RU2441001C2 - Nitrocatechol derivatives as comp inhibitors - Google Patents

Abstract

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

Description

This invention relates to new substituted nitrocatechols, their use in the treatment of certain disorders of the central and peripheral nervous system, and pharmaceutical compositions containing them.

Despite being used in clinical practice for several decades, levodopa (L-DOPA, L-DOPA) remains the gold standard drug for the symptomatic treatment of Parkinson's disease. This has helped to maintain a strong interest in the development of inhibitors of the catechol-O-methyltransferase enzyme (COMT, COMT), based on the hypothesis that inhibition of this enzyme can provide clinical improvements in patients with Parkinson's disease when treated with L-DOPA and an inhibitor of peripheral amino acid decarboxylase inhibitor (AADC). The rationale for using COMT inhibitors as an adjuvant in L-DOPA / AADC therapy is based on their ability to reduce the metabolic O-methylation of L-DOPA to 3-O-methyl-L-DOPA (3-OMD). The period of clinical improvement caused by L-DOPA is short-lived as a result of the short in-vitro half-life of L-DOPA, as opposed to the long half-life of 3-OMD. In addition, 3-OMD competes with L-DOPA for transfer through the blood-brain barrier (BBB, from the blood-brain barrier), which means that only a very limited amount of an orally administered dose of L-DOPA does reach the site of action, i.e. brain. Usually, only a few years after the initial L-DOPA therapy with the usual dosing regimen, the clinical improvement caused by L-DOPA decreases at the end of each dosing cycle, leading to the so-called “wear-out” state of motor fluctuations. A direct relationship between the phenomenon of "wear" and the accumulation of 3-OMD is described (Tohgi H. et al., Neurosci. Letters, 132: 19-22, 1992). It is suggested that this may be due to the delayed penetration of L-DOPA into the brain due to competition for the transport system via BBB with 3-OMD (Reches A. et al., Neurology, 32: 887-888, 1982) or, more simply, a small amount of L-DOPA is able to reach the brain (Nutt JG, Fellman JH, Clin. Neuropharmacol., 7: 35-49, 1984). In fact, inhibition of COMT protects L-DOPA from metabolic degradation at the periphery during O-methylation, so that with repeated doses of L-DOPA, the average plasma concentration of L-DOPA increases. In addition to reduced competition for transfer to the brain, a significantly larger percentage of an orally administered dose of L-DOPA is able to reach the site of action. Thus, inhibition of COMT enhances the bioavailability of L-DOPA, and the period of antiparkinsonian action lengthens with single doses of L-DOPA (Nutt J.G., Lancet, 351: 1221-1222, 1998).

The most effective COMT inhibitors described to date are 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (tolcapone, 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 (US patent US 6512136), all of which have inhibition constants in the low nanomolar range. Having essentially the same pharmacophore, tolkapon differs from entacapone and BIA 3-202 in that it easily penetrates the central nervous system (CNS) and is able to inhibit cerebral COMT, as well as peripheral COMT. It can be assumed that central inhibition may be less significant if the more significant effect of COMT inhibition is to prevent peripheral destruction of L-DOPA. Indeed, the use of COMT inhibitors, which do not penetrate the brain at clinically appropriate 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 relates to the ability of these nitrocatechol-based xenobiotics to cause severe liver damage (hepatotoxicity). Indeed, shortly after its release, tolcapone was withdrawn from sale after several cases of hepatotoxicity became known, including three sudden deaths from fatal fulminant hepatitis. Today, tolkapon can be used only for patients with Parkinson's disease, who are not susceptible to other methods of treatment, and strictly only with constant monitoring of liver function, which is expensive and inconvenient for the patient. Although the actual mechanistic causes of hepatic toxicity associated with tolcapone are not fully understood, in vitro studies have shown that tolcapone can be reduced metabolically to reactive intermediates and it is believed that they can form covalent adducts with liver proteins, causing hepatocellular damage (Smith KS et al., Chem. Res. Toxicol., 16: 123-128, 2003).

Entacapone, on the contrary, having the same nitrocatechol pharmacophore with tolcapone, is not associated with hepatic toxicity and, as a rule, is considered a safe medicinal substance. Unfortunately, however, entacapone is a significantly less effective COMT inhibitor than tolcapone and has a much shorter half-life in vivo. This means that entacapone has a very limited duration of action and, as a result, the drug substance should be administered in very large doses with each dose of L-DOPA taken by the patient. In this regard, the clinical efficacy of entacapone has been questioned - indeed, a recent study (Parashos SA et al., Clin. Neuropharmacol., 27 (3): 119-123, 2004) showed that the main reason for stopping treatment with entacapone in patients with the disease Parkinson's is a palpable lack of effectiveness.

As a result, there is still a clear clinical need for a safe and effective COMT inhibitor for adjunctive therapy in the treatment of symptoms of Parkinson's disease. Preferably, the COMT inhibitor has greater efficacy and duration of COMT inhibition than entacapone, which would lead to greater clinical efficacy. More preferably, the COMT inhibitor, in contrast to tolcapone, has limited access to the central nervous system, i.e. it should preferably inhibit peripheral COMT than central COMT. Even more preferably, the COMT inhibitor combines the above features and, in addition, does not have the ability to cause hepatic toxicity, as established with tolcapone.

We have now unexpectedly discovered that some nitrocatechols are very effective COMT inhibitors that are also free or have a very reduced risk of toxicity. In addition, it was unexpectedly found that the absence of toxic effects of these compounds is determined by the chemical functional group of the non-catechol substituent connected to the heterocyclic ring.

To date, the prior art describes only one example of nitrocatechol [1,2,4] -oxadiazole (example 75 of Australian patent AU-B-69764/87), which is 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] -oxadiazole with a methyl group occupying the C-3 position of the heterocyclic oxadiazole ring and a nitrocatechol pharmacophore attached to C-5.

We examined the oxadiazole compound 1 mentioned above and found that it is moderately active in the COMT inhibition assay (59% control, see experimental section). Unfortunately, however, compound 1 shows a significant risk of toxicity (55% cell viability, see experimental section). In this regard, it cannot be considered that this particular compound 1 represents the correct solution to the real problem of creating an effective and clinically safe COMT inhibitor.

We unexpectedly found that if the central ring is replaced by an oxidized pyridyl ring (i.e., pyridine N-oxide), the resulting pyridine N-oxide compounds exhibit greatly reduced toxicity or even no risk of toxicity, while still being able to maintain inhibition of COMT better than entacapone. If the position of the nitrocatechol pharmacophore is “switched” from C-5 to the C-3 position of the oxadiazole ring, then the resulting compounds are usually less active with respect to inhibition of COMT. The regioisomeric 1,3,4-oxadiazoles, in which the nitrocatechol pharmacophore is attached to the C-2 of the oxadiazole central ring, are also usually less active with respect to COMT inhibition. For example, consider the regioisomers 2 and 3 of oxadiazole 1 of the prior art, which we also synthesized and evaluated in vivo:

Despite the fact that both 2 and 3 show a reduced risk of toxicity relative to 1, with respect to COMT inhibition, 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 the correct positional arrangement of heteroatoms in the central oxadiazole ring and the inclusion of the pyridine N-oxide functional group are unexpectedly decisive for obtaining a synergism between high COMT inhibitory activity and safety for this type of COMT inhibitor.

Thus, the present invention relates to nitrocatechol COMT inhibitors that lack or have a very reduced risk of toxicity. In addition, it was unexpectedly found that the inclusion of a nitrogen-containing heterocyclic group in an N-oxidized form, such as, for example, pyridine N-oxide, determines the insufficiency of toxic effects of nitrocatechol compounds. Moreover, we unexpectedly found that the compounds of general formula I are COMT inhibitors that are endowed with comparable properties of bioactivity, bioavailability and, in particular, safety:

where R ₁ and R ₂ independently from each other represent hydrogen or a group that hydrolyzes under physiological conditions, possibly substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents an oxygen, nitrogen or sulfur atom; n is the number 0, 1, 2 or 3, and m is the number 0 or 1; R ₃ represents a pyridine N-oxide group according to formula A, B or C, which is attached as shown by an unlabeled bond:

where R ₄ , R ₅ , R ₆ and R ₇ independently represent hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₂ - aryloxy or C ₆ -C ₁₂ thioaryl group, C ₁ -C ₆ alkanoyl or C ₇ -C ₁₃ aroyl group, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, C ₃ -C _12- cycloalkylamino, C ₃ -C ₁₂ heterocycloalkylamino, C ₁ -C ₆ alkylsulfonyl, C ₆ -C ₁₂ arylsulfonyl, halogen, C ₁ -C ₆ haloalkyl, trifluoromethyl, cyano, nitro or heteroaryl group; or two or more taken together, the radicals R ₄ , R ₅ , R ₆ and R ₇ are aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings, and where P is a central part, which is preferably a planar part and which is even more preferably selected from regioisomers of 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, 4-methyl-4H-1,2,4-triazole-3,5-diyl, 1 3,5-triazine-2,4-diyl, 1,2,4-triazin-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazole-4,5-diyl , 1-alkyl-3- (alkoxycarbonyl) -1H-pyrrole-2,5-diyl, where alkyl p represented by methyl, ethyl, n-propyl and n-butyl, and where alkoxy is methoxy, ethoxy, n-propoxy and isopropoxy, 1-alkyl-1H-pyrrol-2,5-diyl, where alkyl is methyl, ethyl, n- propyl and n-butyl, thiazole-2,4-diyl, 1H-pyrazole-1,5-diyl, pyrimidin-2,4-diyl, oxazole-2,4-diyl, carbonyl, 1H-imidazole-1,5- diyl, isoxazole-3,5-diyl, furan-2,4-diyl, 3-alkoxycarbonylfuran-2,4-diyl, where alkoxy is methoxy, ethoxy, n-propoxy and isopropoxy, benzene-1,3-diyl and ( Z) -1-cyanoethen-1,2-diyl.

In the above definition, the regioisomers of the central part include both regioisomers realized by permutation of the nitrocatechol fragment and - (X) _n - (Y) _m —R ₃ fragment.

Preferably, the C ₁ -C ₆ alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl. Preferably, the C ₁ -C ₆ thioalkyl radicals are thiomethyl, thioethyl, thio-n-propyl, thio-isopropyl, thio-n-butyl, thio-n-pentyl and thio-n-hexyl. Preferably, the C ₁ -C ₆ alkoxy moieties are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. Preferably, the C ₆ -C ₁₂ aryloxy moieties are phenoxy or naphthoxy, which may be substituted. Preferably, the C ₆ -C ₁₂ thioaryl residues are thiophenyl and thionaphthyl, which may be substituted. Preferably, the C ₁ -C ₆ alkanoyl moieties are methanoyl, ethanoyl, propanoyl or butanoyl. Preferably, the C ₇ -C ₁₃ aroyl residues are benzoyl and naphthoyl. Preferably, the C ₁ -C ₆ alkylamino moieties are methylamino, ethylamino, n-propylamino, isopropylamino and n-butylamino. Preferably, the C ₁ -C ₆ dialkylamino moieties are dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, di-isopropylamino, methylethylamino, methylpropylamino and ethylpropylamino. Preferably, the C ₃ -C ₁₂ cycloalkylamino residues are pyrrolidino, piperidino, cyclohexylamino and dicyclohexylamino. Preferably, the C ₃ -C ₁₂ heterocycloalkylamino residues are morpholino, 2,6-dimethylmorpholino, 3,5-dimethylmorpholino, piperazino, N-methylpiperazino and N-ethylpiperazino. Preferably, the C ₁ -C ₆ alkylsulfonyl or C ₆ -C ₁₂ arylsulfonyl moieties are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and tolylsulfonyl. Preferably, the halogen residues are chlorine, bromine, iodine and fluorine. Preferably, the C ₁ -C ₆ haloalkyl radicals are chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl. Preferred heteroaryl residues are pyridyl, pyrimidyl, isoxazolyl, oxazolyl, isoxadiazolyl, oxadiazolyl, triazolyl and tetrazolyl. In cases where two or more taken together residues R ₄ , R ₅ , R ₆ and R ₇ are aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings, the preferred combined residues are indolisinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolisinyl , naphthyridinyl, isoquinolyl and quinolyl.

The central portion is preferably selected from a five-membered heteroaromatic ring which includes 1 to 4 heteroatoms N, O and S. More preferably, the central portion P is selected from the regioisomers of 1,3,4-oxadiazole-2,5-diyl, 1,2,4- oxadiazole-3,5-diyl, 4-methyl-4H-1,2,4-triazole-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-thiadiazole-4,5-diyl, 1-alkyl-3- (alkoxycarbonyl) -1H-pyrrole-2,5-diyl, where alkyl is methyl, ethyl, n-propyl and n-butyl, and where alkoxy is methoxy, ethoxy, n-propoxy and isopropoxy, 1-alkyl-1H -pyrrol-2,5-diyl, where the alkyl is methyl, ethyl, n-propyl and n-butyl, thiazole-2,4-diyl, 1H-pyrazol-1,5-diyl, oxazole-2,4-diyl, carbonyl, 1H-imidazole-1,5-diyl, isoxazole-3,5-diyl, furan-2,4-diyl, 3-alkoxycarbonylfuran-2,4-diyl, where alkoxy is methoxy, ethoxy, n-propoxy and isopropoxy .

Most preferably, the central portion P is selected from 1,3,4-oxadiazole-2,5-diyl and 1,2,4-oxadiazole-3,5-diyl.

Preferred compounds of the above general formula (I) having 1,2,4-oxadiazole-3,5-diyl as the central part include 5- [3- (3,5-dichloro-1-hydroxy-pyridin-4-yl ) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2-chloro-1-hydroxy-pyridin-4-yl) - [ 1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2-morpholin-4-yl-1-hydroxy-pyridin-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-hydroxy-pyridin-3-yl) - [1,2,4 ] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2-chloro-6-methyl-1-hydroxy-pyridin-3-yl) - [1,2, 4] oxadia zol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2-morpholin-4-yl-1-hydroxy-pyridin-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] oxadiazole -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-methi -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-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [ 3- (2-chloro-4,6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2-bromo-4,6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2 -diol, 5- [3- (2-bromo-4,5,6-trimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene- 1,2-diol, 5- [3- (2-chloro-4,5,6-trimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3 -nitrobenzene-1,2-diol, 5- [3- (2,5-dichloro-4,6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl ] -3-none trobenzene-1,2-diol, 5- [3- (2-bromo-5-chloro-4,6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5- yl] -3-nitrobenzene-1,2-diol and 3-nitro-5- [3- (1-hydroxy-2-trifluoromethyl-pyridin-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-nitro phenyl) -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 3- (3- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-5-yl) -5- (trifluoromethyl) pyridine oxide, 1- 3- (3- (3, 4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-5-yl) -2-fluoropyridine, 1- 4- (3- (3,4-dihydroxy-5-nitrophenyl) -1-oxide, 4-oxadiazol-5-yl) -2-fluoropyridine, 1- oxide of 2- (3- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-5-yl) -6-fluoropyridine, 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 methyl pyridine and 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 1,3,4-oxadiazole-2,5-diyl as a 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-oxadiazole -2-yl) -4,6-dimethylpyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -2-methyl-6 1-oxide - (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) p ridin, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1- 3,5-dichloro-4- (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) pyridine oxide, 1- 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) pyridine, 1-oxide 2,5-dichloro-3- (5- (3,4-digi) droxy-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 -fluoropyridine, 1- oxide of 4- (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -2-fluoropyridine, 1-oxide 2- (5- (3 , 4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -6-fluoropyridine, 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-oxadiazole- 2-yl) -6-methylpyridine and 1-oxide 2-bromo-5-chloro-3- (5- (3,4-dihydro B-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -4,6-dimethylpyridine.

