ml). The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate and fil is listed. Evaporation of solvent gave a brown oil, which was chromatographically on silica gel (petroleum ether/ethyl acetate, 4:1)to give 3-methoxy-3'-(1-hydroxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-4-ol as a clear oil of 0.57 g (65%).

C) To a solution of 3-methoxy-3'-(1-hydroxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-4-ol (0.50 g, 1.38 mmol) in acetic acid (10 ml) at room temperature was added 60% nitric acid (0,12 ml of 1.52 mmol) dropwise. The resulting mixture was stirred for thirty minutes, then poured into ice-cold water (100 ml) and the resulting precipitate was filtered, washed with water and dried. After chromatography was carried out on silica gel (petroleum ether/ethyl acetate, 2:1) 5-methoxy-3-nitro-3'-(1-hydroxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-4-ol was obtained as a yellow solid, 0.34 g (60%).

g) To a stirred solution of 5-methoxy-3-nitro-3'-(1-hydroxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-4-ol (0,30 g, 0,738 mmol) in 1,2-dichloroethane (10 ml), cooled in a bath of ice water was added aluminium chloride (0,123 g, 0,922 mmol) at once, then pyridine (0,233 g, 2,95 mmol) dropwise. The resulting red suspension was stirred at 80°C for two hours, then cooled to room temperature and poured into cold 2 n aqueous hydrochloric acid (100 ml). The precipitate was filtered, washed with water and dried, recip is I 5-nitro-3'-(1-hydroxy-6-trifluoromethyl-pyridin-2-yl)-biphenyl-3,4-diol, 0.17 g (59%).

Example 51

As an example, compounds of General formula (I)having a carbonyl fragment as the Central part, (3,4-dihydroxy-5-nitro-phenyl)-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-methanon received during the following procedure:

a) To a solution of 4-benzyloxy-3-methoxy-bromine benzol (2.0 g, PC 6.82 mmol) in tetrahydrofuran (50 ml) at -78°C in an atmosphere of argon was added a 2 n solution of utility in hexano (3.75 ml, 7.5 mmol) dropwise. The resulting mixture was stirred for one hour, after which a solution of N-methoxy-N-methyl-2-trifluoromethyl-nicotinamide (1,76 g, 7.5 mmol) in tetrahydrofuran (20 ml) was added dropwise. The mixture is then brought to room temperature for two hours, then poured into cold 2 n aqueous hydrochloric acid (150 ml). The mixture was extracted with diethyl ether, the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and filtered. Evaporation of solvent gave a brown oil, which was chromatographically on silica gel (petroleum ether/ethyl acetate, 2:1)to give (4-benzyloxy-3-methoxy-phenyl)-(2-trifluoromethyl-pyridine-3-yl)-methanon, 1,72 g (65%).

b) To a stirred solution of (4-benzyloxy-3-methoxy-phenyl)-(2-trifluoromethyl-pyridine-3-yl)-methanone (1.60 g, 4,13 mmol) in dichloromethane (20 ml), cooled in a bath of ice water was added to the complex of urea and hydrogen peroxide (0.85 grams, the remaining 9.08 mmol) at once, then triperoxonane anhydride (1.73 g, compared to 8.26 mmol) dropwise. The resulting mixture was then stirred at room temperature overnight, after which the insoluble product was filtered and washed with dichloromethane (5 ml). The combined filtrate was washed with water and brine, then dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent gave an orange solid, which was recrystallized from ethanol, receiving (4-benzyloxy-3-methoxy-phenyl)-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-methanon, 1.0 g (60%).

C) To a stirred solution of (4-benzyloxy-3-methoxy-phenyl)-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-methanone (0.95 g, 2.36 mmol) in dichloromethane, cooled in a bath of ice water, was added dropwise a 30% solution of bromovalerate in acetic acid (3,54 ml of 17.7 mmol). The resulting solution was stirred at room temperature overnight, then poured into ice-cold water (100 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (10 ml). The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate and filtered. Evaporation of solvent gave a brown oil, which was chromatographically on silica gel (petroleum ether/ethyl acetate, 1:1)to give (4-hydroxy-3-methoxy-phenyl)-(1-hydroxy-2-three is tormentil-pyridine-3-yl)-methanon in the form of a colorless solid, 0,59 g (80%).

g) To a solution of (4-hydroxy-3-methoxy-phenyl)-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-methanone (0.50 g, to 1.59 mmol) in acetic acid (10 ml) at room temperature was added 60% nitric acid (0,14 ml of 1.75 mmol) dropwise. The resulting mixture was stirred for thirty minutes, then poured into ice-cold water (100 ml) and the resulting precipitate was filtered, washed with water and dried. Recrystallization from ethanol gave (4-hydroxy-3-methoxy-5-nitro-phenyl)-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-methanon in the form of a yellow solid, 0.33 g (58%).

d) To a stirred solution of (4-hydroxy-3-methoxy-5-nitro-phenyl)-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-methanone (0,30 g, 0.84 mmol) in 1,2-dichloroethane (10 ml), cooled in a bath of ice water was added aluminium chloride (0.14 g, 1.05 mmol) at once, then pyridine (0.26 g, 3.35 mmol) dropwise. The resulting red suspension was stirred at 80°C for two hours, then cooled to room temperature and poured into cold 2 n aqueous hydrochloric acid (100 ml). The precipitate was filtered, washed with water and dried, obtaining (3,4-dihydroxy-5-nitro-phenyl)-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-methanon, 0,19 g (66%).

