MX2008001094A - Nitrocatechol derivatives as comt inhibitors - Google Patents

Abstract

New compounds of formula I are described. The compounds have potentially valuable pharmaceutical properties in the treatment of some central and peripheral nervous system disorders.

Description

DERIVATIVES OF NITROCATECOL AS COMT INHIBITORS This invention relates to new substituted nitrocatechols, to their use in the treatment of some disorders of the central and peripheral nervous system and to the pharmaceutical compositions containing them. Despite being used in clinical practice for several decades, levodopa (L-DOPA) continues to be the gold standard drug for the symptomatic treatment of Parkinson's disease. This has helped to maintain an intense interest in the development of inhibitors of the enzyme catechol-O-methyltransferase (COMT) based on the hypothesis that the inhibition of this enzyme can provide clinical improvements in patients affected by Parkmson's disease, which they undergo treatment with L-DOPA and a peripheral inhibitor of ammoacid decarboxylase (AADC). The reason for using COMT inhibitors as adjuncts to L-DOPA / AADC therapy is based on its ability to reduce the metabolic O-methylation of L-DOPA to 3-O-met? L-L-DOPA (3-OMD). The duration of clinical improvement induced by L-DOPA is summarized as a result of the short live shelf life of L-DOPA, which contrasts with the shelf life of 3-0MD. Additionally, 3-OMD competes with L-DOPA for transport through the blood-brain barrier (BBB), which means that only one very limited amount of an orally administered dose of L-DOPA actually reaches the site of action, ie the brain. Commonly, within only a few years of starting therapy with L-DOPA with the usual dosing regimen, clinical improvement induced by L-DOPA declines at the end of each dose cycle, giving rise to the so-called "elimination" pattern of the fluctuations of the engine. A close relationship between the phenomenon of "elimination" and accumulation of 3-OMD has been described (Tohgi, H., et al., Neurosci.Letters, 132: 19-22, 1992). It has been speculated that this may result from impaired brain penetration of L-DOPA, due to competition for the transport system through the BBB with 3-OMD (Reches, A. et al., Neurology, 32: 887 -888, 1982) or more simply that there is less L-DOPA available to reach the brain (Nutt, JG, Fellman, JH, Clin.Neuropharmacol., 7: 35-49, 1984). Indeed, COMT inhibition protects L-DOPA from the metabolic decomposition in the periphery through 0-methylation, such that with repeated doses of L-DOPA, the mean plasma concentration of L-DOPA is elevated. In addition to reduced competition for transport to the brain, a significantly higher percentage of the orally administered dose of L-DOPA is able to reach the site of action. Therefore, the inhibition of COMT serves to increase the bioavailability of L-DOPA and the duration of the antiparkinsonian action is prolonged with simple doses of L-DOPA (Nutt, J.G. / Lancet, 351: 1221-1222, 1998). Hitherto the most potent COMT inhibitors reported 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 Al) and BIA 3-202 (US patent 6512136) all have constants of inhibition in the low nanomolar range. Although they share essentially the same pharmacophore, tolcapone differs from entacapone and BIA 3-202 in that it easily enters the central nervous system (CNS) and is able to inhibit cerebral COMT as well as peripheral COMT. One might speculate that central inhibition may be less important if the most significant action of COMT inhibition is to prevent the breakdown of L-DOPA in the periphery. Of course, the use of COMT inhibitors that do not penetrate the brain at clinically relevant doses can avoid the potential, undesirable side effects in the CNS of these agents. Another serious issue that has arisen since the COMT inhibitors were introduced