Preferred compounds of the above general formula (I) having 4-methyl-4H-1,2,4-triazole-3,5-diyl as a central part include 1- 3- (5- (3,4-dihydroxy- 5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -4- (trifluoromethyl) pyridine, 1-oxide 2-chloro-3- (5- (3,4-dihydroxy- 5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -4,6-dimethylpyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) - 4-methyl-4H-1,2,4-triazol-3-yl) -2-methyl-6- (trifluoromethyl) pyridine, 1- oxide 5- (5- (3,4-dihydroxy-5-nitrophenyl) - 4-methyl-4H-1,2,4-triazol-3-yl) -2- (trifluoromethyl) pyridine, 1- oxide 5- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl- 4H-1,2,4-tr iazol-3-yl) -2-methyl-4- (trifluoromethyl) pyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4- triazol-3-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1-oxide 3,5-dichloro-4- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl- 4H-1,2,4-triazol-3-yl) pyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4-triazol- 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-triazol-3-yl) -4,5,6-trimethylpyridine, 1-oxide 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H -1,2,4-triazol-3-yl) -4,5,6-trimethylpyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl -4H-1,2,4-triazol-3-yl) -2- (trifluoromethyl) pyridine, 1-oxide 2,5-dichloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -4 -methyl-4H-1,2,4-triazol-3-yl) -4,6-dimethylpyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H- 1,2,4-triazol-3-yl) -5- (trifluoromethyl) pyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2, 4-triazol-3-yl) -2-fluoropyridine, 1- oxide 4- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl ) -2-fluoropyridine, 1-oxide 2- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -6-fluoropyridine, 1 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -6-methylpyridine oxide, 1-oxide 2 bromo-3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -6-methylpyridine and 1-oxide 2-bromo- 5-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -4,6-dimethylpyridine.

Preferred compounds of the above general formula (I) having 1,3,5-triazine-2,4-diyl as the central part include 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1-oxide , 3,5-triazin-2-yl) -4- (trifluoromethyl) pyridine, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl ) -2-methyl-6- (trifluoromethyl) pyridine, 1- oxide 5- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2- (trifluoromethyl ) pyridine, 1- oxide 5- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2-methyl-4- (trifluoromethyl) pyridine, 1-oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1- 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine xide, 1-oxide 3 - (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2- (trifluoromethyl) pyridine and 1- oxide 3- (4- (3,4-dihydroxy -5-nitrophenyl) -1,3,5-triazin-2-yl) -5- (trifluoromethyl) pyridine.

Preferred compounds of the above general formula (I) having 1,2,4-triazin-3,5-diyl as the central part include 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1-oxide , 2,4-triazin-3-yl) -4- (trifluoromethyl) pyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl ) -2-methyl-6- (trifluoromethyl) pyridine, 1- oxide 5- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -2- (trifluoromethyl ) pyridine, 1- oxide 5- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -2-methyl-4- (trifluoromethyl) pyridine, 1-oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1- 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine xide, 1-oxide 3 - (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -2- (trifluoromethyl) pyridine, 1- oxide 3- (5- (3,4-dihydroxy -5-nitrophenyl) -1,2,4-triazin-3-yl) -5- (trifluoromethyl) pyridine, 1- oxide 4- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2, 4-triazin-3-yl) -2-fluoropyridine and 1- oxide of 2- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -6-fluoropyridine.

Preferred compounds of the above general formula (I) having a (Z) -1-cyanoethen-1,2-diyl fragment as a central moiety include (Z) -3- (1-cyano-2- (3,4) 1-oxide -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- (Z) -5- (1-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2- (trifluoromethyl) pyridine oxide, 1-oxide (Z) -5- (1-cyano-2 - (3,4-dihydroxy-5-nitrophenyl) vinyl) -2-methyl-4- (trifluoromethyl) pyridine, 1-o led (Z) -3- (1-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1-oxide (Z) -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- (trifluoromethyl) pyridine, 1-oxide (Z ) -3- (1-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2-fluoropyridine, 1-oxide (Z) -4- (1-cyano-2- (3,4- dihydroxy-5-nitrophenyl) vinyl) -2-fluoropyridine, 1-oxide (Z) -2- (1-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -6-fluoropyridine, 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 and 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 a central part, a furan-2,4-diyl or 3-alkoxycarbonylfuran-2,4-diyl moiety, wherein alkoxy is methoxy, ethoxy, n-propoxy and isopropoxy, include 1-oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -4- (trifluoromethyl) pyridine, 1-oxide 2-chloro-3- (4- (3 , 4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -4,6-dimethylpyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -3- 1-oxide (ethoxycarbonyl) furan-2-yl) -2-methyl-6- (trifluoromethyl) pyridine, 1- oxide 5- (4- (3,4-dihydroxy-5-nitrophene il) -3- (ethoxycarbonyl) furan-2-yl) -2- (trifluoromethyl) pyridine, 1- oxide 5- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2 -yl) -2-methyl-4- (trifluoromethyl) pyridine, 1-oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2.6 -dimethyl-4- (trifluoromethyl) pyridine, 1-oxide 3,5-dichloro-4- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) pyridine, 1 3- (4- (3,4-dihydroxy-5-nitrophenyl) furan-2-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine oxide, 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 ) truck -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- (ethoxycarbonyl) furan-2-yl) - 2-fluoropyridine, 1- 4- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2-fluoropyridine 1-oxide 2- (4- (3 , 4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -6-fluoropyridine, 1-oxide 2-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) - 3- (ethoxycarbon il) furan-2-yl) -6-methylpyridine, 1-oxide 2-bromo-3- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -6 methyl pyridine and 1-oxide 2-bromo-5-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -4,6-dimethylpyridine.

Preferred compounds of the above general formula (I) having, as a central part, a 1H-imidazole-1,5-diyl moiety include 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-imidazole- 1-oxide 1-yl) -4- (trifluoromethyl) pyridine, 1-oxide 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-imidazol-1-yl) -4,6-dimethylpyridine , 1- 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-imidazol-1-yl) -2-methyl-6- (trifluoromethyl) pyridine oxide, 1- 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-digi) droxy-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-fluoropyridine, 1-oxide 2- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-imidazol-1-yl) -6-fluoropyridine, 1-oxide 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -1H -imidazol-1-yl) -6-methylpyridine and 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 a central part, an isoxazole-3,5-diyl moiety include 3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) - 1-oxide 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) isoxazole -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-dihydroxy-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) isoxazole-5 -yl) -2- (trifluoromethyl) pyridine, 2,5-dichloro-3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -4,6-dimethylpyri 1-oxide ina, 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-fluoropyridine, 1- oxide 4- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2-fluoropyridine, 1-oxide 2- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -6-fluoropyridine, 1-oxide 2-chloro-3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazole- 5-yl) -6-methylpyridine, 1-oxide 2-bromo-3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -6-methylpyridine and 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 a carbonyl fragment as a central part include 3- (3,4-dihydroxy-5-nitrobenzoyl) -4- (trifluoromethyl) pyridine 1-oxide, 2-chloro-3 1-oxide - (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 3- (3,4-dihydroxy-5-nitrobenzoyl) -2,6-dimethyl-4- (trifluoromethyl) pyridine oxide, 3,5-d 1-oxide ichloro-4- (3,4-dihydroxy-5-nitrobenzoyl) pyridine, 1-oxide 3- (3,4-dihydroxy-5-nitrobenzoyl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 1 2-bromo-3- (3,4-dihydroxy-5-nitrobenzoyl) -4,5,6-trimethylpyridine oxide, 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-fluoropyridine, 1- oxide 4- (3,4-dihydroxy-5-nitrobenzoyl) -2-fluoropyr dyne, 1- oxide of 2- (3,4-dihydroxy-5-nitrobenzoyl) -6-fluoropyridine, 1-oxide of 2-chloro-3- (3,4-dihydroxy-5-nitrobenzoyl) -6-methylpyridine, 1- 2-bromo-3- (3,4-dihydroxy-5-nitrobenzoyl) -6-methylpyridine oxide and 1-2-bromo-5-chloro-3- (3,4-dihydroxy-5-nitrobenzoyl) -4 oxide, 6-dimethylpyridine.

Preferred compounds of the above general formula (I) having, as a central part, an oxazole-2,4-diyl moiety include 3- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) - 1-oxide 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) oxazole -2-yl) -2- (trifluoromethyl) pyridine, 5- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -2-methyl-4- (trifluoromethyl) pyridine 1-oxide, 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) oxazole- 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-fluoropyridine, 1 4- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -2-fluoropyridine oxide, 2- (4- (3,4-dihydroxy-5-nitrophenyl) oxazole- 1-oxide 2-yl) -6-fluoropyridine, 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 and 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 a central part, a benzene-1,3-diyl moiety include 3- (3 ', 4'-dihydroxy-5'-nitrobiphenyl-3-yl) -4- 1-oxide (trifluoromethyl) pyridine, 5- (3 ', 4'-dihydroxy-5'-nitrobiphenyl-3-yl) -2- (trifluoromethyl) pyridine 1-oxide, 3,5-dichloro-4- (3' 1-oxide , 4'-dihydroxy-5'-nitrobiphenyl-3-yl) pyridine, 1- oxide 3- (3 ', 4'-dihydroxy-5'-nitrobiphenyl-3-yl) -2- (trifluoromethyl) pyridine and 1- 3- (3 ', 4'-dihydroxy-5'-nitrobiphenyl-3-yl) -5- (trifluoromethyl) pyridine oxide.

Preferred compounds of the above general formula (I) having, as a central part, a 1H-pyrazole-1,5-diyl moiety include 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-pyrazole- 1-oxide 1-yl) -4- (trifluoromethyl) pyridine, 1- oxide 5- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-pyrazol-1-yl) -2- (trifluoromethyl) pyridine, 1- 3,5-dichloro-4- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-pyrazol-1-yl) pyridine oxide, 1- 3- (5- (3,4-dihydroxy-5) oxide -nitrophenyl) -1H-pyrazol-1-yl) -2- (trifluoromethyl) pyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-pyrazol-1-yl) -5 - (trifluoromethyl) pyridine and 1- oxide 4- (5- (3,4-dihydroxy-5-nitro phenyl) -1H-pyrazol-1-yl) -2-fluoropyridine.

Preferred compounds of the above general formula (I) having, as a central portion, a pyrimidin-2,4-diyl moiety include 3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) - 1-oxide 4- (trifluoromethyl) pyridine, 1-oxide 2-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -4,6-dimethylpyridine, 1-oxide 3- (4 - (3,4-dihydroxy-5-nitrophenyl) pyrimidin-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) pyrimidin-2-yl) -2-methyl-4- (trifluoromethyl) pyridine, 1-oxide 3- (4- (3, 4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1-oxide 3,5-dichloro-4- (4- (3,4-dihydroxy-5 -nitrophenyl) pyrimidin-2-yl) pyridine, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 1-oxide 2-bromo-3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -4,5,6-trimethylpyridine, 1-oxide 2-chloro-3- ( 4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -4,5,6-trimethylpyridine, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2 -yl) -2- (trifluoromethyl) pyridine, 1-oxide 2,5-dichloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -4,6-dimethylpyri cell and 1-oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -5- (trifluoromethyl) pyridine.

Preferred compounds of the above general formula (I) having, as a central part, a 1H-pyrrole-2,5-diyl moiety include 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1-methyl- 1-oxide 3- (ethoxycarbonyl) -1H-pyrrol-2-yl) -4- (trifluoromethyl) pyridine, 1-oxide 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl ) -1-methyl-1H-pyrrol-2-yl) -4,6-dimethylpyridine, 1- oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1-methyl-1H-pyrrole-2 -yl) -2-methyl-6- (trifluoromethyl) pyridine, 1- oxide 5- (5- (3,4-dihydroxy-5-nitrophenyl) -1-ethyl-3- (ethoxycarbonyl) -1H-pyrrole-2 -yl) -2- (trifluoromethyl) pyridine, 1-oxide 5- (5- (3,4-digi) Droxy-5-nitrophenyl) -1-methyl-1H-pyrrol-2-yl) -2-methyl-4- (trifluoromethyl) pyridine, 1- 3- (5- (3,4-dihydroxy-5-nitrophenyl) oxide -1-methyl-1H-pyrrol-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-nitropheny l) -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-fluoropyridine, 1-oxide 4- (5- (3,4-dihydroxy-5-nitrophenyl) -1-methyl-1H-pyrrol-2-yl) -2-fluoropyridine, 1- oxide 2- (5- (3,4-dihydroxy-5-nitrophenyl ) -3- (ethoxycarbonyl) -1-methyl-1H-pyrrol-2-yl) -6-fluoropyridine, 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 and 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 a central part, a 2H-tetrazol-2,5-diyl fragment include 3- (5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazole- 1-oxide 2-yl) -4- (trifluoromethyl) pyridine, 1- oxide 5- (5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl) -2- (trifluoromethyl) pyridine, 1- 3,5-dichloro-4- (5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl) pyridine oxide, 1- 3- (5- (3,4-dihydroxy-5) oxide -nitrophenyl) -2H-tetrazol-2-yl) -2- (trifluoromethyl) pyridine and 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 a central part, a 1,2,3-thiadiazole-4,5-diyl fragment include 3- (4- (3,4-dihydroxy-5-nitrophenyl) - 1-oxide 1,2,3-thiadiazol-5-yl) -4- (trifluoromethyl) pyridine, 1-oxide 2-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3- thiadiazol-5-yl) -4,6-dimethylpyridine, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2-methyl- 6- (trifluoromethyl) pyridine, 1- oxide 5- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2- (trifluoromethyl) pyridine, 1-oxide 5- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2-methyl-4- (trifluoromethy ) pyridine, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1 3,5-dichloro-4- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) pyridine oxide, 1- 3- (4- (3, 4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 1-oxide 2-bromo-3- (4- ( 3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -4,5,6-trimethylpyridine, 1-oxide 2-chloro-3- (4- (3,4-dihydroxy -5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -4,5,6-trimethylpyridine, 1-oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2 , 3-thiadiazol-5-yl) -2- (trifluoromethyl) pyridine, 1-oxide 2,5-dichloro-3- (4- (3,4-dihydro si-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -4,6-dimethylpyridine, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2, 3-thiadiazol-5-yl) -5- (trifluoromethyl) pyridine, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2 -fluoropyridine, 1- oxide of 4- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2-fluoropyridine, 1-oxide 2- (4- (3 , 4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -6-fluoropyridine, 1-oxide 2-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -6-methylpyridine, 1-oxide 2-bromo-3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazole- 5-yl) -6-methylpyridine and 1-oxide 2-bromo-5-chloro-3- (4- (3,4-dihydroxy-5-nitroph nile) -1,2,3-thiadiazol-5-yl) -4,6-dimethylpyridine.