Example 52

As an example, compounds of General formula (I), with (Z)-1-cyanate-1,2-diyl fragment as the Central part, 3-(3,4-dihydrox the-5-nitro-phenyl)-2-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-Acrylonitrile was obtained in the following procedure:

a) a Suspension of vanillin (1.0 g, to 6.57 mmol), (1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-acetonitrile (1,33 g, to 6.57 mmol) and piperidine (0,71 ml of 7.23 mmol) in absolute ethanol (10 ml) was stirred at reflux for forty-eight hours and then cooled to room temperature. The resulting precipitate was filtered, washed with water and dried. Recrystallization from isopropanol gave 3-(4-hydroxy-3-methoxy-phenyl)-2-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-Acrylonitrile in the form of white crystals, 0.95 g (43%).

b) To a solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-Acrylonitrile (0,90 g, 2.68 mmol) in acetic acid (20 ml) was added 60% nitric acid (0,23 ml, 2,95 mmol) dropwise. The resulting mixture was stirred at room temperature for thirty minutes, then poured into ice-cold water (100 ml). The yellow precipitate was filtered, washed with water and dried. Recrystallization from isopropanol gave 3-(4-hydroxy-3-methoxy-5-nitro-phenyl)-2-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-Acrylonitrile as a yellow solid, 0,63 g (62%).

C) To a stirred solution of 3-(4-hydroxy-3-methoxy-5-nitro-phenyl)-2-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-Acrylonitrile (0.55 g, 1.44 mmol) in 1,2-dichloroethane (10 ml), cooled in a bath of ice water was added aluminium chloride (0.24 g, of 1.80 mmol) for the Dean of times then pyridine (0,46 g, 5,77 mmol) dropwise. The resulting red suspension was stirred at 80°C for two hours, then cooled to room temperature and poured into cold 2 n aqueous hydrochloric acid (100 ml). The precipitate was filtered, washed with water and dried, obtaining 3-(3,4-dihydroxy-5-nitro-phenyl)-2-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-Acrylonitrile, 0.32 g (60%).

Example 53

As an example, compounds of General formula (I)with 1H-imidazole-1,5-diyl fragment as the Central part, 1-oxide 2-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine was obtained in the following procedure:

a) To a stirred solution of 1-oxide, 2-amino-5-(trifluoromethyl)pyridine (0,445 g, 2.5 mmol) in ethanol (12.5 ml) and acetic acid (0.25 ml) at room temperature was added 3,4-dimethoxy-5-nitrobenzaldehyde (of 0.53 g, 2.5 mmol). The reaction mixture was heated at the temperature of reflux distilled for two hours, then the ethanol is evaporated. The oily residue was dissolved in a mixture of methanol (17 ml) and 1,2-dimethoxyethane (7.5 ml), then 1-(isocyanatomethyl)-4-methylbenzo (TOSMIC) (0.73 g, 3.75 mmol) and potassium carbonate (0,69 g, 5 mmol) was added at once. The resulting mixture was stirred at the temperature of reflux distilled for 3 hours. The reaction mixture is evaporated to dryness and then transferred in dichloromethane (50 is l). The organic phase is washed with water (50 ml) and then dried over anhydrous magnesium sulfate, filtered and evaporated to education brown oil. Column chromatography on silica gel (petroleum ether-ethyl acetate 9:1) gave 1-oxide 2-(5-(3,4-dimethoxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine, 0.56 g (55%).

b) 1-Oxide 2-(5-(3,4-dimethoxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine (0,41 g, 1 mmol) was heated at 140°C in 48% aqueous bromoiodide (6 ml) for 2.5 hours. Dark homogeneous solution was cooled to room temperature and the volatile components were removed by evaporation before the formation of a pale brown crystalline solid, which was dried over P2O5under vacuum. Rubbing the resulting solid with diethyl ether gave 1-oxide 2-(5-(3,4-dihydroxy-5-nitrophenyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)pyridine as a yellow crystalline solid, 0.27 g (71%).

Example 54

As an example, compounds of General formula (I), which is isoxazol-3,5-diyl fragment as the Central part, 1-oxide, 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine was obtained in the following procedure:

a) To a stirred suspension of 1-oxide (E)-3-(3-(3,4-dimethoxy-5-nitrophenyl)acryloyl)-2-(trifluoromethyl)pyridine (1.19 g, 3 mmol) in ethanol (15 m is) was added 50% aqueous solution of hydroxylamine (0,74 ml, 4.5 mmol) and the mixture was heated to 80°C. After stirring for 1 hour fine precipitate began to separate from the reaction mixture. After cooling to room temperature, the yellow precipitate was filtered, washed with ethanol and dried under vacuum, obtaining 1-oxide 3-(3-(3,4-dimethoxy-5-nitrophenyl)-5-hydroxy-4,5-dihydroisoxazole-5-yl)-2-(trifluoromethyl)pyridine, 0,94 g (73%).

b) 1-Oxide 3-(3-(3,4-dimethoxy-5-nitrophenyl)-5-hydroxy-4,5-dihydroisoxazole-5-yl)-2-(trifluoromethyl)pyridine (2.14 g, 5 mmol) was heated in 20 ml of ethyl acetate to 70°C. To the resulting suspension were added triperoxonane acid (0.74 g, 6.5 mmol) dropwise. After 10 minutes the reaction mixture is evaporated to dryness and the residue recrystallized from isopropanol, getting 1-oxide 3-(3-(3,4-dimethoxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine, 1.27 g (62%).

C) 1-Oxide 3-(3-(3,4-dimethoxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine (0,81 g, 2 mmol) were placed in dichloromethane (15 ml) and the yellow suspension was cooled to -78°C in an argon atmosphere, after which tribromide boron (4.5 g, 18 mmol) was added dropwise. The reddish reaction mixture was heated to room temperature and was stirred for 18 hours, then carefully poured into ice-cold water (100 ml) and was stirred for 1 hour. The yellow precipitate was filtered, washed with water and dried over P2O5 under vacuum. Rubbing with boiling ethanol gave 1-oxide 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine as a yellow solid, 0,49 g (64%).