in clinical practice, refers to the potential of these nitrocatechol-based xenobiotics to cause severe hepatic damage (hepatotoxicity). Of course, shortly after its After the release, tolcapone was withdrawn from the market after several cases of hepatotoxicity were reported, including three unfortunate deaths from fatal fulminant hepatitis. Currently, tolcapone can only be used in parkinsonian patients, who have not responded to other treatments and strictly only with regular monitoring of liver function, which is expensive and inconvenient for the patient. Although the real mechanism causes that the toxicity associated with tolcapone is not fully understood, in vitro studies have shown that tolcapone can be reduced metabolically to reactivate intermediates and it has been speculated that these can form covalent adducts with liver proteins, resulting in hepatocellular damage (Smith, KS et al, Chem. Res. Toxicol., 16: 123-128, 2003). On the other hand, entacapone, although it shares the same nitrocatechol pharmacophore with tolcapone, is not associated with liver toxicity and is generally considered a safe drug. However, unfortunately, entacapone is a significantly less potent COMT inhibitor than tolcapone and has a much shorter in-vivo shelf life. This means that entacapone has a very limited duration of effect and as a consequence, the drug must be administered in very high doses, with each dose of L-DOPA taken by the patient. As Thus, the clinical efficacy of entacapone has been questioned - in fact, a recent study (Parashos, SA et al., Clin. Neuropharmacol., 27 (3): 119-123, 2004) revealed that the main reason for discontinuation of treatment with entacapone in patients suffering from Parkinson's disease, was a lack of perceived efficacy. In summary, there is still a clear clinical requirement for an effective and safe COMT inhibitor for joint therapy in the management of Parkinson's disease symptoms. Preferably, the COMT inhibitor should be endowed with greater potency and duration of COMT inhibition than entacapone, which would lead to greater clinical efficacy. More preferably, the COMT inhibitor, other than tolcapone, must have limited access to the CNS, that is, it must preferably inhibit peripheral COMT instead of central COMT. Even more preferably, the COMT inhibitor must combine the aforementioned characteristics and also must not be endowed with the potential to cause liver toxicity as observed with tolcapone. Now we have surprisingly discovered that certain nitrocatechols are very potent COMT inhibitors, which are also devoid of, or have a very low risk of toxicity. In addition, it has unexpectedly been determined that it is the chemical functionality of the non-catecholic substituent, connected to the heterocyclic ring, which determines the lack of toxic effects of the compounds. To date, only one example of a [1, 2, 4] -oxadiazole nitrocatecholic has been reported in the prior art (Example 75 of Australian patent AU-B-69764/87), this is 5- (3- methyl-l, 2, -oxadiazol-5-yl) -3-nitropyrocatechol 1, which has the chemical structure shown below: 1 This substance is a 3,5-disubstituted- [1, 2, 4] -oxadiazole with the methyl group occupying the C-3 position of the heterocyclic oxadiazolyl ring and the nitrocatecholic pharmacophore bound to C-5. We studied the oxadiazolyl compound 1 mentioned above and found that it is moderately active in the COMT inhibition assay (59% control, see experimental section). However, unfortunately, compound 1 presents a significant toxicity risk (55% cell viability, see experimental section). As such, this particular compound 1 can not be considered as represents an adequate solution to the present problem of providing a clinically safe and potent COMT inhibitor. We have surprisingly found that if the central ring is replaced with a pyridyl ring in oxidized form (ie, pyridine