Preferred compounds of the above general formula (I) having, as a central part, a thiazole-2,4-diyl fragment include 3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) - 1-oxide 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) thiazole -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-nitro enyl) 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-dihydroxy-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 of 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) t iazol-2-yl) -5- (trifluoromethyl) pyridine, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -2-fluoropyridine, 1-oxide 4- ( 4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -2-fluoropyridine, 1-oxide 2- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) - 6-fluoropyridine, 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 and 1-oxide 2-bromo-5-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazole -2-yl) -4,6-dimethylpyridine.

In one embodiment of the compound of general formula I, wherein the central part consists of a 1,2,4-oxadiazo-3,5-diyl moiety, can be prepared by a process in which the compound of general formula IIA, IIB or IIB,

where R ₄ , R ₅ , R ₆ and R _{7 are} defined as in the general formula I, they undergo a cyclization reaction including condensation and dehydration with a compound of the general formula III,

where R ₈ and R ₉ independently represent hydrogen or suitable protecting groups for aromatic hydroxyl groups, under conditions suitable for the preparation of oxadiazole derivatives of formula IVA, IVB or IVB,

followed by removal of the hydroxyl protecting groups to give compounds of general formula I, wherein the central portion consists of a 1,2,4-oxadiazo-3,5-diyl moiety.

In another embodiment of the compound of general formula I, wherein the central part consists of a 1,2,4-oxadiazo-3,5-diyl moiety, can be prepared by a process in which the compound of general formula VA, VB or VB,

where R ₄ , R ₅ , R ₆ and R _{7 are} defined as in the general formula I, they undergo a cyclization reaction including condensation and dehydration with a compound of the general formula III under conditions suitable for the preparation of oxadiazole derivatives of the formula VIA, VIB or VIB,

followed by oxidation of the pyridyl nitrogen atom, which gives the compound according to formula IVA, IVB or IVB, as shown above, and finally, if necessary, hydroxyl protecting groups are removed to obtain compounds of general formula I, where the central part consists of 1.2, 4-oxadiazo-3,5-diyl fragment.

Suitable protecting groups for aromatic hydroxyl groups are well known in the art. Examples of suitable protecting groups for aromatic hydroxyl groups include methyl, ethyl, isopropyl, benzyl, 4-methoxybenzyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, tetrahydropyranyl, phenacyl, allyl, trimethylsilyl, tert-butyldimethylcarbonyl, t-butyloxycarbonyl, tert-butylcarbonate, phosphinate, acetal and ketal derivatives.

In a preferred embodiment, one of the groups R ₈ and R ₉ is hydrogen and the other is methyl. In a particularly preferred embodiment, R ₈ is methyl and R ₉ is hydrogen.

In an alternative preferred embodiment, the protecting groups R ₈ and R ₉ are replaced with hydrogen or a group that is hydrolyzable under physiological conditions. The protecting groups R ₈ and R ₉ can be removed independently from each other in separate reaction steps, or they can be removed during a single reaction step. Also, the introduction of a group that is hydrolyzable under physiological conditions can take place either at the same or at a subsequent reaction stage.

In the present invention, conditions suitable for the preparation of oxadiazole derivatives include those that give the oxadiazole derivative in high yield and purity. Preferably, the yield of the desired oxadiazole derivative is at least 70%, more preferably 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%. Based on the subject matter of the present invention, a qualified person can customarily establish the most suitable reaction conditions in order to optimize the yield and purity of oxadiazole. Parameters to be considered by a qualified professional include, but are not limited to, condensation reagents and dehydrating agents, choice of protecting groups R ₈ and R ₉ , solvent system, reaction temperature and reaction time, and solubility of the reagents.

The compound of general formula III requires activation before condensation with the compound of formula IIA-IIB or VA-VB. Suitable reactants for activating a compound of formula III include 1,1-carbonyldiimidazole, thionyl chloride, sulfonyl chloride, N, N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide, phosgene, PCl ₃ , POC ₃ , POC ₃ , POC PCl ₃ , anhydrides, trichlorotriazine and chloromethoxytriazine and the like. Particularly preferred are 1,1-carbonyldiimidazole and thionyl chloride. In some cases, the same reagents can be used to carry out the cyclization step, which consists of condensation and dehydration. Alternative reagents for condensation and / or dehydration include pyridine and tetrabutylammonium fluoride. Preferably, dehydration can be carried out 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 a reagent, such as thionyl chloride, in a suitable solvent or without the need for an additional solvent. Preferably, the excess reagent can then be removed, for example, by distillation, and replaced with a solvent and another reagent, such as pyridine, to carry out the condensation and dehydration steps. Preferred solvent systems for activating a compound of general formula III and cyclization with compounds of general formulas IIA-IIB or VA-VB are dipolar aprotic solvents including dimethylformamide, dimethyl sulfoxide, dimethylacetamide and N-methylpyrrolidinone. Dimethyl sulfoxide and dimethylacetamide are particularly preferred.

Suitable reaction temperatures and reaction times depend on the reactivity of the reagents used to effect the condensation and dehydration. Preferably, the reaction temperature is in the range of 0 ° C. to the boiling point of the solvent system used, more preferably in the range of 20-150 ° C., and most preferably in the range of 25-120 ° C. Preferably, the reaction time is in the range of 30 minutes to 24 hours, more preferably in the range of 1 hour to 18 hours, and most preferably 2-6 hours.

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

In a preferred embodiment of the present invention, condensation and dehydration are carried out in two separate reaction steps. In this particular embodiment, different condensation and dehydration agents and solvent systems can be used to optimize the yield and purity of the resulting product.

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

The amount of condensation and dehydration reagents is not critical. Typical amounts of condensation and dehydration reagents include at least 1 mol, preferably 2.1 mol to 5 mol, more preferably 2.2 to 4 mol and most preferably 2.3 mol to 3 mol per mol of pyridine derivative. In cases where the reagents carrying out the condensation and dehydration also serve as a solvent or cosolvent, the excess amount can be much larger.

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

In the present invention, oxidizing conditions suitable for the preparation of pyridyl N-oxide include conditions which give a pyridyl N-oxide derivative in high yield and purity. Preferably, the yield of the desired pyridyl N-oxide derivative is at least 90%, more preferably 92-99%, even more preferably 94-98%, and most preferably 95-97%. Preferably, the purity of the desired pyridyl N-oxide derivative is at least 90%, more preferably at least 95%, even more preferably at least 99% and most preferably at least 99.5%. Based on the subject matter of the present invention, a qualified person can in the usual way establish the most suitable reaction conditions in order to optimize the yield and purity of pyridyl N-oxide. Parameters to be considered by a qualified professional include, but are not limited to, an oxidizing agent, an amount of an oxidizing agent, a choice of protecting groups, a solvent system, a reaction temperature and a reaction time, and a solubility of the reactants.

Preferred oxidizing agents include hydrogen peroxide, MnO ₂ , peracetic acid, trifluoroacetic acid, tert-butyl hydroperoxide, meta-chloroperoxybenzoic acid, sulfuric acid, Oxon®, a complex of urea with hydrogen peroxide and trifluoroacetic anhydride, and pyridinium trichlorohydrochloride and manganate. A complex of urea with hydrogen peroxide and trifluoroacetic anhydride are particularly preferred.

The preferred amount of oxidizing agent is in the range of equimolar amounts to a 20-fold excess relative to the pyridine derivative. Preferably, the amount of oxidizing agent is in the range of 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.

Preferred oxidation solvent systems are those that are inert to the oxidizing agent. Particularly preferred are halogenated solvents such as dichloromethane, chloroform, chlorobenzene and carbon tetrachloride, aromatic solvents such as benzene and toluene, alkanes such as cyclohexane and hexane, and esters such as THF, 1,4-dioxane and tert-butyl methyl ether .

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

Oxidation of the pyridyl nitrogen atom can be performed at any stage of the process for preparing compounds according to general formula I. Preferably, the oxidation is carried out before the formation of compounds of formulas IIA-IIB or alternatively after the formation of an oxadiazole ring as in the compounds of formulas VIA-VIB.

In another aspect of the invention, compounds of formula IIA, IIB or IIB are prepared by reacting compounds of general formula VIIA, VIIB or VIIB,

with hydroxylamine in the presence of a chelating agent under suitable reaction conditions.

In another aspect of the invention, compounds of formula VA, VB or VB are prepared by reacting compounds of general formula VIIIA, VIIIB or VIIIB,

with hydroxylamine in the presence of a chelating agent under suitable reaction conditions.

In the present invention, suitable reaction conditions for the above reactions include those that give the amidoxime derivative in high yield and purity. Preferably, the yield of the desired amidoxime derivative is at least 70%, more preferably 72-95%, even more preferably 75-90% and most preferably 78-85%. Preferably, the purity of the desired amidoxime derivative is at least 90%, more preferably at least 95%, even more preferably at least 96% and most preferably at least 97%. Based on the subject matter of the present invention, a qualified person can customarily establish the most suitable reaction conditions in order to optimize the yield and purity of amidoxime. Parameters to be considered by a qualified professional include, but are not limited to, the amount of hydroxylamine, the choice of catalyst, the nature of the substituents R ₄ -R ₇ , the solvent system, the reaction temperature and reaction time, and the solubility of the reagents.

The preferred amount of hydroxylamine is in the range of equimolar amounts to a 50-fold excess relative to the pyridine derivative. Preferably, the amount of hydroxylamine is in the range of 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.

Preferred chelating agents include 8-hydroxyquinoline, ortho-phenanthroline and their hydrates and derivatives. A preferred amount of a chelating agent is in the range of 0.1-10 molar%, more preferably 0.5-5 molar%, more preferably 0.75-3 molar% and most preferably 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 dimethyl sulfoxide and the like, or mixtures of these solvents.

Preferably, the reaction temperature is in the range of 0 ° C. to the boiling point of the solvent system used, more preferably in the range of 20-100 ° C., and most preferably in the range of 40-80 ° C. Preferably, the reaction time is in the range of 30 minutes to 24 hours, more preferably in the range of 1 hour to 18 hours, and most preferably 2-8 hours.

In order 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. Solid form preparations include powders, tablets, dispersible granules and capsules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it may also be encapsulating material.

Preferably, the pharmaceutical preparation is in unit dosage form, for example a packaged preparation, the package contains discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.

Dosages may vary depending on the needs of the patient, the severity of the disease, and the particular compound employed. For convenience, the total daily dosage can be divided and administered in parts throughout the day. The proper dosage in a particular situation is determined by the qualifications of a specialist in the medical field.

Materials and methods

Analysis of COMT activity of mice

Samples of the liver of NMRI mice aged 60 days and weighing 20-30 g (Harlan-Interfauna Ibérica, Barcelona, Spain), contained in ten cages under controlled environmental conditions (12-hour day / night cycle and room temperature 24 ° C) used in all experiments. Salt-perfused tissues obtained from anesthetized pentobarbitone (60 mg / kg) mice were used in all experiments. Tissues were immediately removed and homogenized in 5 mM phosphate buffer, pH 7.8, and stored at -80 ° C.

COMT activity was evaluated by the ability to methylate adrenaline to methanephrine, as previously described (Vieira-Coelho MA, Soares-da-Silva P., Brain Res, 1999, 821, 69-78). Aliquots of 0.5 ml of liver homogenates were preincubated for 20 minutes with 0.4 ml of phosphate buffer (5 mM); then the reaction mixture was incubated for 10 minutes with adrenaline (500 μM; 0.1 ml) in the presence of a saturated concentration of S-adenosyl-L-methionine, a methyl donor (250 μM). The incubation medium also contained pargyline (100 μM), MgCl ₂ (100 μM) and EGTA (1 mm). Pre-incubation and incubation was carried out at 37 ° C under conditions of protection from light with continuous shaking and without oxygen saturation. At the end of the incubation period, the tubes were transferred to ice and the reaction was stopped by adding 200 μl of 2 M perchloric acid. The samples were then centrifuged (200 × g, 4 minutes, 4 ° C) and 500 μl aliquots of the supernatant filtered through 0.22 μm Spin-X filter tubes (Costar) were used to analyze methanephrine using high performance liquid chromatography with electrochemical detection.

In experiments designed to evaluate the effects of the test compounds on COMT liver, the test compounds (in 5% carboxymethyl cellulose) were administered to the hungry mice in the evening from the gastric tube. Then, at certain intervals, the liver was removed and used to determine the activity of COMT, as described above.

The analysis of the activity of COMT rats

The liver of male Uistar rats aged 60 days and weighing 240-260 g (Harlan-Interfauna Ibérica, Barcelona, Spain), two cages each under controlled environmental conditions (12-hour day / night cycle and room temperature 24 ° C) used in all experiments. After decapitation, organs were immediately removed and homogenized in 5 mM phosphate buffer at pH 7.8. COMT activity was evaluated by its ability to methylate adrenaline to methanephrine. Aliquots of 0.5 ml of liver homogenates were preincubated for 20 minutes with 0.4 ml of phosphate buffer (5 mM); then the reaction mixture was incubated for 5 minutes with epinephrine (1000 μM; 0.1 ml) in the presence of a saturated concentration of S-adenosyl-L-methionine (500 μM), a methyl donor; the incubation medium also contained pargyline (100 μM), MgCl ₂ (100 μM) and EGTA (1 mm). Pre-incubation and incubation was carried out at 37 ° C under conditions of protection from light with continuous shaking and without oxygen saturation.

In experiments designed to evaluate the bioavailability of the test compounds when administered orally, the compounds were administered via the gastric tube to rats that were hungry in the evening. Then, at certain time intervals, the animals were killed by decapitation, the liver was removed and used to determine the activity of COMT, as described above. At the end of the incubation period (5 minutes), the tubes were transferred to ice and the reaction was stopped by adding 200 μl of 2 M perchloric acid. The samples were then centrifuged (200 × g, 4 minutes, 4 ° C) and 500 μl aliquots of the supernatant filtered through 0.22 μm Spin-X filter tubes (Costar) were used to analyze methanephrine. Metanephrine analysis was performed by high performance liquid chromatography with electrochemical detection. The lower detection limits of methanephrine ranged from 350 to 500 fmol (0.5 to 1.0 pmol / mg protein / h).