Example 55

As an example, compounds of General formula (I)having a furan-2,4-diyl fragment as the Central part, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine was obtained in the following procedure:

a) To a stirred solution of 3-(3-ethoxy-3-oxopropanoic)-2-(trifluoromethyl)pyridine-1-oxide (1.39 g, 5 mmol) in pyridine (25 ml) was added 2-bromo-1-(3,4-dimethoxy-5-nitrophenyl)alanon (1,67 g, 5.5 mmol). The reaction mixture was heated to 70°C. and was stirred for 5 hours, then cooled to room temperature and was poured into 6 n aqueous HCl (100 ml). The precipitate was filtered, washed with water and dried over P2O5under vacuum. The solid is recrystallized from dichloromethane/isopropanol, receiving crude 1-oxide 3-(4-(3,4-dimethoxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine, of 1.05 g (43%).

b) 1-Oxide 3-(4-(3,4-dimethoxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine (482 mg, 1 mmol) were placed in dichloromethane (8 ml). The yellowish suspension was cooled to -78°C in an argon atmosphere and tribromide boron (0,85 ml, 9 mmol) was added dropwise. The reddish reaction mixture was heated to whom atoi temperature and was stirred for 18 hours, then carefully poured into ice-cold water (100 ml) and was stirred for 1 hour. The yellow precipitate was filtered, washed with water and dried over P2O5under vacuum. Recrystallization solid from ethanol gave 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-3-(etoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine as a yellow solid, 0.31 g (68%).

Example 56

As an example, compounds of General formula (I)having oxazol-2,4-diyl fragment as the Central part, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine was obtained in the following procedure:

a) To a solution of 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoacetate (4,24 g, 15 mmol) in xylene (30 ml) was added 1-oxide 3-carbarnoyl-2-(trifluoromethyl)pyridine (3,40 g, 16.5 mmol) and athirat boron TRIFLUORIDE (of 0.18 ml, 15 mmol). The resulting yellow solution was heated under reflux for 18 hours and then cooled to room temperature. After evaporation of the solvent the residue was separated between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with brine and dried over anhydrous magnesium sulfate, filtered and evaporated. Pure 1-oxide 3-(4-(3,4-dimethoxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine were obtained using column chromatography is and silica gel (petroleum ether/ethyl acetate 2:1) as pale yellow solid, 2.58 g (42%).

b) 1-Oxide 3-(4-(3,4-dimethoxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine (1.23 g, 3 mmol) were placed in dichloromethane (25 ml). The yellowish suspension was cooled to -78°C in an argon atmosphere and tribromide boron (2.55 ml, 27 mmol) was added dropwise. The red reaction mixture was heated to room temperature and was stirred for 18 hours. Then it was carefully poured into ice water (100 ml) and was stirred for 1 hour. The resulting yellow precipitate was filtered, washed with water and dried over P2O5under vacuum. The solid is recrystallized from ethanol, getting 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine as a yellow solid, 0.65 g (57%).

Example 57

As an example, compounds of General formula (I), with 1,2,4-triazine-3,5-diyl fragment as the Central part, 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-(trifluoromethyl)pyridine was obtained in the following procedure:

a) To a stirred solution of 1-oxide, (Z)-3-carbamoylmethyl-2-(trifluoromethyl)pyridine (1.10 g, 5 mmol) in ethanol (30 ml) was added 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoazetidin (1.19 g, 5 mmol). The reaction mixture was heated under reflux for 5 hours and then cooled to room temperature and the solvent was removed by evaporation. Estato which was dissolved in dichloromethane (30 ml) and the organic phase is washed with water and dried over anhydrous magnesium sulfate, was filtered and evaporated. The crude product is recrystallized from isopropanol, getting 1-oxide 3-(5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-(trifluoromethyl)pyridine, 1,69 g (80%).

b) 1-Oxide 3-(5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-(trifluoromethyl) pyridine (1.27 g, 3 mmol) were placed in dichloromethane (25 ml). The yellowish solution was cooled to -78°C in an argon atmosphere and tribromide boron (2.55 ml, 27 mmol) was added dropwise. The red reaction mixture was heated to room temperature and was stirred for 18 hours. Then it was carefully poured into ice water (100 ml) and was stirred for 1 hour. The yellow precipitate was filtered, washed with water and dried over P2O5under vacuum. The solid is recrystallized from dichloromethane-ethanol, getting 1-oxide 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-triazine-3-yl)-2-(trifluoromethyl)pyridine as a yellow solid, 0.84 g (71%).

Example 58

As an example, compounds of General formula (I)with 1,3,5-triazine-2,4-diyl fragment as the Central part, 1-oxide, 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2-(trifluoromethyl)pyridine was obtained in the following procedure:

a) To a solution of (E)-N-((dimethylamino)methylene)-3,4-dimethoxy-5-nitrobenzamide (1.12 g, 4 mmol) in ethanol (30 ml) was added 1-oxide 3-carbamimidoyl-2-(trifluoromethyl)pyridine (of 0.82 g, 4 mmol). Reactio the ing the mixture was heated under reflux for 5 hours. Was cooled to room temperature and the solvent was removed by evaporation. Then the residue was dissolved in a mixture of dichloromethane/isopropanol (50 ml, 70:30) and the organic phase is washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product is recrystallized from ethanol, getting 1-oxide 3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2-(trifluoromethyl)pyridine, 1.27 g (75%).

b) Part 1-oxide-3-(4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2-(trifluoromethyl)pyridine (1,269 g, 3 mmol) were placed in dichloromethane (25 ml). The yellowish solution was cooled to -78°C in an argon atmosphere and tribromide boron (2.55 ml, 27 mmol) was added dropwise. The red reaction mixture was heated to room temperature and was stirred for 18 hours, then carefully poured into ice-cold water (100 ml) and was stirred for 1 hour. The yellow precipitate was filtered, washed with water and dried over P2O5under vacuum. Recrystallization from a mixture of dichloromethane-ethanol gave 1-oxide 3-(4-(3,4-dihydroxy-5-nitrophenyl)-1,3,5-triazine-2-yl)-2-(trifluoromethyl)pyridine as a yellow solid, 1.07 g (90%).