N-oxide), that the resulting pyridine N-oxide compounds show very low toxicity, or are even devoid of risk of toxicity, while it is still concomitantly possible to maintain an inhibition of COMT higher than entacapone. If the position of the nitrocatechol pharmacophore is "changed" from C-5 to the C-3 position of the oxadiazole ring, then the resulting compounds are commonly less active in terms of COMT inhibition. Regioisomeric 1, 3, 4-oxadiazoles, wherein the nitrocatechol pharmacophore is coupled to C-2 of the oxadiazolyl central ring, are also usually less active in terms of COMT inhibition. For example, consider regioisomers 2 and 3 of oxadiazole 1 of the prior art, which we have also synthesized and evaluated in vivo; Although each of compounds 2 and 3 present a reduced toxicity risk relative to 1, in terms of compound 2 for COMT inhibition, they showed only 79% control and compound 3 was only marginally better at 64%. Therefore, it can be concluded that it is the combination of the correct positional arrangement of the heteroatoms in the central oxadiazole ring and the incorporation of the functional group N-oxide of pyridine is unexpectedly crucial to obtain synergy between the COMT inhibitory activity and the safety for this type of COMT inhibitor. Accordingly, the present invention relates to nitrocatecholic COMT inhibitors that are devoid of, or have a very low risk of toxicity. Furthermore, it has unexpectedly been determined that it is the introduction of a nitrogen-based heterocyclic group in the N-oxidized form, such as, for example, a pyridine N-oxide, which determines the lack of toxic effects of the nitrocatechol compounds . We have also surprisingly found that the compounds of the general formula I are COMT inhibitors, which are endowed with balanced properties of bioactivity, bioavailability and, in particular, safety: 00 Wherein Ri and R2 are independently from each other hydrogen or a group that is hydrolysable under physiological conditions, optionally substituted alkanoyl or lower aroyl; X represents a methylene group; Y represents an oxygen, nitrogen or sulfur atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a pyridine N-oxide group according to formula A, B or C, which is connected as indicated by the unmarked link: wherein R 4, R 5, R 7 and R 7 independently of each other represent hydrogen, alkyl of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, carbon, aryloxy of 6-12 carbon atoms or a thioaryl group of 6-12 carbon atoms, alkanoyl of 1-6 carbon atoms or aroyl group of 7-13 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms, cycloalkylamino of 3-12 carbon atoms, heterocycloalkylamino of 3-12 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, arylsulfonyl of 6-12 carbon atoms, halogen, haloalkyl of 1 -6 carbon atoms, trifluoromethyl, cyano, nitro or a heteroaryl group; or two or more of the residues R4, R5, R6 and R7 taken together represent aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings and wherein P represents a central unit, which is preferably a flat unit and which is still more preferably selected from the regioisomers of 1,3-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3, 5-diyl, 4-methyl-4H-1, 2,4-triazol-3, 5-diyl, 1 , 3,5-triazin-2,4-diyl, 1,2,4-triazin-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazole-4,5-diyl , l-alkyl-3- (alkoxycarbonyl) -lH-pyrrole-2, 5-diyl, wherein alkyl is represented by methyl, ethyl, n-propyl and n-butyl and wherein alkoxy is represented by methoxy, ethoxy, n-propoxy and isopropoxy, l-alkyl-lH-pyrrole-2, 5-diyl, wherein alkyl is represented by methyl, ethyl, n-propyl and n-butyl, thiazol-2, -diyl, 1-H-pyrazole -l, 5-diyl, pyrimidin-2,4-diyl, oxazol-2,4-diyl, carbonyl, lH-imidazol-1,5-diyl, isoxazole- 3,5-diyl, furan-2,4-diyl, 3-alkoxycarbonylfuran-2,4-diyl, wherein alkoxy is represented by