Plasma L-DOPA and 3-O-methyl-L-DOPA

Starved rats were administered orally tolkapon, entacapone and compounds of general formula I (all at 3 mg / kg each) or vehicle (0.5% carboxymethyl cellulose, 4 ml / kg). After 1, 6 or 23 hours, L-DOPA (12 mg / kg) plus benserazide (3 mg / kg) or only vehicle (0.5% carboxymethyl cellulose, 4 ml / kg) was orally administered to rats. After one hour, the rats were anesthetized with sodium pentobarbitone (60 mg / kg, intraperitoneally), blood was taken from the vena cava, and the entire brain was quickly 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 animal experiments were carried out in accordance with European Directive No. 86/609 and the rules of the 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 Derivatives

L-DOPA and 3-O-methyl-L-DOPA in blood samples were analyzed by HPLC with electrochemical detection as previously described (Soares-da-Silva et al., Brain Res. 2000; 863: 293-297). Briefly aliquots of 20 μl were introduced into the chromatograph. The chromatographic system consisted of a pump (Gilson 307) and a 5 μm stainless steel ODS2 column (Biophase; Bioanalytical Systems, West Lafayette, IN) 25 cm long and 4.6 mm in diameter; samples were injected using an automatic sample dispenser (Gilson 231) connected to a Gilson diluent (Gilson 401). The mobile phase was a degassed citric acid solution of 0.1 mM; sodium octyl sulfate 0.5 mM; sodium acetate 0.1 M; Na ₂ EDTA 0.17 mm; dibutylamine 1 mm and methanol (10% vol./about.), adjusted to a pH of 3.5 with 2M PCA (pyrrolidone carboxylic acid) and pumped at a speed of 1.0 ml min ^-1 . Detection was performed electrochemically with a glassy carbon electrode, an Ag / AgCl reference electrode, and an amperometric detector (Gilson 142); the detector cell was controlled at 0.75 V. The generated current was processed using Gilson Unipoint HPLC software.

Cell toxicity

A method that detects the cellular toxicity of a test substance is derived from the described Pedrosa and Soares-da-Silva (Br.J. Pharmacol., 137, 1 1305-1313, 2002). Briefly, Neuro 2A mouse neuroblastoma cells were plated on 96-well plates in 200 μl per well of cell culture medium (CMA, calcium-magnesium acetate) in a humid atmosphere of CO ₂ / air (5% / 95%) at 37 ° C. The control of the test system before incubation consisted of morphological control (optical microscopy) of the cultured cells: attachment, distribution and density. Five days after plating (after 24 hours the cells became fused), the test compounds were incubated for 24 hours with cultured cells. Cultivation without a test sample or with ethanol was performed in parallel as a negative and positive control. All incubations contained the same percentage of solvent required for the test compound.

Cell viability was measured using calcein-AM (Molecular Probes, Eugene, OR, USA). Calcein-AM penetrating the membrane, a non-fluorescent dye, was absorbed and converted by intracellular esterases into calcein, which penetrates the membrane, which emits green fluorescence. After treatment with a test sample or vehicle for 24 hours, the cells were washed twice with Hanks medium (medium composition, in mm: NaCl 137; KCl 5; MgSO ₄ 0.8; Na ₂ HPO ₄ 0.33; KH ₂ PO ₄ 0.44 ; CaCl ₂ 0.25; MgCl ₂ 1.0; Tris HCl 0.15 and sodium butyrate 1.0, pH = 7.4) and placed with 2 μM calcein-AM in Hanks's medium at room temperature for 30 minutes. Fluorescence was measured at excitation wavelengths of 485 nm and 530 nm emission on an apparatus for reading tablets. To determine the minimum staining for calcein-AM (calcein _min ), eight wells were treated with ethanol for 30 minutes before adding calcein-AM. The percent viability was then calculated as [(calcein _{sample —} calcein _min )] / [(calcein _{control —} calcein _min )] × 100.

results

Table 1 shows the effects of standard COMT inhibitors, tolcapone and entacapone, and compounds of the general formula I on the COMT activity of the liver of mice 3 hours after their oral administration (3 mg / kg). Table 1 also shows cell viability 24 hours after exposure to tocapone, entacapone and compounds of general formula I (all 30 μM each) on Neuro 2A cells.

Table 1 The activity of COMT in the liver of mice (% control) after administration of 3 mg / kg of the (orally) listed compounds and the viability of Neuro 2A cells (% viable cells) No. (X) n, (Y) n R ₃ COMT activity (% control) % viable cells Tolkapon 13.9 27,2 Entacapone 79.8 81.4 one n = m = 0 -CH ₃ 59.9 55.1 2 n = m = 0 -CH ₃ 78.8 92.5 3 n = m = 0 -CH ₃ 63.6 100.5 four n = m = 0

42.1 98.3 5 n = m = 0

58.4 93.8 6 n = m = 0

101.0 107.1 7 n = m = 0

14.2 56.9 8 n = m = 0

55,4 106.7 9 n = m = 0

80.6 79.7 10 n = m = 0

95.2 69.3 eleven n = m = 0

63.9 105.7 12 n = m = 0

92.9 91.7 13 n = m = 0

102.3 fourteen n = m = 0

76.8 83.5 fifteen n = m = 0

79.2 97.1 16 n = m = 0

85.9 64.6 17 n = m = 0

89.9 96.0 eighteen n = m = 0

21,2 93,4 19 n = m = 0

45,2 100.1 twenty n = m = 0

56.6 21 n = m = 0

95.6 22 n = m = 0

111.6 23 n = m = 0

43 41.1 24 n = m = 0

71.8 93.7 25 n = m = 0

23.1 100,2 26 n = m = 0

35.5 110.9 27 n = m = 0

47.5 95.7 28 n = m = 0

11.3 87.0 29th n = m = 0

10.9 62,2 thirty n = m = 0

8.8 81.8 31 n = m = 0

0.8 37,2 32 n = m = 0

9.7 26.6 33 n = m = 0

39.8 45.0 34 n = m = 0

88.6 89.0 35 n = m = 0

81.2 88.0 36 n = m = 0

22.9 76.3 37 n = m = 0

42.5 92.3 38 n = m = 0

16.3 86.0 39 X = CH ₂ ,
n = 1, m = 0

53.8 94.9 40 n = m = 0

55,2 69.1 41 n = m = 0

fourteen 95.1 42 n = m = 0

9,4 96.4 43 X = CH ₂ ,
n = 1, m = 0

27,2 101.5 44 X = CH ₂ ,
n = 1
Y = 0
m = 1

24.5 45 n = m = 0

30,4 86.6 46 n = m = 0

43.1 53.0 47 n = m = 0

25,2 81.2 Note: * shows the place of attachment of the substituent N-oxide pyridine to the molecule

It was also found that the compounds of general formula I are effective inhibitors of COMT in rat liver, the greatest inhibitory effect is achieved within 1-3 hours after their oral administration (Table 2). The maximum inhibitory effect of entacapone (Ent) and tolcapone (Tolk) was observed within 1 hour after administration (Table 2). Nine hours after administration, entacapone does not have COMT inhibitory effects and tolcapone exhibits minimal inhibitory effects (~ 16% inhibition), while compounds of the general formula I continue to inhibit COMT activity at 22% -90% of control levels (Table 2).

Table 3 shows the percent changes in the levels of L-DOPA and 3-O-methyl-L-DOPA (3-OMD) in the plasma of rats treated with L-DOPA plus benserazide 2 hours after the administration of entacapone, tolcapone and compounds of the general formula I (3 mg / kg). L-DOPA plus benserazide was administered one hour before plasma sampling. This point in time was chosen because it represents t _max for L-DOPA. As you can see, the compounds of general formula I caused significant increases in plasma L-DOPA, accompanied by a marked decrease in 3-O-methyl-L-DOPA in plasma.

Table 3 The effect of these compounds (3 mg / kg; oral administration) on the changes (% control) of L-DOPA and 3-O-methyl-L-DOPA (3-OMD) levels in the plasma of rats treated with L-DOPA plus benserazide Compound L-DOPA
% increase 3-OMD
% reduction L-DOPA / 3-OMD Entacapone 68.5 -55.6 3.8 Tolkapon 202.4 -89.0 27.6 eighteen 61,4 -63.9 4,5 29th 105.1 -80.7 10.6 thirty 103.5 -75.0 8.1 41 95.2 -72.3 7.1 42 30.7 -43.4 2,3 43 74.9 -48.3 3.4 45 100.8 -54.3 4.4 47 102.9 -58.5 4.9

Output

The compounds of general formula I are very effective catechol-O-methyltransferase (COMT) inhibitors with significantly reduced toxicity. The compounds of general formula I possess potentially valuable pharmaceutical properties in the treatment of certain disorders of the central and peripheral nervous system, when inhibition of O-methylation of catecholamines can be of therapeutic benefit, such as affective disorders, Parkinson's disease and Parkinson's disorders, tired legs syndrome, gastrointestinal diseases, the state of the formation of edema and hypertension. The ability to use an effective long-acting inhibitor with an improved safety profile opens up new prospects in the treatment of Parkinson's disease and Parkinson's disorders, gastrointestinal diseases, edema and hypertension, improving the safety of nitrocatechol inhibitors of COMT and at the same time improving or maintaining the duration and selectivity of COMT inhibition . This is especially important when referring to the treatment of patients with Parkinson's disease who are taking L-DOPA plus a peripheral AADC inhibitor, due to the fact that this is a long-term treatment.

The invention disclosed herein is illustrated by the following preparation examples, which are not to be considered to limit the scope of the invention. Alternative methods and similar structures may be apparent to those skilled in the art.

Example 1

3-Nitro-5- [3- (1-hydroxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] benzene-1,2-diol (compound 4, Table 1)

a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.5 g, 1.32 mmol) in dimethylformamide (5 ml) was added 1,1-carbonyldiimidazole (0.246 g, 1.52 mmol) at room temperature at once. After stirring for one hour, N'-hydroxypyridine-4-carboximidamide (0.208 g, 1.52 mmol) was added at a time, 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 extracted with 20% isopropanol / dichloromethane. The organic extracts were washed with water and brine, then dried (Na ₂ SO ₄ ), filtered and evaporated to form a solid residue, which was recrystallized from ethanol. 4- [5- (3,4-Bis-benzyloxy-5-nitrophenyl) - [1,2,4] oxadiazol-3-yl] pyridine was obtained as a beige solid (0.395 g, 62%).

b) A stirred solution of the above pyridine compound (0.331 g, 0.689 mmol) in dichloromethane (15 ml) was cooled in an ice water bath and meta-chloroperoxybenzoic acid (0.179 g, 1.03 mmol) was added in portions. The resulting mixture was stirred in the cold for thirty minutes and then at room temperature for thirty minutes, after which it was again cooled in an ice water bath. More meta-chloroperoxybenzoic acid (0.17 g, 1.03 mmol) was added and then the mixture was stirred at room temperature for an hour and a half. Water (20 ml) was added and the organic phase was separated and washed with saturated aqueous sodium bicarbonate, water and brine, then dried (Na ₂ SO ₄ ), filtered and evaporated to give a yellow oil. The addition of diethyl ether led to the formation of a precipitate, which was filtered and recrystallized from a mixture of dichloromethane / isopropanol. 4- [5- (3,4-bis-benzyloxy-5-nitro-phenyl) - [1,2,4] oxadiazol-3-yl] pyridine 1-oxide was obtained as white crystals (0.239 g, 70% )

c) A solution of the above dibenzyl ether (0.232 g, 0.468 mmol) in dichloromethane (5 ml) was cooled to -78 ° C, stirring under argon atmosphere and treated with boron tribromide (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 was quenched by carefully adding methanol. After stirring at room temperature for one hour, the volatiles were evaporated and the residue was treated with ethanol / toluene and evaporated a second time. The yellow residue was triturated with boiling ethanol and filtered still warm to give the title product as a yellow solid (0.102 g, 69%), mp. 280-282 ° C.

Example 2

3-Nitro-5- [3- (1-hydroxy-pyridin-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 dimethylformamide (5 ml) at room temperature was added 1,1-carbonyldiimidazole (0.174 g, 1.073 mmol) at a time. The resulting mixture was stirred for ninety minutes, after which 1-N'-hydroxypyridin-3-carboximidamide oxide (0.156 g, 1.022 mmol) was added at a time. The resulting mixture was stirred at room temperature for two hours, then at 75 ° C. overnight. After cooling to room temperature, the mixture was poured into water (100 ml) and the precipitate was filtered off, washed with water, then dried in air and recrystallized from diethyl ether. 3- [5- (3,4-Dimethoxy-5-nitrophenyl) - [1,2,4] oxadiazol-3-yl] pyridine 1-oxide was obtained as a white solid (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 under argon was added boron tribromide dropwise (0.445 g, 1.799 mmol). The reaction mixture was warmed to room temperature and stirred for ninety minutes before being carefully poured 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 (Na ₂ SO ₄ ), filtered and evaporated. 2-Methoxy-3-nitro-5- [3- (1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] phenol was obtained as a yellow solid (0.12 g, 82%).

c) A stirred suspension of the above methyl ester (0.108 g, 0.327 mmol) in 1,2-dichloroethane (10 ml) was treated with aluminum chloride (0.087 g, 0.654 mmol) at room temperature under argon, then pyridine (0.207 g, 2.62) mmol) dropwise. The mixture was then heated under reflux for seven hours, after which more aluminum chloride (0.087 g, 0.654 mmol) and pyridine (0.207 g, 2.62 mmol) were added and the mixture was stirred under 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 off, washed with water and dried at 50 ° C in vacuo. The desired product was obtained as an orange solid (0.075 g, 72%), mp 278-280 ° C.