Example 59

As an example, compounds of General formula (I)with pyrrole-2,5-diyl fragment as the Central part, ethyl ester 5-(3,4-dihydroxy-5-nitrophenyl)-1-methyl-2-(2-trifluoromethyl-1-oxopyridine-3-yl)-1H-pyrrol-karbonovoi acid was obtained in the following procedure:

a) To a stirred solution of methylamine (0.63 ml, 33% tO solution, 5 mmol) in ethanol (25 ml) and acetic acid (0.5 ml) at room temperature was added ethyl ester of 3-oxo-3-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-propionic acid (1.39 g, 5 mmol). The reaction mixture was heated under reflux for two hours, after which the solvent was removed by evaporation under vacuum. To a solution of the crude product in dimethylformamide (25 ml) was added potassium carbonate (2,07 g, 15 mmol) at once, then 1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-bromo-Etalon (of 2.51 g of 5.50 mmol) and the mixture is then stirred at 100°C. as soon As starting material was no longer detected by TLC, the reaction mixture was cooled to room temperature and poured into ice-cold 1 n aqueous hydrochloric acid (100 ml). The resulting precipitate was filtered, washed with water and dried. The residue was chromatographically on silica gel. Homogeneous fractions were combined and evaporated, obtaining the ethyl ester of 5-(3,4-bis-benzyloxy-5-nitro-phenyl)-1-methyl-2-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-1H-pyrrole-3-carboxylic acid, to 2.41 g (79%).

b) a Solution of ethyl ester 5-(3,4-bis-benzyloxy-5-nitro-phenyl)-1-methyl-2-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-1H-pyrrole-3-carboxylic acid (0.2 g, 0.30 mmol) in dichloromethane (10 ml) was cooled to -78°C With stirring, and treated in an atmosphere of ar is she tribromide boron (0,30 g, to 1.21 mmol). The resulting dark purple suspension was then stirred at room temperature for one hour before re-cooling to -78°C. the Mixture was suppressed, carefully adding methanol. After stirring at room temperature for thirty minutes, the volatile components are evaporated and the residue was stirred with 2 n hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered, washed with water (25 ml) and then cold isopropanol (5 ml)to give ethyl ester of 5-(3,4-dihydroxy-5-nitro-phenyl)-1-methyl-2-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-1H-pyrrole-3-carboxylic acid as a yellow solid, 0,13 g (93%).

Example 60

As an example, compounds of General formula (I)having 2N-tetrazol-2,5-diyl fragment as the Central part, 5-[2-(5-trifluoromethyl-1-oxy-pyridine-2-yl)-2H-tetrazol-5-yl]-3-nitrobenzene-1,2-diol was obtained in the following procedure:

a) a Mixture of 3,4-bis-benzyloxy-5-nitro-benzonitrile (0.54 g, 1.50 mmol), sodium azide (0.15 g, 2.25 mmol) and ammonium chloride (0.12 g, 2.25 mmol) in dimethylformamide (3 ml) was stirred at 85°C for 20 hours. After cooling to room temperature the reaction mixture was poured into water (30 ml) and acidified with diluted hydrochloric acid. The resulting precipitate was collected, washed with water and dried, obtaining 5-3,4-bis-benzyloxy-5-nitro-phenyl)-2H-tetrazol, of 0.53 g (87%).

b) 2-Chloro-5-trifluoromethyl-1-oxy-pyridine (0.20 g, 1.00 mmol) was added to a stirred suspension of 5-(3,4-bis-benzyloxy-5-nitro-phenyl)-2H-tetrazole (0.4 g, 1.00 mmol) and potassium carbonate (0.14 g, 1 mmol) in acetonitrile (10 ml). The reaction mixture was stirred at room temperature until completion, then was diluted with dichloromethane and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness before the formation of the crude residue, which was recrystallized from a mixture of dichloromethane/isopropanol, receiving 2-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-tetrazol-2-yl]-5-trifluoromethyl-1-oxy-pyridine, 0.40 g (71%).

C) a Solution of 2-[5-(3,4-bis-benzyloxy-5-nitro-phenyl)-tetrazol-2-yl]-5-trifluoromethyl-1-oxy-pyridine (0,282 g, 0.5 mmol) in dichloromethane (15 ml) was cooled to -78°C With stirring in an argon atmosphere and treated with tribromide boron (1,00 g, 4.00 mmol) dropwise. The resulting dark purple suspension was then stirred at room temperature for one hour before re-cooling to -78°C. the Mixture was suppressed, carefully adding methanol. After stirring at room temperature for thirty minutes, the volatile components are evaporated and the residue was stirred with 2 n hydrochloric acid (5 ml) for thirty minutes. The resulting solid substance of hoteltravel and, washed with water (25 ml) and then cold isopropanol (5 ml)to give 5-[2-(5-trifluoromethyl-1-oxy-pyridine-2-yl)-2H-tetrazol-5-yl]-3-nitrobenzene-1,2-diol as a yellow solid, 0.17 g (90%).