methoxy, ethoxy, n-propoxy and isopropoxy, benzene-1,3-diyl and (Z ) -1-cyanoethen-l, 2-diyl. In the above definition, the regioisomers of the central unit include both regioisomers realizable by exchange of the nitrocatechol portion and the - (X) n- (Y) m-R3 portion. Preferably, the alkyl residues of 1-6 carbon atoms represent methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl. Preferably, the thioalkyl residues of 1-6 carbon atoms represent thiomethyl, thioethyl, thio-n-propyl, thio-isopropyl, thio-n-butyl, thio-n-pentyl and thio-n-hexyl. Preferably, the alkoxy residues of 1-6 carbon atoms represent methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. Preferably, the aryloxy residues of 6-12 carbon atoms represent phenoxy or naphthoxy which may optionally be substituted. Preferably, the thioaryl residues of 6-12 carbon atoms represent thiophenyl and thionaphthyl which may optionally be substituted. Preferably, alkanoyl residues of 1-6 carbon atoms represent methanoyl, ethanoyl, or propanoyl. butanoyl Preferably, the aroyl residues of 7-13 atoms carbon represent benzoyl and naphthoyl. Preferably, the alkylamino residues of 1-6 carbon atoms represent methylamino, ethylamino, n-propylamino, isopropylamino and n-butylamino. Preferably, the dialkylamino residues of 1-6 carbon atoms represent dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, di-isopropylamino, methylethylamino, methylpropylamino and ethylpropylamino. Preferably, the cycloalkylamino residues of 3-12 carbon atoms represent pyrrolidino, piperidino, cyclohexylamino and dicyclohexylamino. Preferably, the heterocycloalkylamino residues of 3-12 carbon atoms represent morpholino, 2,6-dimethylmorpholino, 3,5-dimethylmorpholino, piperazino, N-methylpiperazino and N-ethylpiperazino. Preferably, the residues of alkylsulfonyl of 1-6 carbon atoms or arylsulfonyl of 6-12 carbon atoms represent methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and tolylsulfonyl. Preferably, the halogen residues represent chlorine, bromine, iodine and fluorine. Preferably, haloalkyl of 1-6 carbon atoms represents chloromethyl, fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl. Preferably, the heteroaryl residues represent pyridyl, pyrimidyl, isoxazolyl, oxazolyl, isoxadiazolyl, oxadiazolyl, triazolyl and tetrazolyl. In cases where two or more of the waste R4, R5, R6 and R7 all together represent aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings, the preferred combined residues are indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, naphthyridinyl, isoquinolyl and quinolyl. Preferably, the central unit is selected from a heteroaromatic five-membered ring, which includes from 1-4 of the heteroatoms N, 0 and S. More preferably, the central unit P is selected from the regioisomers of 1,3,4-oxadiazole -2, 5-diyl, 1, 2, 4-oxadiazol-3,5-diyl, 4-methyl-4H-l, 2,4-triazol-3, 5-diyl, 3,5-triazin-2,4 -diyl, 1, 2, -triazin-3, 5-diyl, 2H-tetrazol-2, 5-diyl, l, 2,3-thiadiazole-4,5-diyl, l-alkyl-3- (alkoxycarbonyl) - 1H-pyrrole-2, 5-diyl, wherein alkyl is represented by methyl, ethyl, n-propyl and n-butyl and wherein alkoxy is represented by methoxy, ethoxy, n-propoxy and isopropoxy, 1-alkyl-1H- pyrrole-2, 5-diyl, wherein alkyl is represented by methyl, ethyl, n-propyl and n-butyl, thiazole-2,4-diyl, 1-H-pyrazole-1, 5-diyl, oxazole-2, 4-diyl, carbonyl, lH-imidazol-1,5-diyl, isoxazol-3, 5-diyl, furan-2,4-diyl, 3-alkoxycarbonylfuran-2,4-diyl, wherein alkoxy methoxy, ethoxy, n -propoxy and isopropoxy. More preferably, the central unit P is selected from 1,3,4-oxadiazol-2,5-diyl and 1,4,4-oxadiazole-3,5-diyl.