Example 3

3-Nitro-5- [3- (1-hydroxy-pyridin-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) was added 1,1-carbonyldiimidazole (0.821 g, 5.06 mmol) at room temperature at once. The resulting yellow mixture was stirred for ninety minutes, after which 1-N'-hydroxypyridin-2-carboximidamide oxide (0.775 g, 5.06 mmol) was added at a time. The resulting mixture was stirred at room temperature overnight and then poured into water (100 ml). The resulting precipitate was filtered off, washed with water and then transferred to dichloromethane (30 ml). The organic layer was washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated to a white solid (1.37 g, 86%).

b) To a stirred suspension of the solid obtained above (1.355 g, 3.77 mmol) in tetrahydrofuran (14 ml) at room temperature in an argon atmosphere was added a 1N 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 which time a new precipitate formed. The mixture was filtered and the solid was washed with several parts of cold tetrahydrofuran. 2- [5- [3,4-Dimethoxy-5-nitrophenyl) - [1,2,4] oxadiazol-3-yl] pyridine 1-oxide was obtained as a white solid (0.97 g, 75 %).

c) Boron tribromide (3.5 g, 13.97 mmol) was added dropwise to a stirred suspension of the above dimethyl ether (0.961 g, 2.79 mmol) in dichloromethane (15 ml) at -78 ° C under argon atmosphere. The resulting purple suspension was then stirred at room temperature for seven hours before being cooled in an ice water bath. The mixture was carefully quenched by the addition of methanol. The resulting yellow mixture was stirred at room temperature for one hour, after which the precipitate was filtered off and washed with methanol. The solid was triturated with boiling ethanol and filtered while still warm. After drying, the desired compound was obtained as an orange solid (0.712 g, 81%), mp. 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) was added 1,1-carbonyldiimidazole at room temperature ( 0.494 g, 3.048 mmol) at a time and the mixture was stirred at room temperature for ninety minutes. After this, 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 water (100 ml). Saline (10 ml) was added and the resulting precipitate was removed during filtration, washed with water and dried in air. The solid was then dissolved in dichloromethane (20 ml) and activated carbon was added at the tip of the spatula. After stirring for twenty minutes, the suspension was filtered through celite and the filtrate was evaporated, yielding a yellow oil, which solidified on a support. After recrystallization from dichloromethane / petroleum ether, 3- (3,4-bis-benzyloxy-5-nitrophenyl) -5-methyl- [1,2,4] oxadiazole was obtained as a pale yellow solid (0.537 g, 51%) .

b) Boron tribromide (0.318 g, 1.269 mmol) was added dropwise to a stirred solution of the above solid (0.128 g, 0.307 mmol) in dichloromethane (15 ml) at -78 ° C under argon atmosphere. The resulting purple suspension was stirred at room temperature for one hour, then cooled again to -78 ° C. The mixture was quenched by carefully adding methanol, and after stirring at room temperature for one hour, the solvents were evaporated. The yellow residue was triturated with diethyl ether, filtered and dried. The desired compound was obtained as a yellow solid (0.070 g, 96%), mp. 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, 1.93 mmol) in tetrahydrofuran (10 ml) was added 1,1-carbonyldiimidazole (0.343 g, 2.12 mmol) at room temperature in one once and the mixture was stirred at room temperature for one hour, then at 70 ° C for two hours, after which acetic acid hydrazide (0.157 g, 2.12 mmol) was added. 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 was filtered off and washed with water. 3,4-Dimethoxy-5-nitro-benzoic acid N'-acetyl hydrazide was obtained as a white solid (0.296 g, 54%).

b) A suspension of the solid obtained above (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. It was extracted with dichloromethane and the organic extracts washed with water and brine, then dried, filtered and evaporated to give a white solid. Recrystallization from dichloromethane / petroleum ether gave 2- (3,4-dimethoxy-5-nitro-phenyl) -5-methyl- [1,3,4] oxadiazole as white crystals (0.151 g, 56%).

c) Boron tribromide (0.685 g, 2.74 mmol) was added dropwise to a stirred solution of the solid obtained above (0.145 g, 0.547 mmol) in dichloromethane (10 ml) at -78 ° C under argon atmosphere. The resulting purple suspension was stirred at room temperature overnight, then again cooled to -78 ° C. The reaction was quenched by the addition of methanol, and after stirring at room temperature for one hour, the volatiles were evaporated. Toluene (20 ml) was added to the residue and evaporated a second time. The residue was triturated with boiling ethanol and filtered still warm, obtaining the desired product as an orange solid (0.107 g, 82%), mp 245-246 ° C.

Example 6

5- [3- (3,5-Dichloro-1-hydroxy-pyridin-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-dibenzyloxy-5-nitrobenzoic acid (0.50 g, 1.32 mmol) in dimethylformamide (5 ml) was added 1,1-carbonyldiimidazole (0.246 g, 1.52 mmol) at room temperature at one time and the mixture was stirred for ninety minutes, after which 3,5-dichloro-N'-hydroxy-1-hydroxyisonicotinamidine (0.337 g, 1.52 mmol) was added at a time. The resulting mixture was stirred at room temperature overnight and then poured into ice water (100 ml). Saline solution (10 ml) was added and the precipitate was filtered off, washed with water and dissolved in 30% isopropanol / dichloromethane. Then dichloromethane was distilled off and the resulting isopropanol suspension was left at 0 ° C for one hour. The solid was then filtered off, washed with cold isopropanol and dried, yielding a white solid (0.756 g, 98%).

b) A portion of this solid (0.664 g, 1.14 mmol) and 1,1-carbonyldiimidazole (0.185 g, 1.14 mmol) was dissolved in dimethylformamide (10 ml) and stirred at 100 ° C for nine hours, then at room temperature all night. The resulting mixture was poured into ice water (100 ml) and then acidified to pH 1-2, 2N hydrochloric acid was added dropwise. The yellow precipitate that formed was filtered off, washed with water and dissolved in 10% isopropanol / dichloromethane (50 ml). The organic phase was dried, filtered and evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate / petroleum ether (1: 1) solvent mixture. The homogeneous fractions were combined and evaporated, and the residue was recrystallized from dichloromethane / isopropanol to give 2-benzyloxy-4- [3- (3,5-dichloro-1-hydroxypyridin-4-yl) - [1,2,4] oxadiazole- 5-yl] -6-nitro-phenol as a yellow solid (0.263 g, 49%).

c) Boron tribromide (0.371 g, 1.5 mmol) was added dropwise to a stirred suspension of the solid obtained above (0.24 g, 0.505 mmol) in dichloromethane (5 ml) at -78 ° C under argon atmosphere. The resulting purple suspension was stirred at room temperature for one hour, then cooled again to −78 ° C. and quenched by the addition of methanol. After stirring at room temperature for one hour, the solvents were removed by evaporation. The resulting yellow foam was recrystallized from dichloromethane / isopropanol to give the desired product as a yellow solid (0.153 g, 79%), mp. 252-253 ° C.

Example 7

5- [3- (2-Chloro-1-hydroxy-pyridin-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-dibenzyloxy-5-nitrobenzoic acid (0.50 g, 1.32 mmol) in dimethylformamide (5 ml) was added 1,1-carbonyldiimidazole (0.246 g, 1.52 mmol) at room temperature at one time and the mixture was stirred for one hour, after which 2-chloro-N'-hydroxy-1-hydroxy-isonicotinamidine (0.284 g, 1.52 mmol) was added at a time. The resulting mixture was stirred at room temperature for thirty minutes, 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, 2 N hydrochloric acid was added dropwise. The mixture was extracted with ethyl acetate and the organic extracts washed with water and brine, then dried, filtered and evaporated to an orange solid, which was recrystallized from dichloromethane / isopropanol to give 4- [5- (3,4-bis-benzyloxy-5-) 1-oxide nitro-phenyl) - [1,2,4] oxadiazol-3-yl] -2-chloro-pyridine in the form of pale orange crystals (0.265 g, 38%).

b) To a stirred solution of the above solid (0.25 g, 0.471 mmol) in dichloromethane (5 ml) at -78 ° C in an argon atmosphere was added boron tribromide (0.59 g, 2.36 mmol) dropwise. The resulting dark purple suspension was stirred at room temperature for one hour, then cooled again to -78 ° C. The reaction was quenched by the addition of methanol, and after stirring at room temperature for one hour, the solvents were removed by evaporation. Ethanol (5 ml) and toluene (20 ml) were added to the residue and evaporated a second time. The residue was triturated with boiling ethanol and filtered still warm, obtaining the desired product as yellow crystals (0.12 g, 72%), which decomposed above 300 ° C.

Example 8

2,5-Dichloro-3- (5- (3,4-dihydroxy-2-nitrophenyl) -1,2,4-oxadiazol-3-yl) -4,6-dimethylpyridine 1-oxide

a) To a stirred suspension of 3-hydroxy-4-methoxy-2-nitrobenzoic acid (0.900 g, 4.22 mmol) in N, N-dimethylacetamide (10.35 ml) 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-dimethylnicotinimidamide (1.19 g, 5.107 mmol) was added to 2.7 ml of N, N-dimethylacetamide at a time. The resulting mixture was stirred for one hour and forty-five minutes, then heated at 135 ° C. for one hour. The reaction mixture was poured into a mixture of ice with 2 N HCl. The precipitate was filtered off, washed with water and dried in vacuo to give 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 to as a yellow solid (0.317 g, 18%).

b) To a stirred suspension of the above solid (0.315 g, 0.766 mmol) in dichloromethane (4.3 ml), a urea and hydrogen peroxide addition complex (0.231 g, 2.451 mmol) was added at room temperature. The resulting suspension was cooled to 0 ° C. and trifluoroacetic anhydride (0.483 g, 2.30 mmol) was added dropwise. The mixture was stirred at room temperature for twenty-four hours, then water was added and stirred for one hour. The precipitate was filtered off, washed with water and dried. The crude product was chromatographed in dichloromethane / methanol (99: 1). Evaporation of the pure fractions afforded 2,5-dichloro-3- (5- (3-hydroxy-4-methoxy-2-nitrophenyl) -1,2,4-oxadiazol-3-yl) -4,6-dimethylpyridine 1-oxide as yellow crystals (0.195 g, 59%).

c) To a stirred suspension of the above solid (0.143 g, 0.335 mmol) in N-methylpyrrolidone (2.5 ml) at 0 ° C in argon atmosphere was added aluminum chloride (0.056 g, 0.42 mmol) at a time, after which was added pyridine (0.106 g, 1.34 mmol). The resulting solution was heated at 60 ° C for twenty-five minutes, then again cooled to room temperature and poured into a mixture of ice with 2 N HCl. After stirring at room temperature for forty-five minutes, the precipitate was filtered off, washed with water and dried under vacuum. The crude product was recrystallized from a mixture of dichloromethane / isopropanol. After drying, the desired compound was obtained as yellow crystals (0.101 g, 73%), mp. 230 ° C (decomp.).

Example 9-17

Using the above method and related procedures known to a person skilled in the art and using the corresponding N-hydroxy-1-hydroxy-isonicotinamidines, the following compounds were prepared:

3-nitro-5- [3- (1-hydroxy-2-phenyl-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] benzene-1,2-diol, mp . 264-264.8 ° C (compound 9, table 1);

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

5- [3- (2-morpholin-4-yl-1-hydroxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol , mp 277-280 ° C (compound 11, table 1);

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

5- [3- (2,6-dimethyl-1-hydroxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, t .pl. 280-282 ° C (compound 15, table 1);

5- [3- (2-methanesulfonyl-1-hydroxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, mp . 282-285 ° C (compound 16, table 1);

5- [3- (2-methylsulfanyl-1-hydroxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, mp . 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 (compound 18, Table 1)

a) To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.291 g, 0.769 mmol) in dimethylformamide (5 ml) was added 1,1-carbonyldiimidazole (0.131 g, 0.808 mmol) at a time. After stirring for ninety minutes, N'-hydroxy-1-hydroxy-4-trifluoromethyl-nicotinamidine (0.17 g, 0.769 mmol) was added at a time. The resulting mixture was stirred for two hours and then poured into ice water (100 ml). The precipitate was filtered off, washed with water and dried in air to give a white solid (0.192 g, 43%).

b) To a stirred solution of the above solid (0.192 g, 0.33 mmol) in tetrahydrofuran (10 ml) at room temperature in an argon atmosphere was added dropwise a 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 extracted with dichloromethane. The organic extracts were washed with water and brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was chromatographed on silica gel using a dichloromethane / methanol (99: 1) solvent mixture as eluent. The homogeneous fractions were combined and evaporated, and the residue was then recrystallized from dichloromethane / isopropanol. 3- [5- (3,4-bis-benzyloxy-5-nitro-phenyl) - [1,2,4] oxadiazol-3-yl] -4-trifluoromethyl-pyridine 1-oxide was obtained as a white solid ( 0.092 g, 49%).

c) To a stirred solution of the above solid (0.09 g, 0.16 mmol) in dichloromethane (5 ml) at -78 ° C under argon atmosphere was added boron tribromide (0.16 g, 0.64 mmol) dropwise . The resulting purple suspension was stirred at room temperature for one hour, then cooled again to -78 ° C and quenched carefully by adding methanol. After stirring at room temperature for one hour, the precipitate was filtered off, washed with water and dried at 50 ° C in vacuo to give the desired compound as yellow crystals (0.048 g, 79%), mp 239-240 ° C.

Example 19-35

Using the above method and related procedures known to a person skilled in the art, and using the corresponding N'-hydroxy-1-hydroxy-isonicotinamidines, the following compounds were prepared:

5- [3- (5-bromo-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, mp . 258-260 ° C (compound 19, table 1);

5- [3- (6-methyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, mp . 325-326 ° C (compound 20, table 1);

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

5- [3- (6-chloro-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, mp . 268-270 ° C (compound 23, table 1);

5- [3- (2-chloro-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, mp . 265-267 ° C (compound 24, table 1);

5- [3- (2-chloro-6-methyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol , mp 218-220 ° C (compound 25, table 1);

5- [3- (2-morpholin-4-yl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol , mp 175-177 ° C (compound 26, table 1);

5- [3- (6-methylsulfanyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, mp . 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, mp . 269.5-271.3 ° C (compound 28, table 1);

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

3-nitro-5- [3- (1-hydroxy-quinolin-4-yl) - [1,2,4] oxadiazol-5-yl] benzene-1,2-diol, m.p. 306-307 ° C (compound 34, table 1);

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

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

Example 36

5- [3- (2-Bromo-6-methyl-1-hydroxy-pyridin-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-dibenzyloxy-5-nitrobenzoic acid (1.355 g, 3.576 mmol) in dimethylformamide (10 ml) was added 1,1-carbonyldiimidazole (0.667 g, 4.113 mmol) at a time. After stirring for ninety minutes, 2-bromo-N'-hydroxy-6-methylnicotinamidine (0.946 g, 4.113 mmol) was added and the mixture was stirred overnight, then poured into water (100 ml). Salt solution (10 ml) was added and the precipitate was filtered off, washed with water and dissolved in dichloromethane (50 ml). The organic layer was washed with water and brine, then dried (Na ₂ SO ₄ ), filtered and evaporated to a white foam (1.91 g, 90%).

b) To a solution of the above solid (1.91 g, 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. It was poured into ice water (150 ml) and acidified to pH 1-2, dropwise adding 2 N hydrochloric acid. The mixture was extracted with dichloromethane and the organic extracts washed with water and brine, then dried (Na ₂ SO ₄ ), filtered and evaporated to an orange solid. Recrystallization from dichloromethane / ethanol gave 3- [5- (3,4-bis-benzyloxy-5-nitrophenyl) - [1,2,4] oxadiazol-3-yl] -2-bromo-6-methyl-pyridine as an orange solid (0.702 g, 38%).

c) To a stirred solution of the above solid (0.609 g, 1.063 mmol) in dichloromethane (15 ml), an addition complex of urea and hydrogen peroxide (0.525 g, 5.579 mmol) was added at room temperature. The resulting suspension was cooled to 0 ° C and trifluoroacetic anhydride (1.12 g, 5.314 mmol) was added dropwise. The mixture was stirred at room temperature for five hours, then the insoluble product was filtered off and washed with a small volume of dichloromethane. The combined filtrate was stirred with a 10% aqueous sodium metabisulfite solution (10 ml) for fifteen minutes until the excess peroxides was destroyed, then the phases were separated. The organic phase was washed with water, saturated aqueous sodium bicarbonate, again with water and brine, then dried (Na ₂ SO ₄ ), filtered and evaporated to a white solid. Recrystallization twice from dichloromethane / ethanol afforded 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%).

d) To a stirred solution of the above solid (0.337 g, 0.572 mmol) in dichloromethane (10 ml) at -78 ° C under argon atmosphere was added boron tribromide (0.717 g, 2.86 mmol) dropwise. The resulting purple suspension was stirred at room temperature for one hour, then cooled again to −78 ° C. and quenched by the addition of methanol. After stirring at room temperature for one hour, the solvents were evaporated. Ethanol (5 ml) and toluene (20 ml) were added to the residue and evaporated a second time. The residue was stirred in boiling ethanol and filtered still warm. After drying, the desired compound was obtained as orange crystals (0.187 g, 80%), mp. 246-247 ° C.