Example 61

As an example, compounds of General formula (I)with 1,3-thiazole-2,4-diyl fragment as the Central part, 5-[2-[2-(trifluoromethyl)-1-oxy-pyridine-3-yl]-[1,3]-thiazol-4-yl]-3-nitrobenzene-1,2-diol was obtained in the following procedure:

a) a Mixture of 2-(trifluoromethyl)-1-oxy-pyridine-3-thioamide group by forming (0.24 g, 1.10 mmol) and 1-[3,4-bis(benzyloxy)-5-nitrophenyl]-2-brometea (0.50 g, 1.10 mmol) was heated under reflux overnight in absolute ethanol (5 ml). After cooling to room temperature the reaction mixture was poured into water (50 ml). The resulting precipitate was filtered, washed with water (25 ml) and dried. Recrystallization from dichloromethane/isopropanol gave 3-[4-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,3]-thiazol-2-yl]-2-trifluoromethyl-1-oxy-pyridine, 0.55 g (87%).

b) a Solution of 3-[4-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,3]-thiazol-2-yl]-2-trifluoromethyl-1-oxy-pyridine (0.15 g, 0.26 mmol) in dichloromethane (10 ml) was cooled to -78°C and treated in an argon atmosphere by tribromide boron (0.26 g, of 1.03 mmol). The resulting dark purple suspension was then stirred at room temperature for one hour, then cooling again to -78°C. See the camping extinguished, carefully adding methanol. After stirring at room temperature for thirty minutes, the volatile components are evaporated and the residue was stirred with 2 n hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered, washed with water (25 ml) and then cold isopropanol (5 ml)to give 5-[2-[2-(trifluoromethyl)-1-oxy-pyridine-3-yl]-[1,3]-thiazol-4-yl]-3-nitrobenzene-1,2-diol as a yellow solid, 0.09 g (87%).

Example 62

As an example, compounds of General formula (I), with 1,2,4-triazole-3,5-diyl fragment as a Central part 5-[4-methyl-5-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-4H-[1,2,4]triazole-3-yl]-3-nitro-benzene-1,2-diol was obtained in the following procedure:

a) To a stirred solution of 3,4-dimethoxy-5-nitro-benzoyl chloride (0.50 g, 2.04 mmol) in dichloromethane (10 ml) at 0°C was added dropwise methylamine (of 1.02 ml, 2.04 mmol, 2 M in THF). The reaction mixture was stirred at room temperature until the disappearance of all starting material was then diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness before the formation of the crude residue, which was recrystallized from a mixture of dichloromethane/isopropanol, receiving 3,4-dimethoxy-N-methyl-5-nitro-benzamide, of 0.44 g (89%).

b) To mix suspense and 3,4-dimethoxy-N-methyl-5-nitro-benzamide (0.40 g, of 1.66 mmol) in toluene (10 ml) was added pentachloride phosphorus (0,38 g and 1.83 mmol) parts. Upon completion of addition, the reaction mixture was heated under reflux until complete disappearance of starting material. Evaporation to dryness led to the crude solid substance was washed with diethyl ether, obtaining 3,4-dimethoxy-N-methyl-5-nitro-benzimidazolinone, and 0.37 g (85%).

C) a Mixture of 2-trifluoromethyl-1-hydroxy-3-pyridylcarbonyl (0,47 g of 2.50 mmol), sodium azide (0.24 g, 3.75 mmol) and ammonium chloride (0.20 g, 3.75 mmol) in dimethylformamide (2.5 ml) was stirred at 85°C for 20 hours. After cooling to room temperature the reaction mixture was poured into water (20 ml) and acidified with diluted hydrochloric acid. The resulting precipitate was collected, washed with water and dried, obtaining 3-(2H-tetrazol-5-yl)-2-trifluoromethyl-1-oxy-pyridine, 0.52 g (90%).

g) 3,4-Dimethoxy-N-methyl-5-nitro-benzimidazolinone (0.26 g, a 1.08 mmol) was added to a stirred solution of 3-(2H-tetrazol-5-yl)-2-trifluoromethyl-1-oxy-pyridine (0,23 g, 1 mmol) in anhydrous pyridine (3 ml), preheated to 50°C. the resulting mixture was carefully heated to 75 -90°C and maintained this temperature until stopped the release of nitrogen. Then the mixture was poured into water (30 ml) and was extracted with dichloromethane (25 ml). The organic phase was separated, dried over betw denim magnesium sulfate, was filtered and evaporated to dryness. The resulting residue was purified using chromatography, obtaining 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-2-trifluoromethyl-1-oxy-pyridine, 0.25 g (59%).

d) To a stirred suspension of 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-yl]-2-trifluoromethyl-1-oxy-pyridine (0.20 g, 0.47 mmol) in dichloromethane (20 ml) at -78°C in an atmosphere of argon was added tribromide boron (0,47 g, 1.88 mmol) dropwise. The resulting purple suspension was then stirred at room temperature for seven hours, then cooled in a bath of ice water. The mixture was carefully suppressed by adding methanol. After stirring at room temperature for thirty minutes, the volatile components are evaporated and the residue was stirred with 2 n hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered, washed with water (25 ml) and then cold isopropanol (5 ml)to give after drying, 5-[4-methyl-5-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-4H-[1,2,4]triazole-3-yl]-3-nitro-benzene-1,2-diol in the form of an orange solid, 0.16 g (86%).

Example 63

As an example, compounds of General formula (I)with 1,2,3-thiadiazole-4,5-diyl fragment as the Central part, 5-[5-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-[1,2,3]thiadiazole-4-yl]-3-nitrobenzene-1,2-diol was obtained during follow what her procedure:

a) a Mixture of 1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-ethanone (0.50 g, of 0.93 mmol), ethylcarbazole (0.11 g, 1.06 mmol) and para-toluensulfonate acid (4 mg) in toluene (10 ml) was heated under reflux until the termination azeotropic distillation of water. The reaction mixture was cooled to room temperature, the solvents evaporated to dryness and the crude solid is triturated with diethyl ether (15 ml), filtered and dried, obtaining the ethyl ester of N'-[1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-ethylidene]-hydrazinecarboxamide acid, 0,49 g (84%).

b) a Mixture of ethyl ester of N'-[1-(3,4-bis-benzyloxy-5-nitro-phenyl)-2-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-ethylidene]-hydrazinecarboxamide acid (0.40 g, 0.64 mmol) in thionyl chloride (2 ml) was heated under reflux until until starting material is no longer detected by TLC. The excess solvent was removed and the residue was purified by chromatography on silica gel using a mixture of dichloromethane/ethanol as eluent. Homogeneous fractions were combined and evaporated, getting 3-[4-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,3]thiadiazole-5-yl]-2-trifluoromethyl-1-oxy-pyridine, 0,19 g (51%).