Preferred compounds of the above general formula (I) having 1, 2,4-oxadiazol-3, 5-diyl as the central unit include 5- [3- (3,5-dichloro-1-oxy-pyridin-4) -yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 5- [3- (2-chloro-l-oxy-? iridin-4-yl) ) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-1,2-diol, 5- [3- (2-morpholin-4-yl-l-oxy-pyridin-4-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-1,2-diol, 3-nitro-5- [3- (l-oxy-trifluoromethyl-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -benzene-1,2-diol, 5- [3- (4-bromo-l-oxy-pyridin-3-yl) - [1,2,4] ] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, 5- [3- (2-chloro-6-methyl-l-oxy-pyridin-3-yl) - [1,2, 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, 5- [3- (2-morpholin-4-yl-l-oxy-pyridin-3-yl) - [1,2 , 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, 3-nitro-5- [3- (1-oxy-6-trifluoromethyl-pyridin-3-yl) - [1, 2,4] oxadiazol-5-yl] -benzene-1,2-diol, 5- [3- (2-methyl-l-oxy-6-trifluoromethyl-pyridin-3-yl) - [1, 2.4 ] oxadiazol-5-yl] -3-nitro-benzene-l, 2-di ol, 5- [3- (6-methyl-l-oxy-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-2 -diol, 5- [3- (2,6-dimethyl-l-oxy-4-trifluoromethyl-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-ben. cen-l, 2-diol, 5- [3- (2-methyl-l-oxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-1, 2-diol, 5- [3- (6-methyl-1-oxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazole -5-yl] -3-nitro-benzene-177,2-diol, 5- [3- (2-bromo-6-methyl-1-oxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3- Nitro-benzene-1,2-diol, 5- [3- (2-chloro-4,6-dimethyl-l-oxy-pyridin-3-yl) - [1,4,2-oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, 5- [3- (2-bromo-4,6-dimethyl-l-oxy-pyridin-3-yl) - [1,2,4] oxadiazole-5 -yl] -3-nitro-benzene-1, 2-diol, 5- [3- (2-bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitrobenzene-l, 2-diol, 5- [3- (2-chloro-4,5,6-trimethyl-l-oxy-pyridin-3-yl) - [l , 2,4] oxadiazol-5-yl] -3-nitrobenzene-l, 2-diol, 5- [3- (2,5-dichloro-4,6-dimethyl-l-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitrobenzene-l, 2-diol, 5- [3- (2-bromo-5-chloro-, 6-dimethyl-l-oxy-pyridine- 3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-l, 2-diol, and 3-nitro-5- [3- (l-oxy-2-trifluoromethyl-pyridine- 3-yl) - [1, 2, 4] oxadiazol-5-yl] -benzene-1,2-diol, 3- (3- (3,4-dihydroxy-5-nitrophenyl) -1-oxide, 2,4-oxadiazol-5-yl) -4- (trifluoromethyl) pyridine, 2-chloro-3- (3- (3, -dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole- 5-yl) -4,6-dimethylpyridine, 3- (3- (3,4-dihi) -oxide) droxy-5-nitrophenyl) -1,2, -oxadiazol-5-yl) -2-methyl-6- (trifluoromethyl) pyridine, 5- (3- (3,4-dihydroxy-5-nitrophenyl) 1-oxide) -1,2,4-oxadiazol-5-yl) -2- (trifluoromethyl) pyridine, 5- (3- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiaz-1-oxide. ol-5-yl) -2-methyl-4- (trifluoromethyl) pyridine, 3- (3- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-5-yl-1-oxide ) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 3,5-dichloro-4- (3- (3, -dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-5-1-oxide -yl) pyridine, 3- (3- (3,4-dihydroxy-5-nitrophenyl) -oxide-1 - 1,2,4-oxadiazol-5-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 2-bromo-3- (3- (3,4-dihydroxy-5-) -oxide nitrophenyl) -1,2, 4-oxadiazol-5-yl) -4,5,6-trimethylpyridine, 2-chloro-3- (3- (3,4-dihydroxy-5-nitrophenyl) -1-oxide , 2,4-oxadiazol-5-yl) -4,5,6-trimethylpyridine, 3- (3- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-1-oxide -yl) -2- (trifluoromethyl) pyridine, 2-5-dichloro-3- (3- (3, -dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-5-yl) -1-oxide 4,6-dimethylpyridine, 3- (3- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-5-yl) -5- (trifluoromethyl) pyridine 1-oxide, 1-oxide 3- (3- (3, 4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-5-yl) -2-fluoropyridine, 4- (3- (3,4-dihydroxy) -oxide -5-nitrophenyl) -l, 2,4-oxadiazol-5-yl) -2-fluoropyridine, 2- (3- (3,4-dihydroxy-5-nitrophenyl) -1, 2, 4- 1-oxide oxadiazol-5-yl) -6-fluoropyridine, 2-chloro-3- (3- (3,4-dihydroxy-5-nitrophenyl) -1-oxide, 2,4-oxadiazol-5-y) -6-methylpyridine, 