Example 37-41

Using the above method and related procedures known to a person skilled in the art and using the appropriate N'-hydroxy-nicotinamidines, the following compounds were prepared:

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

5- [3- (2-bromo-4,6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2 -diol, so pl. 205-207 ° C (compound 38, table 1);

3-nitro-5- [3- (1'-hydroxy-pyridin-3-ylmethyl) - [1,2,4] oxadiazol-5-yl] benzenediol, m.p. 232 ° C (compound 39, table 1);

3-nitro-5- [3- (1'-hydroxy-6-trifluoromethyl-pyridin-3-ylmethyl) - [1,2,4] oxadiazol-5-yl] benzene-1,2-diol, t. pl. 195.2 ° C (compound 43, table 1);

3-nitro-5- [3- (1'-hydroxy-5-trifluoromethyl-pyridin-2-yloxymethyl) - [1,2,4] oxadiazol-5-yl] benzene-1,2-diol, t. pl. 222 ° C (compound 44, table 1).

Example 42

5- [3- (2-Bromo-4,5,6-trimethyl-1-hydroxy-pyridin-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-dibenzyloxy-5-nitrobenzoic acid (0.945 g, 2.49 mmol) in dimethylformamide (10 ml) was added at room temperature 1,1-carbonyldiimidazole (0.465 g, 2.87 mmol) in one times and the resulting mixture was stirred for two hours, after which 2-bromo-N'-hydroxy-4,5,6-trimethyl-nicotinamidine (0.74 g, 2.87 mmol) was added at a time. The resulting mixture was stirred at room temperature overnight and then poured into water (150 ml). Salt solution (10 ml) was added and the resulting precipitate was filtered off and washed with water. The solid was then dissolved in dichloromethane (50 ml) and the organic phase was washed with water and brine, then dried, filtered and evaporated to an off-white solid (1.40 g, 91%).

b) To a stirred solution of the above solid (1.39 g, 2.245 mmol) in tetrahydrofuran (20 ml) at room temperature in an argon atmosphere was added a 1N solution of tetrabutylammonium fluoride in tetrahydrofuran (2.47 ml, 2.47 mmol). After stirring at room temperature overnight, the almost black reaction mixture was poured into water (150 ml) and extracted with dichloromethane. The organic extracts were washed with water and brine, then dried, filtered and evaporated to a brown oil. The addition of dichloromethane (4 ml) and diethyl ether (4 ml) led to 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 in as a beige solid (0.879 g, 65%).

c) To a stirred solution of the pyridine obtained above (0.621 g, 1.033 mmol) in dichloromethane (20 ml) at room temperature was added a urea complex with hydrogen peroxide (1.018 g, 10.82 mmol) at a time. The resulting suspension was cooled in an ice-water bath and trifluoroacetic anhydride (2.23 g, 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 off and washed with a small volume of dichloromethane. The combined filtrate was stirred with a 10% aqueous sodium metabisulfite solution for fifteen minutes and then the phases were separated. The organic phase was washed with water, saturated aqueous sodium bicarbonate, again with water and brine, then dried, filtered and evaporated to a foamy pale orange solid. This solid was chromatographed on silica gel using a mixture of petroleum ether / ethyl acetate (1: 1) as eluent. The homogeneous product containing 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 a foamy pale yellow solid (0.342 g, 54%).

d) To a stirred solution of the above solid (0.325 g, 0.527 mmol) in dichloromethane (10 ml) at -78 ° C under argon atmosphere was added boron tribromide (0.66 g, 2.633 mmol) dropwise. The resulting dark purple suspension was stirred at room temperature for one hour, then cooled again to −78 ° C. and carefully quenched, adding methanol dropwise. After stirring at room temperature for one hour, the solvents were removed by evaporation. Toluene (20 ml) and ethanol (5 ml) were added to the residue and evaporated a second time. The resulting yellow solid was triturated with boiling ethanol (15 ml) and filtered while still warm. The desired product was obtained as a yellow solid (0.172 g, 75%), mp. 242-243 ° C.

Example 43-46

Using the above method and related procedures known to a person skilled in the art, and using the corresponding N'-hydroxy-nicotinamidine, the following compounds were prepared:

5- [3- (2-chloro-4,5,6-trimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-1,2 -diol, so pl. 246-247.3 ° C (compound 41, table 1);

5- [3- (2,5-dichloro-4,6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-1,2 -diol, so pl. 237-240 ° C (compound 45, table 1);

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

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

Example 47

As an example, a compound of general formula (I) having a 2H-pyrazol-1,5-diyl fragment as a central portion, 3-nitro-5- [2- (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -2H-pyrazol-3-yl] benzene-1,2-diol was prepared according to the following procedure:

a) To a stirred solution of 1- (3,4-dimethoxy-5-nitro-phenyl) -3-dimethylamino-prop-2-en-1-one (0.5 g, 1.79 mmol) and (2-trifluoromethyl -pyridin-3-yl) -hydrazine (0.33 g, 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 off, washed with ethanol and dried to give 3- [5- (3,4-dimethoxy-5-nitro-phenyl) -pyrazol-1-yl] -2-trifluoromethyl-pyridine, 0.58 g (82%).

b) To a solution of 3- [5- (3,4-dimethoxy-5-nitro-phenyl) -pyrazol-1-yl] -2-trifluoromethyl-pyridine (0.50 g, 1.27 mmol) in dichloromethane (10 ml), cooled in an ice water bath, a complex of urea with hydrogen peroxide (0.26 g, 2.76 mmol) was added at a time, then trifluoroacetic anhydride (0.53 g, 2.52 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight, and then the insoluble product was filtered off. The filtrate was washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated to an off-white solid. Recrystallization from ethanol gave 3- [5- (3,4-dimethoxy-5-nitro-phenyl) -pyrazol-1-yl] -2-trifluoromethyl-pyridine 1-oxide, 0.34 g (65%).

c) A suspension of 1- oxide of 3- [5- (3,4-dimethoxy-5-nitro-phenyl) -pyrazol-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 off, washed with water and dried, obtaining 3-nitro-5- [2- (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -2Н pyrazol-3-yl] benzene-1,2-diol, 0.16 g (57%).

Example 48

As an example, a compound of general formula (I) having a 1,3,4-oxadiazole-2,5-diyl fragment as a central portion, 3-nitro-5- [5- (1-hydroxy-2-trifluoromethyl-pyridine- 3-yl) - [1,3,4] oxadiazol-2-yl] benzene-1,2-diol was prepared according to the following procedure:

a) A mixture of 3,4-dimethoxy-5-nitrobenzoic acid (0.53 g, 2.34 mmol) and 1,1-carbonyldiimidazole (0.42 g, 2.59 mmol) was heated in tetrahydrofuran (10 ml) with reverse refrigerator for three hours and then cooled to room temperature. 2-trifluoromethyl-nicotinic acid hydrazide (0.53 g, 2.57 mmol) was added at a time, and the yellowish mixture was stirred under reflux overnight and then cooled to room temperature. The mixture was poured into cold water (100 ml) and a copious precipitate was filtered off, washed with water and dried, yielding 2-trifluoromethyl-nicotinic acid N '- (3,4-dimethoxy-5-nitro-benzoyl) -hydrazide, 0.71 g ( 73%).

b) A suspension of 2'-trifluoromethyl-nicotinic acid N'-3,4-dimethoxy-5-nitro-benzoyl) hydrazide (0.60 g, 1.44 mmol) in phosphorus oxychloride (10 ml) was stirred at 130 ° C. for three hours, receiving a pale yellow solution. The mixture was cooled to room temperature and then poured into ice water (200 ml). The white precipitate was filtered off, washed with water and dried, yielding 3- [5- (3,4-dimethoxy-5-nitrophenyl) - [1,3,4] oxadiazol-2-yl] -2-trifluoromethyl-pyridine, 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 an ice-water bath, a urea complex with hydrogen peroxide (0.23 g, 2.45 mmol) was added at a time, then trifluoroacetic anhydride (0.47 g, 2, 24 mmol) dropwise. The resulting mixture was stirred at room temperature overnight, and then the insoluble product was filtered off. The filtrate was washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated to an off-white solid. Recrystallization from ethanol afforded 1- oxide 3- [5- (3,4-dimethoxy-5-nitrophenyl) - [1,3,4] oxadiazol-2-yl] -2-trifluoromethyl-pyridine, 0.39 g (83%).

g) Suspension of 1- oxide 3- [5- (3,4-dimethoxy-5-nitrophenyl) - [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% hydrogen bromide 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 was recrystallized from isopropanol to give 3-nitro-5- [5- (1-hydroxy-2-trifluoromethyl-pyridin-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, a compound of general formula (I) having a pyrimidin-2,4-diyl fragment as a central portion, 3-nitro-5- [2- (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -pyrimidine -4-yl] benzene-1,2-diol was prepared according to the following procedure:

a) A stirred suspension of 1- (3,4-dimethoxy-5-nitro-phenyl) -3-dimethylamino-prop-2-en-1-one (0.28 g, 1.0 mmol), 1-hydroxy-2 trifluoromethyl-nicotinamidine (0.31 g, 1.5 mmol) and potassium tert-butoxide (0.17 g, 1.5 mmol) in absolute ethanol (5 ml) were heated at 80 ° C in a closed 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 off, washed with water and dried to give 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-pyridin-3-yl) -pyrimidine (0.25 g, 0.59 mmol) 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 off, washed with water and dried to give 3-nitro-5- [2- (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -pyrimidin-4 -yl] -benzene-1,2-diol, 0.21 g (90%).

Example 50

As an example, a compound of general formula (I) having a benzene-1,3-diyl fragment as a central portion, 5-nitro-3 '- (1-hydroxy-6-trifluoromethyl-pyridin-2-yl) biphenyl-3 , 4-diol was prepared according to the following procedure:

a) To a stirred solution of 4-benzyloxy-3-methoxyphenylboronic acid (1.0 g, 3.87 mmol) and 2- (3-bromo-phenyl) -6-trifluoromethyl-pyridine 1-oxide (1.12 g, 3 , 52 mmol) in toluene (10 ml) and ethanol (1 ml) at room temperature in an argon atmosphere was added a 2 N aqueous solution of sodium carbonate (5.41 ml, 10.82 mmol), 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 were washed with water and brine, then dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent gave a brown oil, which was chromatographed on silica gel (petroleum ether / ethyl acetate, 9: 1) to give 2- (4'-benzyloxy-3'-methoxybiphenyl-3-yl) -6-trifluoromethyl-pyridine 1-oxide as clear oil, 1.11 g (70%).

b) To a solution of 2- (4'-benzyloxy-3'-methoxybiphenyl-3-yl) -6-trifluoromethyl-pyridine 1-oxide (1.10 g, 2.44 mmol) in dichloromethane (20 ml), cooled in an ice water bath, a 30% solution of hydrogen bromide in acetic acid (4 ml, 20 mmol) was added dropwise. The resulting solution was stirred at room temperature for six hours, then poured into ice 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 the solvent gave a brown oil, which was chromatographed 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, 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, 60% nitric acid (0.12 ml, 1.52 mmol) was added dropwise. The resulting mixture was stirred for thirty minutes, then poured into ice water (100 ml) and the resulting precipitate was filtered off, washed with water and dried. Chromatography 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 yellow solid, 0.34 g (60%).

d) 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 an ice-water bath, aluminum chloride (0.123 g, 0.922 mmol) was added at a time, then pyridine (0.233 g, 2.95 mmol) was added 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 off, washed with water and dried, yielding 5-nitro-3 '- (1-hydroxy-6-trifluoromethyl-pyridin-2-yl) biphenyl-3,4-diol, 0.17 g (59%).

Example 51

As an example of a compound of general formula (I) having a carbonyl fragment as a central part, (3,4-dihydroxy-5-nitro-phenyl) - (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -methanone was obtained during the following procedure:

a) To a solution of 4-benzyloxy-3-methoxy-bromobenzene (2.0 g, 6.82 mmol) in tetrahydrofuran (50 ml) at -78 ° C under argon atmosphere was added a 2 n solution of butyllithium in hexanes (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 was then brought to room temperature over two hours, then poured into cold 2 N aqueous hydrochloric acid (150 ml). The mixture was extracted with diethyl ether, the combined organics were washed with water and brine, dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent gave a brown oil, which was chromatographed on silica gel (petroleum ether / ethyl acetate, 2: 1) to obtain (4-benzyloxy-3-methoxy-phenyl) - (2-trifluoromethyl-pyridin-3-yl) -methanone, 1, 72 g (65%).

b) To a stirred solution of (4-benzyloxy-3-methoxy-phenyl) - (2-trifluoromethyl-pyridin-3-yl) -methanone (1.60 g, 4.13 mmol) in dichloromethane (20 ml), cooled In an ice water bath, a complex of urea with hydrogen peroxide (0.85 g, 9.08 mmol) was added at a time, then trifluoroacetic anhydride (1.73 g, 8.26 mmol) was added dropwise. The resulting mixture was then stirred at room temperature overnight, after which the insoluble product was filtered off 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 to give (4-benzyloxy-3-methoxy-phenyl) - (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -methanone, 1.0 g (60% )

c) To a stirred solution of (4-benzyloxy-3-methoxy-phenyl) - (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -methanone (0.95 g, 2.36 mmol) in dichloromethane, cooled on A bath of ice water, a 30% solution of hydrogen bromide in acetic acid (3.54 ml, 17.7 mmol) was added dropwise. The resulting solution was stirred at room temperature overnight, then poured into ice 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 the solvent gave a brown oil, which was chromatographed on silica gel (petroleum ether / ethyl acetate, 1: 1) to give (4-hydroxy-3-methoxy-phenyl) - (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) - methanone as a colorless solid, 0.59 g (80%).

d) To a solution of (4-hydroxy-3-methoxy-phenyl) - (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -methanone (0.50 g, 1.59 mmol) in acetic acid (10 ml ) 60% nitric acid (0.14 ml, 1.75 mmol) was added dropwise at room temperature. The resulting mixture was stirred for thirty minutes, then poured into ice water (100 ml) and the resulting precipitate was filtered off, washed with water and dried. Recrystallization from ethanol gave (4-hydroxy-3-methoxy-5-nitro-phenyl) - (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -methanone as a yellow solid, 0.33 g (58% )

d) To a stirred solution of (4-hydroxy-3-methoxy-5-nitro-phenyl) - (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) -methanone (0.30 g, 0.84 mmol) in 1,2-dichloroethane (10 ml), cooled in an ice water bath, was added aluminum chloride (0.14 g, 1.05 mmol) at a time, then pyridine (0.26 g, 3.35 mmol) was added 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 off, washed with water and dried, yielding (3,4-dihydroxy-5-nitro-phenyl) - (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) methanone, 0.19 g (66%).