C) a Solution of 3-[4-(3,4-bis-benzyloxy-5-nitro-phenyl)-[1,2,3]thiadiazole-5-yl]-2-trifluoromethyl-1-oxy-pyridine (0.15 g, 0.26 mmol) in dichloromethane (10 ml) was cooled to -78°C, Eremeeva, and was treated in an argon atmosphere by tribromide boron (0.26 g, of 1.03 mmol). The resulting dark purple suspension was then stirred at room temperature for one hour, and then again cooling to -40°C. the Mixture was suppressed, carefully adding methanol. After stirring at room temperature for thirty minutes, the volatile components are evaporated and the residue was stirred with 2 n hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered, washed with water (25 ml) and then cold isopropanol (5 ml)to give 5-[5-(2-trifluoromethyl-1-oxy-pyridine-3-yl)-[1,2,3]thiadiazole-4-yl]-3-nitrobenzene-1,2-diol as a yellow solid, 0.09 g (89%).

Example 64

As an example, compounds of General formula (I), with 1,2,4-oxadiazol-3,5-diyl fragment as the Central part, 5-[5-[2-(trifluoromethyl)-1-oxopyridine-3-yl]-[1,2,4]-oxadiazol-3-yl]-3-nitrobenzene-1,2-diol was obtained by the following procedure:

a) To a stirred solution of 2-triftormetilfosfinov acid (or 0.38 g, 2 mmol) in dimethylformamide (10 ml) at room temperature was added 1,1-carbonyldiimidazole (0.34 g, 2.10 mmol) at once. The resulting yellow mixture was stirred for ninety minutes, then 3,4-bis(benzyloxy)-N'-hydroxy-5-nitrobenzamide (0,79 g, 2 mmol) was added at once. Obtained is the result mixture was stirred at room temperature for two hours and then poured into water (100 ml). The resulting precipitate was filtered, washed with water and dried. After recrystallization from dichloromethane/isopropanol 3,4-bis(benzyloxy)-5-nitro-N'-(2-trifluoromethyl)nicotinergic)benzamide was obtained as a pale yellow solid, 0.88 g (78%).

b) To mix the solution obtained above solid (0.26 g, 0.46 mmol) in tetrahydrofuran (15 ml) at room temperature in an argon atmosphere was added 1 n solution of tetrabutylammonium fluoride in tetrahydrofuran (0.7 ml, 0.7 mmol). The resulting clear yellow solution was stirred at room temperature for four hours. Additional tetrabutylammonium fluoride (0.7 mmol) was added and the reaction mixture was stirred for fifteen hours at room temperature and then ten hours at 55°C. After cooling to room temperature the reaction mixture was poured into water (150 ml). The resulting precipitate was filtered, washed with water and dried. The crude product was chromatographically on silica gel using dichloromethane as eluent. Homogeneous fractions were combined and evaporated, getting 3-[3-[3,4-bis(benzyloxy)-5-nitrophenyl]-[1,2,4]-oxadiazol-5-yl]-2-(trifluoromethyl)pyridine in the form of off-white solids, 0.21 g (82%).

C) To a stirred solution of 3-[3-[3,4-bis(benzyloxy)-5-nitrophenyl]-[12,4]-oxadiazol-5-yl]-2-(trifluoromethyl)pyridine (0.33 g, of 0.60 mmol) in dichloromethane (6 ml) at 0°C was added a complex of urea and hydrogen peroxide (0.28 g, 3 mmol) and triperoxonane anhydride (0,43 ml, 3.00 mmol). Then the reaction mixture was stirred at room temperature for 60 hours, the solids were filtered off. The organic phase is then treated with an aqueous solution of Na2S2O5(0.6 g, of 3.45 mmol, dissolved in 20 ml of water), of 0.4 n hydrochloric acid (20 ml), a saturated solution Panso3(20 ml), water (20 ml) and brine (20 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographically on silica gel using dichloromethane/ethanol as eluent. Homogeneous fractions were combined and evaporated and the residue was recrystallized from dichloromethane/isopropanol, getting 3-[3-[3,4-bis(benzyloxy)-5-nitrophenyl]-[1,2,4]-oxadiazol-5-yl]-2-(trifluoromethyl)-1-oxy-pyridine as a yellow solid, 0,23 g (68%).

g) a Solution of 3-[3-[3,4-bis(benzyloxy)-5-nitrophenyl]-[1,2,4]-oxadiazol-5-yl]-2-(trifluoromethyl)-1-hydroxy-pyridine (0.10 g, 0.18 mmol) in dichloromethane (5 ml) was cooled to -78°C With stirring in an argon atmosphere and treated with tribromide boron (0.18 g, of 0.74 mmol) dropwise. The resulting dark purple suspension was then stirred at room temperature for one hour, after which about the best cooling to -78°C. The mixture is extinguished, carefully adding methanol. After stirring at room temperature for thirty minutes, the volatile components are evaporated and the residue was stirred with 2 n hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered, washed with water (25 ml) and then cold isopropanol (5 ml)to give 5-[5-[2-(trifluoromethyl)-1-oxopyridine-3-yl]-[1,2,4]-oxadiazol-3-yl]-3-nitrobenzene-1,2-diol as a yellow solid, 0.06 g (88%).

1. The compound of formula (I):

where R1and R2represent hydrogen or a group which is hydrolyzed under physiological conditions, possibly substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents an oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3represents the group N-oxide of pyridine according to the formula a, B or C, which is attached, as shown unmarked link:

where R4, R5, R6and R7independently from each other represent an aryl, a heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio,6-C12-aryloxy or6-C12-aaltio group, C1With 6-alkylsulfonyl or C6-C12-arylsulfonyl, halogen, C1-C6-haloalkyl, trifluoromethyl or heteroaryl group; or two or more together residue R4, R5, R6and R7represent an aromatic ring, and where P represents the Central part, preferably selected from the regioisomers 1,3,4-oxadiazol-2,5-deila, 1,2,4-oxadiazol-3,5-deila, 4-methyl-4H-1,2,4-triazole-3,5-deila, 1,3,5-triazine-2,4-Diil, 1,2,4-triazine-3,5-deila, 2H-tetrazol-2,5-deila, 1,2,3-thiadiazole-4,5-deila, 1-alkyl-3-(alkoxycarbonyl)-1H-pyrrole-2,5-deila, where the alkyl presents the stands, thiazol-2,4-Diil, 1H-pyrazole-1,5-deila, pyrimidine-2,4-Diil, oxazol-2,4-Diil, carbonyl, 1H-imidazol-1,5-deila, isoxazol-3,5-deila, furan-2,4-Diil, benzene-1,3-deila and (Z)-1-cyanate-1,2-deila, and where the regioisomers Central parts include both regioisomer implemented by the permutation nitrocatechols fragment -(X)n(Y)m-R3the fragment.

2. The compound according to claim 1, comprising 5-[3-(3,5-dichloro-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-chloro-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-morpholine-4-yl-1-oxy-pyridine-4-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 3-nitro-5-[3-(1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, 5-[3-(2-chloro-6-methyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-nitro-benzene-1,2-diol, 5-[3-(2-morpholine-4-yl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 3-nitro-5-[3-(1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol, 5-[3-(2-methyl-1-hydroxy-6-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2,6-dimethyl-1-hydroxy-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-methyl-1-hydroxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(6-methyl-1-hydroxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-6-methyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol,5-[3-(2-chloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitro-benzene-1,2-diol, 5-[3-(2-bromo-4,5,6-trimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2-chloro-4,5,6-trimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol, 5-[3-(2-bromo-5-chloro-4,6-dimethyl-1-oxy-pyridine-3-yl)-[1,2,4] oxadiazol-5-yl]-3-nitrobenzene-1,2-diol and 3-nitro-5-[3-(1-hydroxy-2-trifluoromethyl-pyridine-3-yl)-[1,2,4]oxadiazol-5-yl]-benzene-1,2-diol.

3. The method of treatment of a subject suffering from some Rosstroy is your Central and peripheral nervous system, where the reduction of O-methylation of catecholamines may provide therapeutic benefit, such as Parkinson's disease and parkinsonism disorders, gastrointestinal disease, condition the formation of edema and hypertension, which is administered to the subject an amount of a compound according to claim 1 or 2, is effective for treatment of these diseases entity.

4. Pharmaceutical composition having activity of COMT inhibitor, comprising a therapeutically effective amount of a compound according to claim 1 or 2 in combination with a pharmaceutically acceptable carrier.

5. The use of compounds according to claim 1 or 2 in the manufacture of medicinal products for the treatment of a subject suffering from disorders of the Central or peripheral nervous system.

6. The use of compounds according to claim 1 or 2 in the manufacture of a medicine for the treatment of affective disorders, Parkinson's disease and parkinsonism disorders, tired leg syndrome, gastrointestinal diseases, conditions of formation of edema and hypertension.

7. The use of compounds according to claim 1 or 2 as an inhibitor of COMT.

8. The use of compounds according to claim 1 or 2 for the manufacture of a medicine for use as an inhibitor of COMT.

9. Method of preparing compounds according to formula I, comprising a stage in which the compound of formula IIA, IIB is whether IIB

where R4, R5, R6and R7defined as in General formula I in claim 1, is subjected to cyclization with the compound of the formula III

where R8and R9independently of one another represent hydrogen or a suitable protective group for an aromatic hydroxyl groups, under conditions suitable for obtaining oxadiazoline derivatives of the formula IVA, IV or IVB

perhaps with the subsequent removal of the protective groups R8and/or R9.

10. Method of preparing compounds according to formula I, comprising a stage in which the compound of formula VA, V or VB

where R4, R5, R6and R7defined as in General formula I in claim 1, is subjected to cyclization with the compound of the formula III under conditions suitable for obtaining oxadiazoline derivatives of the formula VIA, VI or VIB

with subsequent oxidation peredelnogo nitrogen atom that gives compound according to formula IVA, IV or IVB, possibly with subsequent removal of the protective groups R8and/or R .

11. The method according to claim 9 or 10, where the compound of formula III activate during the reaction with thionyl chloride or 1,1-carbonyl diimidazol.

12. The way pop or 10, where the phase cyclization, consisting of the condensation and dehydration, are conducted sequentially in the same reaction vessel.

13. The method according to claim 9 or 10, where the phase cyclization is performed in the presence of a suitable organic base.

14. The method according to item 13, where the stage cyclization is performed in the presence of pyridine.

15. The method according to any of PP, 10 or 14, where the group R8and R9independently from each other or together removed and replaced with hydrogen or a group which is hydrolyzed under physiological conditions.

16. The method according to any of PP, 10 or 14, where R8and R9the compounds of formula III are independently from each other represent methyl or hydrogen.

17. The method according to clause 16, where the methyl group is removed during the reaction with aluminium chloride and pyridine in N-methylpyrrolidinone.

18. The method according to any of p, 10, 14 or 17, where the condensation and dehydration is performed in a dipolar aprotic solvent.