Example 52

As an example, a compound of general formula (I) having a (Z) -1-cyanoethen-1,2-diyl fragment as a central portion, 3- (3,4-dihydroxy-5-nitro-phenyl) -2- (1 -oxy-6-trifluoromethyl-pyridin-3-yl) acrylonitrile was obtained during the following procedure:

a) Suspension of vanillin (1.0 g, 6.57 mmol), (1-hydroxy-6-trifluoromethyl-pyridin-3-yl) -acetonitrile (1.33 g, 6.57 mmol) and piperidine (0.71 ml, 7.23 mmol) in absolute ethanol (10 ml) was stirred under reflux for forty-eight hours and then cooled to room temperature. The resulting precipitate was filtered off, washed with water and dried. Recrystallization from isopropanol gave 3- (4-hydroxy-3-methoxy-phenyl) -2- (1-hydroxy-6-trifluoromethyl-pyridin-3-yl) -acrylonitrile as 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 water (100 ml). The yellow precipitate was filtered off, 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 an ice water bath, aluminum chloride (0.24 g, 1.80 mmol) was added at a time, 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 off, washed with water and dried, yielding 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, a compound of general formula (I) having a 1H-imidazole-1,5-diyl fragment as a central moiety, 1- oxide 2- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-imidazole- 1-yl) -5- (trifluoromethyl) pyridine was obtained during the following procedure:

a) To a stirred solution of 1-oxide 2-amino-5- (trifluoromethyl) pyridine (0.445 g, 2.5 mmol) in a mixture of ethanol (12.5 ml) and acetic acid (0.25 ml) was added at room temperature 3 , 4-dimethoxy-5-nitrobenzaldehyde (0.53 g, 2.5 mmol). The reaction mixture was heated at reflux for two hours, then ethanol was evaporated. The oily residue was dissolved in a mixture of methanol (17 ml) and 1,2-dimethoxyethane (7.5 ml), followed by 1- (isocyanomethylsulfonyl) -4-methylbenzene (TOSMIC) (0.73 g, 3.75 mmol) and carbonate potassium (0.69 g, 5 mmol) was added at a time. The resulting mixture was stirred at reflux for 3 hours. The reaction mixture was evaporated to dryness and then transferred to dichloromethane (50 ml). The organic phase was washed with water (50 ml) and then dried over anhydrous magnesium sulfate, filtered and evaporated to a brown oil. Silica gel column chromatography (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 hydrogen bromide (6 ml) for 2.5 hours. The dark homogeneous solution was cooled to room temperature and the volatiles were removed by evaporation to a pale brown crystalline solid, which was dried over P ₂ O ₅ in vacuo. Trituration of 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 substances, 0.27 g (71%).

Example 54

As an example, a compound of general formula (I) having an isoxazol-3,5-diyl fragment as a central moiety, 1- 3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) - 2- (trifluoromethyl) pyridine was obtained during 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 ml) was added a 50% aqueous hydroxylamine solution (0.74 ml, 4.5 mmol) and the mixture was heated to 80 ° C. After stirring for 1 hour, the fine precipitate began to separate from the reaction mixture. After cooling to room temperature, the yellow precipitate was filtered off, washed with ethanol and dried in vacuo to give 1- 3- (3- (3,4-dimethoxy-5-nitrophenyl) -5-hydroxy-4,5-dihydroisoxazol-5-yl oxide ) -2- (trifluoromethyl) pyridine, 0.94 g (73%).

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

c) 3- (3- (3,4-dimethoxy-5-nitrophenyl) isoxazol-5-yl) -2- (trifluoromethyl) pyridine 1-oxide (0.81 g, 2 mmol) was placed in dichloromethane (15 ml) and the yellowish suspension was cooled to −78 ° C. under argon, after which boron tribromide (4.5 g, 18 mmol) was added dropwise. The reddish reaction mixture was warmed to room temperature and stirred for 18 hours, then carefully poured into ice water (100 ml) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P ₂ O ₅ in vacuo. 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, a compound of general formula (I) having a furan-2,4-diyl fragment as a central portion, 1- 3- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan 1-oxide -2-yl) -2- (trifluoromethyl) pyridine was obtained during the following procedure:

a) To a stirred solution of 3- (3-ethoxy-3-oxopropanoyl) -2- (trifluoromethyl) pyridin-1-oxide (1.39 g, 5 mmol) in pyridine (25 ml) was added 2-bromo-1- ( 3,4-dimethoxy-5-nitrophenyl) ethanone (1.67 g, 5.5 mmol). The reaction mixture was heated to 70 ° C and stirred for 5 hours, then cooled to room temperature and poured into 6 N aqueous HCl (100 ml). The precipitate was filtered off, washed with water and dried over P ₂ O ₅ in vacuo. The solid was recrystallized from dichloromethane / isopropanol to give crude 3- (4- (3,4-dimethoxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2- (trifluoromethyl) pyridine 1-oxide 05 g (43%).

b) 3- (4- (3,4-dimethoxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2- (trifluoromethyl) pyridine 1-oxide (482 mg, 1 mmol) was placed in dichloromethane (8 ml). The yellowish suspension was cooled to −78 ° C. under argon, and boron tribromide (0.85 ml, 9 mmol) was added dropwise. The reddish reaction mixture was warmed to room temperature and stirred for 18 hours, then carefully poured into ice water (100 ml) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P ₂ O ₅ in vacuo. Recrystallization of the solid from ethanol gave 3- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2- (trifluoromethyl) pyridine 1-oxide as a yellow solid, 0.31 g (68%).

Example 56

As an example, a compound of general formula (I) having an oxazol-2,4-diyl fragment as a central portion, 1- oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) - 2- (trifluoromethyl) pyridine was obtained during the following procedure:

a) To a solution of 2- (3,4-dimethoxy-5-nitrophenyl) -2-oxoethyl acetate (4.24 g, 15 mmol) in xylene (30 ml) was added 1-oxide 3-carbamoyl-2- (trifluoromethyl) pyridine (3.40 g, 16.5 mmol) and boron trifluoride etherate (0.18 ml, 15 mmol). The resulting yellow solution was refluxed for 18 hours and then cooled to room temperature. After evaporation of the solvent, the residue was partitioned 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 3- (4- (3,4-dimethoxy-5-nitrophenyl) oxazol-2-yl) -2- (trifluoromethyl) pyridine 1-oxide was obtained by column chromatography on silica gel (petroleum ether / ethyl acetate 2: 1) in as a pale yellow solid, 2.58 g (42%).

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

Example 57

As an example, a compound of general formula (I) having a 1,2,4-triazin-3,5-diyl fragment as a central portion, 3- (5- (3,4-dihydroxy-5-nitrophenyl) - 1-oxide 1,2,4-triazin-3-yl) -2- (trifluoromethyl) pyridine was obtained during the following procedure:

a) To a stirred solution of 1-oxide (Z) -3-carbamohydrazonoyl-2- (trifluoromethyl) pyridine (1.10 g, 5 mmol) in ethanol (30 ml) was added 2- (3,4-dimethoxy-5-nitrophenyl ) -2-oxoacetaldehyde (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. The residue was dissolved in dichloromethane (30 ml) and the organic phase was washed with water and dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was recrystallized from isopropanol to give 3- (5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -2- (trifluoromethyl) pyridine 1-oxide, 1.69 g (80%).

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

Example 58

As an example, a compound of general formula (I) having a 1,3,5-triazine-2,4-diyl fragment as a central portion, 3- (4- (3,4-dihydroxy-5-nitrophenyl) - 1-oxide 1,3,5-triazin-2-yl) -2- (trifluoromethyl) pyridine was obtained during 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 (0.82 g, 4 mmol). The reaction mixture was heated under reflux for 5 hours. Cooled to room temperature and the solvent was removed by evaporation. The residue was then dissolved in a mixture of dichloromethane / isopropanol (50 ml, 70:30) and the organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was recrystallized from ethanol to give 3- (4- (3,4-dimethoxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2- (trifluoromethyl) pyridine 1-oxide, 1.27 g (75%).

b) A portion of 3- (4- (3,4-dimethoxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2- (trifluoromethyl) pyridine 1-oxide (1.269 g, 3 mmol) was placed in dichloromethane (25 ml). The yellowish solution was cooled to −78 ° C. under argon, and boron tribromide (2.55 ml, 27 mmol) was added dropwise. The red reaction mixture was warmed to room temperature and stirred for 18 hours, then carefully poured into ice water (100 ml) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P ₂ O ₅ in vacuo. Recrystallization from dichloromethane-ethanol gave 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2- (trifluoromethyl) pyridine 1-oxide as a yellow solid substances, 1.07 g (90%).

Example 59

As an example of a compound of general formula (I) having a pyrrole-2,5-diyl fragment as a central portion, 5- (3,4-dihydroxy-5-nitrophenyl) -1-methyl-2- (2-trifluoromethyl) ethyl ester -1-hydroxypyridin-3-yl) -1H-pyrrole-3-carboxylic acid was obtained during the following procedure:

a) To a stirred solution of methylamine (0.63 ml, 33% EtOH solution, 5 mmol) in a mixture of ethanol (25 ml) and acetic acid (0.5 ml) was added ethyl ether 3-oxo-3- (1 -oxy-2-trifluoromethyl-pyridin-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 in vacuo. To a solution of the crude product in dimethylformamide (25 ml) was added potassium carbonate (2.07 g, 15 mmol) at a time, then 1- (3,4-bis-benzyloxy-5-nitro-phenyl) -2-bromo-ethanone (2.51 g, 5.50 mmol) and the mixture was then stirred at 100 ° C. As soon as the starting material ceased to be detected by TLC, the reaction mixture was cooled to room temperature and poured into glacial 1N aqueous hydrochloric acid (100 ml). The resulting precipitate was filtered off, washed with water and dried. The residue was chromatographed on silica gel. The homogeneous fractions were combined and evaporated to give 5- (3,4-bis-benzyloxy-5-nitro-phenyl) -1-methyl-2- (2-trifluoromethyl-1-hydroxy-pyridin-3-yl) -1H ethyl ester -pyrrole-3-carboxylic acid, 2.41 g (79%).

b) Ethyl ester solution 5- (3,4-bis-benzyloxy-5-nitro-phenyl) -1-methyl-2- (2-trifluoromethyl-1-hydroxy-pyridin-3-yl) -1H-pyrrole-3 -carboxylic acid (0.2 g, 0.30 mmol) in dichloromethane (10 ml) was cooled to -78 ° C, stirring, and treated in an argon atmosphere with boron tribromide (0.30 g, 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 quenched by carefully adding methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered off, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- (3,4-dihydroxy-5-nitro-phenyl) -1-methyl-2- (1- hydroxy-2-trifluoromethyl-pyridin-3-yl) -1H-pyrrole-3-carboxylic acid as a yellow solid, 0.13 g (93%).

Example 60

As an example, a compound of general formula (I) having a 2H-tetrazol-2,5-diyl fragment as a central portion, 5- [2- (5-trifluoromethyl-1-hydroxy-pyridin-2-yl) -2H-tetrazole -5-yl] -3-nitrobenzene-1,2-diol was obtained during 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 dilute hydrochloric acid. The resulting precipitate was collected, washed with water and dried, yielding 5- (3,4-bis-benzyloxy-5-nitrophenyl) -2H-tetrazole, 0.53 g (87%).

b) 2-Chloro-5-trifluoromethyl-1-hydroxy-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 complete, then diluted with dichloromethane and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to form a crude residue, which was recrystallized from a mixture of dichloromethane / isopropanol to obtain 2- [5- (3,4-bis-benzyloxy-5-nitro-phenyl) -tetrazole -2-yl] -5-trifluoromethyl-1-hydroxy-pyridine, 0.40 g (71%).

c) A solution of 2- [5- (3,4-bis-benzyloxy-5-nitro-phenyl) -tetrazol-2-yl] -5-trifluoromethyl-1-hydroxy-pyridine (0.282 g, 0.5 mmol) in dichloromethane (15 ml) was cooled to -78 ° C, stirring in an argon atmosphere and treated with boron tribromide (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 quenched by carefully adding methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered off, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- [2- (5-trifluoromethyl-1-hydroxy-pyridin-2-yl) -2H-tetrazol-5- yl] -3-nitrobenzene-1,2-diol as a yellow solid, 0.17 g (90%).

Example 61

As an example, a compound of general formula (I) having a 1,3-thiazol-2,4-diyl fragment as a central portion, 5- [2- [2- (trifluoromethyl) -1-hydroxy-pyridin-3-yl] - [1,3] -thiazol-4-yl] -3-nitrobenzene-1,2-diol was obtained during the following procedure:

a) A mixture of 2- (trifluoromethyl) -1-hydroxy-pyridin-3-carbothioamide (0.24 g, 1.10 mmol) and 1- [3,4-bis (benzyloxy) -5-nitrophenyl] -2-bromoethanone (0.50 g, 1.10 mmol) was refluxed 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 off, 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-hydroxy-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-hydroxy-pyridine (0.15 g, 0.26 mmol) in dichloromethane (10 ml) was cooled to -78 ° C and treated in an argon atmosphere with boron tribromide (0.26 g, 1.03 mmol). The resulting dark purple suspension was then stirred at room temperature for one hour, after which it was again cooled to -78 ° C. The mixture was quenched by carefully adding methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered off, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- [2- [2- (trifluoromethyl) -1-hydroxypyridin-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, a compound of general formula (I) having a 1,2,4-triazole-3,5-diyl moiety as a central portion, 5- [4-methyl-5- (2-trifluoromethyl-1-hydroxy-pyridine- 3-yl) -4H- [1,2,4] triazol-3-yl] -3-nitro-benzene-1,2-diol was obtained during the following procedure:

a) Methylamine (1.02 ml, 2.04) was added dropwise 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. mmol, 2 M in THF). The reaction mixture was stirred at room temperature until all starting material disappeared, then diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to form a crude residue, which was recrystallized from a mixture of dichloromethane / isopropanol to obtain 3,4-dimethoxy-N-methyl-5-nitro-benzamide, 0.44 g (89%) .

b) To a stirred suspension of 3,4-dimethoxy-N-methyl-5-nitro-benzamide (0.40 g, 1.66 mmol) in toluene (10 ml) was added phosphorus pentachloride (0.38 g, 1.83 mmol ) parts. Upon completion of the addition, the reaction mixture was heated under reflux until the starting material completely disappeared. Evaporation to dryness led to a crude solid which was washed with diethyl ether to give 3,4-dimethoxy-N-methyl-5-nitro-benzimidoyl chloride, 0.37 g (85%).

c) A mixture of 2-trifluoromethyl-1-hydroxy-3-pyridinecarbonitrile (0.47 g, 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 dilute hydrochloric acid. The resulting precipitate was collected, washed with water and dried, yielding 3- (2H-tetrazol-5-yl) -2-trifluoromethyl-1-hydroxypyridine, 0.52 g (90%).

g) 3,4-Dimethoxy-N-methyl-5-nitro-benzimidoyl chloride (0.26 g, 1.08 mmol) was added to a stirred solution of 3- (2H-tetrazol-5-yl) -2-trifluoromethyl-1- hydroxypyridine (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 at this temperature until the evolution of nitrogen ceased. The mixture was then poured into water (30 ml) and extracted with dichloromethane (25 ml). The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The resulting residue was purified by chromatography to give 3- [5- (3,4-dimethoxy-5-nitro-phenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] -2 trifluoromethyl-1-hydroxy-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] triazol-3-yl] -2-trifluoromethyl-1- hydroxypyridine (0.20 g, 0.47 mmol) in dichloromethane (20 ml) at -78 ° C under argon atmosphere was added boron tribromide (0.47 g, 1.88 mmol) dropwise. The resulting purple suspension was then stirred at room temperature for seven hours, and then cooled in an ice water bath. The mixture was carefully quenched by the addition of methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered off, washed with water (25 ml) and then with cold isopropanol (5 ml) to obtain, after drying, 5- [4-methyl-5- (2-trifluoromethyl-1-hydroxy-pyridin-3-yl) - 4H- [1,2,4] triazol-3-yl] -3-nitro-benzene-1,2-diol as an orange solid, 0.16 g (86%).