19. The method according to p, where condensation and dehydration perform in dimethylacetamide, N-methylpyrrolidinone or dimethyl sulfoxide.

20. The method according to any of p, 14, 17 or 19, where peredelnyj the nitrogen atom oxadiazolines the compounds of formula VIA, VI or VIB oxidized by peroxide in the of aroda, peracetic acid, cryptanalyses acid or a complex of urea - hydrogen peroxide and triperoxonane anhydride.

21. The method according to any of p, 14, 17 or 19, where the compound of formula IIA, IIB or IIB receive during the reaction of compounds VIIA, VII or VIIB, respectively

where R4, R5, R6and R7defined as in General formula 1 in claim 1, with hydroxylamine in the presence of chelat forming agent under conditions suitable for obtaining derivatives amidoxime.

22. The method according to any of p, 14, 17 or 19, where the compound of formula VA, V or VB receive during the reaction of compound VIIIA, VIII or VIIIB, respectively

where R4, R5, R6and R7defined as in General formula I in claim 1, with hydroxylamine in the presence of chelat forming agent under conditions suitable for obtaining derivatives amidoxime.

23. The method according to claim 19, where the chelate forming agent selected from the group consisting of 8-hydroxyquinoline solution, ortho-phenanthroline and their hydrates, or derivatives.

24. The method according to claim 20, where the chelate forming agent selected from the group consisting of 8-hydroxyquinoline solution, ortho-phenanthroline and their hydrates, or derivatives.

25. The method of obtaining connection of the clusters according to the formula I, when oxidised to the corresponding pyridine compound to compound N-oxide of pyridine.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where R is a group selected from: i) hydrogen; ii) phenyl and iii) thiophenyl; Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl group, R1 is selected from: i) hydrogen; ii) straight C1-C6alkyl; iii) C6 or C10 aryl; iv) C(O)OR5; and v) 2-methylthiazol-4-yl; R5 denotes a straight or branched C1-C6alkyl; and index x equals 0 or 1. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent having human protein tyrosine phosphatase beta (HPTP-β) inhibiting action and use in treatment.

EFFECT: compounds can be used as human protein tyrosine phosphatase beta inhibitors.

11 cl, 1 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

Mglur5 modulators // 2439068

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel compounds of general formula I:

(where values R1-R5, X and Z are defined in invention description), pharmaceutical composition, which contains them, and application of claimed compounds as MGLUR5 modulators for inhibition of transient relaxations of lower esophageal sphincter or for treatment or prevention of gastroesophageal reflux disease.

EFFECT: obtaining compounds for treatment or prevention of gastroesophageal reflux disease.

14 cl, 87 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula in which R1 means hydrogen or alkyl with 1-4 carbon atoms, R2 means hydrogen and L means an alkandiyl group with 1-4 carbon atoms, one CH2-group in which can be substituted by with oxygen atom or a group of formula: or in which * means a conjunction with nitrogen atom, R3 means hydrogen, methyl, propane-2-yl, propane-1-yl, imidazol-4-ylmethyl, hydroxymethryl or 4-aminobutan-4-yl, or R3 is connected with R1 together with which forms (CH2)3- or (CH2)4- -group, R4 means hydrogen or methyl, R5 means alkyl with 1-4 carbon atoms, and R6 means hydrogen or alkyl with 1-4 carbon atoms, and also to its salt and to a method of preparing it.

EFFECT: there are prepared new compounds which can find application in medicine for treating and/or preventing diseases, first of all thromboembolic diseases.

5 cl, 4 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

in modification 11, characterised by the following spectral data in the near infrared region [cm-1]: 4086, 4228, 4418, 4457, 4634, 4905, 5846, 5911, 6026, 6081, 6582, as well as to the amorphous form of this compound, characterised by the following spectral data in the near infrared region [cm-1]: 4006, 4081, 4224, 4307, 4403, 4634, 4875, 5193, 5865, 6017, 6073, 6696, 7028, 8452, 8873.

EFFECT: novel polymorphous and amorphous form of compounds of formula I is obtained, having high solubility compared to the existing modification.

6 cl, 7 ex, 8 tbl, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), in which (i) R1 denotes C1-C6-alkyl or hydrogen; and R2 denotes hydrogen or a -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7 or -Z-C(O)-R7 group; and R3 denotes an undefined pair or C1-C6-alkyl; or (ii) R1 and R3 together with a nitrogen atom with which they are bonded form a 5-6-member heterocycloalkyl ring; and R2 denotes an undefined pair or a -R7 , -Z-Y-R7 group; or (iii) R1 and R2 together with a nitrogen atom with which they are bonded form a 6-member heterocycloalkyl ring, where said ring is substituted with a -Y-R7 group, and R3 denotes an undefined pair or C1-C6-alkyl; R4 and R5 are independently selected from a group consisting of phenyl, C3-C6-cycloalkyl; R6 denotes -OH, C1-C6-alkyl, C1-C6-alkoxy or a hydrogen atom; A denotes an oxygen or sulphur atom; X denotes a C1-C6-alkylene group; R7 denotes C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl in group R7 can be optionally substituted with one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulphonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine in group R7 can be optionaly substituted with C1-C6-alkyl; R8 denotes C1-C6-alkyl or a hydrogen atom; Z denotes a C1-C10-alkylene or C2-C10-alkenylene group; Y denotes a bond or an oxygen atom; R9 and R10 independently denote a hydrogen atom, C1-C6-alkyl group, isoxazole or 8-hydroxy-1H-quinolin-2-one-(C1-C6-hydroxyalkyl); and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition having activity with respect to M3 muscarinic receptor; use of the compounds of formula (I) to produce a medicinal agent for treating and a method of treating diseases or conditions in which M3 muscarinic receptor activity is involved.

EFFECT: compounds of given formula have activity with respect to M3 muscarinic receptor.

26 cl, 8 dwg, 91 ex

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