Example 63

As an example, a compound of general formula (I) having a 1,2,3-thiadiazole-4,5-diyl fragment as a central portion, 5- [5- (2-trifluoromethyl-1-hydroxy-pyridin-3-yl) - [1,2,3] thiadiazol-4-yl] -3-nitrobenzene-1,2-diol was obtained during the following procedure:

a) Mixture of 1- (3,4-bis-benzyloxy-5-nitro-phenyl) -2- (2-trifluoromethyl-1-hydroxy-pyridin-3-yl) -ethanone (0.50 g, 0.93 mmol ), ethyl carbazate (0.11 g, 1.06 mmol) and para-toluenesulfonic acid (4 mg) in toluene (10 ml) were heated under reflux until the azeotropic distillation of water ceased. The reaction mixture was cooled to room temperature, the solvents were evaporated to dryness and the crude solid was triturated with diethyl ether (15 ml), filtered and dried, yielding N '- [1- (3,4-bis-benzyloxy-5-nitro-phenyl ethyl ester) ) -2- (2-trifluoromethyl-1-hydroxy-pyridin-3-yl) ethylidene] hydrazinecarboxylic 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-hydroxy-pyridin-3-yl) -ethylidene] -hydrazinecarboxylic acid (0.40 g, 0.64 mmol) in thionyl chloride (2 ml) was heated under reflux until the starting material was no longer detected by TLC. Excess solvent was removed and the residue was purified by silica gel chromatography using a mixture of dichloromethane / ethanol as eluent. The homogeneous fractions were combined and evaporated to give 3- [4- (3,4-bis-benzyloxy-5-nitro-phenyl) - [1,2,3] thiadiazol-5-yl] -2-trifluoromethyl-1-hydroxy- pyridine, 0.19 g (51%).

c) A solution of 3- [4- (3,4-bis-benzyloxy-5-nitro-phenyl) - [1,2,3] thiadiazol-5-yl] -2-trifluoromethyl-1-hydroxy-pyridine (0, 15 g, 0.26 mmol) in dichloromethane (10 ml) was cooled to -78 ° C, stirring, and treated in an argon atmosphere with boron tribromide (0.26 g, 1.03 mmol). The resulting dark purple suspension was then stirred at room temperature for one hour, after which it was again cooled to -40 ° C. The mixture was quenched by carefully adding methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered off, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- [5- (2-trifluoromethyl-1-hydroxy-pyridin-3-yl) - [1,2,3 ] thiadiazol-4-yl] -3-nitrobenzene-1,2-diol as a yellow solid, 0.09 g (89%).

Example 64

As an example, a compound of general formula (I) having a 1,2,4-oxadiazole-3,5-diyl moiety as a central portion, 5- [5- [2- (trifluoromethyl) -1-hydroxypyridin-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-trifluoromethylnicotinic acid (0.38 g, 2 mmol) in dimethylformamide (10 ml) was added 1,1-carbonyldiimidazole (0.34 g, 2.10 mmol) at room temperature at a time. The resulting yellow mixture was stirred for ninety minutes, after which 3,4-bis (benzyloxy) -N'-hydroxy-5-nitrobenzamidine (0.79 g, 2 mmol) was added at a time. The resulting mixture was stirred at room temperature for two hours and then poured into water (100 ml). The resulting precipitate was filtered off, washed with water and dried. After recrystallization from dichloromethane / isopropanol 3,4-bis (benzyloxy) -5-nitro-N '- (2-trifluoromethyl) nicotinoyloxy) benzimidamide was obtained as a pale yellow solid, 0.88 g (78%).

b) To a stirred solution of the above solid (0.26 g, 0.46 mmol) in tetrahydrofuran (15 ml) at room temperature in an argon atmosphere was added a 1N 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 off, washed with water and dried. The crude product was chromatographed on silica gel using dichloromethane as the eluent. The homogeneous fractions were combined and evaporated to give 3- [3- [3,4-bis (benzyloxy) -5-nitrophenyl] - [1,2,4] -oxadiazol-5-yl] -2- (trifluoromethyl) pyridine as off-white solid, 0.21 g (82%).

c) To a stirred solution of 3- [3- [3,4-bis (benzyloxy) -5-nitrophenyl] - [1,2,4] -oxadiazol-5-yl] -2- (trifluoromethyl) pyridine (0.33 g, 0.60 mmol) in dichloromethane (6 ml) at 0 ° C, a complex of urea with hydrogen peroxide (0.28 g, 3 mmol) and trifluoroacetic anhydride (0.43 ml, 3.00 mmol) were added. Then the reaction mixture was stirred at room temperature for 60 hours, the solid residues were filtered. The organic phase was then sequentially treated with an aqueous solution of Na ₂ S ₂ O ₅ (0.6 g, 3.45 mmol dissolved in 20 ml of water), 0.4 N hydrochloric acid (20 ml), saturated NaHCO ₃ solution (20 ml) , water (20 ml) and saline (20 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed on silica gel using dichloromethane / ethanol as the eluent. The homogeneous fractions were combined and evaporated and the residue was recrystallized from dichloromethane / isopropanol to give 3- [3- [3,4-bis (benzyloxy) -5-nitrophenyl] - [1,2,4] -oxadiazol-5-yl] -2 - (trifluoromethyl) -1-hydroxy-pyridine as a yellow solid, 0.23 g (68%).

d) Solution of 3- [3- [3,4-bis (benzyloxy) -5-nitrophenyl] - [1,2,4] -oxadiazol-5-yl] -2- (trifluoromethyl) -1-hydroxypyridine ( 0.10 g, 0.18 mmol) in dichloromethane (5 ml) was cooled to -78 ° C, stirring in an argon atmosphere and treated with boron tribromide (0.18 g, 0.74 mmol) dropwise. The resulting dark purple suspension was then stirred at room temperature for one hour, after which it was again cooled to -78 ° C. The mixture was quenched by carefully adding methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for thirty minutes. The resulting solid was filtered off, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- [5- [2- (trifluoromethyl) -1-hydroxypyridin-3-yl] - [1,2,4 ] -oxadiazol-3-yl] -3-nitrobenzene-1,2-diol as a yellow solid, 0.06 g (88%).

Claims (25)

1. The compound of formula (I):

where R ₁ and R ₂ represent hydrogen or a group that hydrolyzes under physiological conditions, optionally 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; R ₃ represents a pyridine N-oxide group according to formula A, B or C, which is attached as shown by an unlabeled bond:

where R ₄ , R ₅ , R ₆ and R ₇ independently represent aryl, heterocycle, hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylthio, C ₆ -C ₁₂ aryloxy or C ₆ A C ₁₂ arylthio group, a C ₁ -C ₆ alkylsulfonyl or a C ₆ -C ₁₂ arylsulfonyl, halogen, a C ₁ -C ₆ haloalkyl, trifluoromethyl or heteroaryl group; or where two or more taken together, the residues R ₄ , R ₅ , R ₆ and R ₇ represent an aromatic ring, and where P represents a central part, preferably selected from the regioisomers of 1,3,4-oxadiazole-2,5-diyl, 1,2,4-oxadiazole-3,5-diyl, 4-methyl-4H-1,2,4-triazole-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-thiadiazole-4,5-diyl, 1-alkyl-3- (alkoxycarbonyl) -1H-pyrrole- 2,5-diyl, where the alkyl is methyl, thiazole-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidin-2,4-diyl, oxazole-2,4-diyl, carbonyl, 1H-imidazole -1,5-diyl, isoxazole-3,5-diyl, fur n-2,4-diyl, benzene-1,3-diyl and (Z) -1-cyanoethyl-1,2-diyl and wherein regioisomers central portion include two regioisomers implemented permutation nitrokateholovogo fragment and - (X) _n - (Y) _m -R ₃ fragment. 2. The compound according to claim 1, including 5- [3- (3,5-dichloro-1-hydroxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro benzene-1,2-diol, 5- [3- (2-chloro-1-hydroxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1 , 2-diol, 5- [3- (2-morpholin-4-yl-1-hydroxy-pyridin-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-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1, 2-diol, 5- [3- (2-morpholin-4-yl-1-hydroxy-pyridin-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] oxadiazole -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-hydroxy-pyridin-3-yl) - [1 , 2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2-chloro-4,6- imethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2-bromo-4 , 6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2- bromo-4,5,6-trimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-1,2-diol, 5- [3- (2-chloro-4,5,6-trimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-1,2-diol, 5- [3- (2,5-Dichloro-4,6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-1,2-diol , 5- [3- (2-bromo-5-chloro-4,6-dimethyl-1-hydroxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene- 1,2-diol and 3-nitro-5- [3- (1-hydroxy-2-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] ben zol-1,2-diol. 3. A method of treating a subject suffering from certain disorders of the central and peripheral nervous system, where a decrease in O-methylation of catecholamines can be of therapeutic benefit, such as Parkinson's disease and Parkinson’s disorders, gastrointestinal diseases, conditions of edema formation and hypertension, in which the subject is administered an amount compounds according to claim 1 or 2, effective for the treatment of these diseases of the subject. 4. A pharmaceutical composition having a COMT inhibitor activity 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 a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of a subject suffering from disorders of the central or peripheral nervous system. 6. The use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of affective disorders, Parkinson's disease and Parkinson's disorders, tired legs syndrome, gastrointestinal diseases, edema and hypertension conditions. 7. The use of compounds according to claim 1 or 2 as an inhibitor of COMT. 8. The use of a compound according to claim 1 or 2 for the manufacture of a medicament for use as a COMT inhibitor. 9. A method of producing compounds according to formula I, comprising the stages in which the compound of formula IIA, IIB or IIB

where R ₄ , R ₅ , R ₆ and R _{7 are} defined as in the general formula I in claim 1, are cyclized with a compound of formula III

where R ₈ and R ₉ independently represent hydrogen or suitable protecting groups for aromatic hydroxyl groups, under conditions suitable for the preparation of oxadiazole derivatives of formula IVA, IVB or IVB

possibly followed by deprotection of R ₈ and / or R ₉ . 10. A method of producing compounds according to formula I, comprising the stages in which the compound of formula VA, VB or VB

where R ₄ , R ₅ , R ₆ and R _{7 are} defined as in the general formula I in claim 1, they are cyclized with a compound of formula III under conditions suitable for the preparation of oxadiazole derivatives of formula VIA, VIB or VIB

followed by oxidation of the pyridyl nitrogen atom, which gives the compound according to the formula IVA, IVB or IVB, possibly followed by the removal of the protective groups R ₈ and / or R ₉ . 11. The method according to claim 9 or 10, where the compound of formula III is activated during the reaction with thionyl chloride or 1,1-carbonyldiimidazole. 12. The method according to claim 9 or 10, wherein the cyclization step, consisting of condensation and dehydration, is carried out sequentially in one reaction vessel. 13. The method according to claim 9 or 10, where the cyclization step is carried out in the presence of a suitable organic base. 14. The method according to item 13, where the stage of cyclization is performed in the presence of pyridine. 15. The method according to any one of claims 9, 10 or 14, wherein the R ₈ and R ₉ groups are independently removed or together removed and replaced with hydrogen or a group that hydrolyzes under physiological conditions. 16. The method according to any one of claims 9, 10 or 14, wherein R ₈ and R _{9 of the} compound of formula III are independently methyl or hydrogen. 17. The method according to clause 16, where the methyl group is removed during the reaction with aluminum chloride and pyridine in N-methylpyrrolidinone. 18. The method according to any one of claims 9, 10, 14 or 17, where the condensation and dehydration is performed in a dipolar aprotic solvent. 19. The method according to p, where the condensation and dehydration is performed in dimethylacetamide, N-methylpyrrolidinone or dimethyl sulfoxide. 20. The method according to any one of claims 10, 14, 17 or 19, wherein the pyridyl nitrogen atom of the oxadiazole compound of formula VIA, VIB or VIB is oxidized with hydrogen peroxide, peracetic acid, trifluoroacetic acid or a urea-hydrogen peroxide complex and trifluoroacetic anhydride. 21. The method according to any one of claims 9, 14, 17 or 19, where the compound of formula IIA, IIB or IIB is obtained during the reaction of compounds VIIA, VIIB or VIIB, respectively

where R ₄ , R ₅ , R ₆ and R _{7 are} defined as in general formula 1 in claim 1, with hydroxylamine in the presence of a chelating agent under conditions suitable for the preparation of amidoxime derivatives. 22. The method according to any one of claims 10, 14, 17 or 19, where the compound of formula VA, VB or VB is obtained during the reaction of compounds VIIIA, VIIIB or VIIIB, respectively

where R ₄ , R ₅ , R ₆ and R _{7 are} defined as in the general formula I in claim 1, with hydroxylamine in the presence of a chelating agent under conditions suitable for the preparation of amidoxime derivatives. 23. The method according to claim 19, where the chelating agent is selected from the group consisting of 8-hydroxyquinoline, ortho-phenanthroline and their hydrates or derivatives. 24. The method according to claim 20, where the chelating agent is selected from the group consisting of 8-hydroxyquinoline, ortho-phenanthroline and their hydrates or derivatives. 25. A method of producing compounds according to formula I, wherein the corresponding pyridine compound is oxidized to a pyridine N-oxide compound.