2-bromo-3- (3- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazole-1-oxide -yl) -6-methylpyridine, and 1-oxide of 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-oxadiazol-2,5-diyl as the central unit include 3- (5- (3,4-dihydroxy-5-nitrophenyl ) -l, 3, 4-oxadiazol-2-yl) -4- (trifluoromethyl) pyridine, 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -1, 3-oxide , 4- oxadiazol-2-yl) -4,6-dimethylpyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1,4,4-oxadiazol-2-yl) -2-methyl-1-oxide -6- (trifluoromethyl) pyridine, 5- (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -2- (trifluoromethyl) pyridine 1-oxide. 5- (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -2-methyl-4- (trifluoromethyl) pyridine oxide, 3-1-oxide (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 3,5-dichloro-1-oxide -4- (5- (3,4-dihydroxy-5-nitrophenyl) -1,4,4-oxadiazol-2-yl) pyridine, 3- (5- (3,4-dihydroxy) -3-oxide nitrophenyl) -1,3,4-oxadiazol-2-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 2-bromo-3- (5- (3,4-dihydroxy) -5-nitrophenyl) -1, 3, 4-oxadiazol-2-yl) -4,5,6-trimethylpyridine, 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -oxide ) -1, 3, 4-oxadiazol-2-yl) -4,5,6-trimethylpyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4- oxadiazol-2-yl) - 2- (trifluoromethyl) pyridine, 2-5-dichloro-3- (5- (3, -dihydroxy-5-nitrophenyl) -1, 3, 4-oxadiazol-2-yl) -4, 6- 1-oxide dimethylpyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl) -5- (trifluoromethyl) pyridine 1-oxide, 3- (1-oxide) 5- (3, 4-dihydroxy-5-nitrophenyl) -1, 3, 4-oxadiazol-2-yl) -2-fluoropyridine, 4- (5- (3,4-dihydroxy-5-nitrophenyl) -1-oxide ) -1, 3, -oxadiazol-2-yl) -2-fluoropyridine, .2- (5- (3, -dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl-1-oxide. ) -6-fluoropyridine, 2-chloro-3- (5- (3, 4-dihydroxy-5-oxide nitrophenyl) -1, 3, 4-oxadiazol-2-yl) -6-methylpyridine, 2-bromo-3- (5- (3,4-dihydroxy-5-nitrophenyl) -1, 3, 4-oxide -oxadiazol-2-yl) -6-methylpyridine, and 1-oxide of 2-bromo-5-chloro-3- (5 (3,4-dihydroxy-5-nitrophenyl) -1, 3, 4-oxadiazole-2 -yl) -4,6-dimethylpyridine. Preferred compounds of the above general formula (I) having a 4-methyl-4H-1,2,4-triazol-3, 5-diyl as the central unit include 3- (5- (3, 4-oxide) -dihydroxy-5-nitrophenyl) -4-methy1-4H-1, 2,4-triazol-3-yl) -4- (trifluoromethyl) pyridine, 2-chloro-3- (5- (3, 4-dihydroxy-5-nitrophenyl) -4-methi1-4H-1,2,4-triazol-3-yl) -4,6-dimethylpyridine, 3- (5- (3,4-dihydroxy) -oxide 5-nitrophenyl) -4-methyl-4H-l, 2, -triazol-3-yl) -2-methyl-1-6- (trifluoromethyl) pyridine, 5- (5- (3,4-dihydroxy) 5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -2- (trifluoromethyl) pyridine, 5- (5- (3,4-dihydroxy-5-nitrophenyl) -1-oxide ) -4-methy1-4H-1,2,4-triazol-3-yl) -2-methyl-4- (trifluoromethyl) pyridine, 3- (5- (3,4-dihydroxy-5-) nitrophenyl) -4-methy1-4H-1,2,4-triazol-3-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 3,5-dichloro-4- (5-dichloro) - (3, 4-dihydroxy-5-nitrophenyl) -4-methyl-4H-l, 2,4-triazol-3-yl) pyridine, 3- (5- (3, 4- dihydroxy-5-nitrophenyl) -4-methyl-4H-l, 2,4-triazol-3-yl) -6-methyl-2-pheny1-4- (trifluoromethyl) pyridine, 1-oxide of 2-bromo-3 - (5- (3, 4-dihydroxy-5-nitrophenyl) -4-methi1-4H-l, 2,4-triazol-3-yl) -4,5,6- trimethylpyridine, 2-chloro-3- (5- (3, -dihydroxy-5-nitrophenyl) -4-methyl-4H-l, 2,4-triazol-3-yl) -4,5,6-oxide -trimethylpyridine, 3- (5- (3, -dihydroxy-5-nitrophenyl) -4-methyl-4H-l, 2,4-triazol-3-yl) -2- (trifluoromethyl) pyridine 1-oxide, 1 -2,5-dichloro-3- (5- (3, 4-dihydroxy-5-nitrophenyl) -4 -methyl-4H-l, 2,4-triazol-3-yl) -4,6-dimethylpyridine oxide , 3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-l, 2,4-triazol-3-yl) -5- (trifluoromethyl) pyridine 1-oxide, 1- 3- (5- (3, 4-dihydroxy-5-nitrophenyl) -4-methyl-4H-l, 2,4-triazol-3-yl) -2-fluoropyridine oxide, 1-oxide of 4- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2-triazol-3-yl) -2-fluoropyridine, 1-oxide of 2- ( 5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -6-fluoropyridine, 2-chloro-3- (5-) (3, -dihydroxy-5-nitrophenyl) -4-methyl-4H-l, 2,4-triazol-3-yl) -6-methylpyridine, 1-oxide of 2-bromo-3- (5- (3,4-dihydroxy-5-nitrophenyl) -4-methyl-4H-1,2,4-triazol-3-yl) -6-methylpyridine and 1- 2-bromo-5-chloro-3- (5- (3) oxide, 4-dihydroxy-5-nitrophenyl) -4-methyl-4H-l, 2,4-triazol-3-yl) -4, β-dimethylpyridine. Preferred compounds of the above general formula (I) having 1, 3, 5-triazin-2,4-diyl as the central unit include 3- (4- (3,4-dihydroxy-5-nitrophenyl-1-oxide ) -1, 3, 5-triazin-2-yl) -4- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazine-1-oxide -2-yl) -2-methyl-6- (trifluoromethyl) pyridine, 1-oxide of 5- (4- (3,4- dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2- (trifluoromethyl) pyridine, 5- (4- (3,4-dihydroxy-5-nitrophenyl) -1-oxide, 3, 5-triazin-2-yl) -2-methyl-1-4- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazine-1-oxide -2-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-1-oxide il) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl-1-oxide ) -2- (trifluoromethyl) pyridine, and 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -5- (trifluoromethyl) pyridine-1-oxide . Preferred compounds of the above general formula (I) having 1, 2,4-triazin-3, 5-diyl as the central unit include 3- (5- (3,4-dihydroxy-5-nitrophenyl-1-oxide ) -1, 2, 4-triazin-3-yl) -4- (trifluoromethyl) pyridine, 3- (5- (3,4-Dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -2-methyl-6- (trifluoromethyl) pyridine 1-oxide, 1-oxide - (5- (3,4-dihydroxy-5-nitrophenyl) -l, 2,4-triazin-3-yl) -2- (trifluoromethyl) pyridine, 1-oxide of 5- (5- (3, 4- dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -2-methyl-4 - (trifluoromethyl) pyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1-oxide ) -l, 2,4-triazin-3-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -l-1-oxide , 2,4-triazin-3-yl) -6-methy1-2-pheny1-4- (trifluoromethyl) pyridine, 3- (5- (3,4-dihydroxy-5-) -oxide nitrophenyl) -l, 2,4-triazin-3-yl) -2- (trifluoromethyl) pyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1, 2, 4- 1-oxide triazin-3-yl) -5- (trifluoromethyl) pyridine, 4- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl-1-oxide) -2- fluoropyridine and 2- (5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-triazin-3-yl) -6-fluoropyridine 1-oxide. Preferred compounds of the above general formula (I) having a (Z) -1-cyanoethane-1,2-diyl portion as the central unit include (Z) -3- (l-cyano-2- ( 3,4-dihydroxy-5-nitrophenyl) vinyl) -4- (trifluoromethyl) pyridine, 1-oxide of (Z) -2-chloro-3- (1-cyano-2- (3,4-dihydroxy-5- nitrophenyl) vinyl) -4,6-dimethylpyridine, (Z) -3- (l-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2-methyl-6- (trifluoromethyl) ) pyridine, 1-oxide of (Z) -5- (l-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2- (trifluoromethyl) pyridine, 1-oxide of (Z) -5 - (l-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2-methyl-4 - (trifluoromethyl) pyridine, 1-oxide of (Z) -3- (l-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1-oxide of (Z) -3,5-dichloro-4- (1-cyano-2-) (3,4-dihydroxy-5-nitrophenyl) vinyl) pyridine, 1-oxide of (Z) -3- (l-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -6-methyl- 2-phenyl-4- (trifluoromethyl) pyridine, 1-oxide ( Z) -2-bromo-3- (l-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -4,5,6-trimethylpyridine, 1-oxide of (Z) -2-chloro- 3- (l-cyano-2- (3, 4- dihydroxy-5-nitrophenyl) vinyl) -4,5,6-trimethylpyridine, 1-oxide of (Z) -3- (l-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2- (trifluoromethyl) pyridine, 1-oxide of (Z) -2,5-dichloro-3- (1-cyano-2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -4,6-dimethylpyridine, 1- (Z) -3- (l-cyano-2- (3, 4-dihydroxy-5-nitrophenyl) vinyl) -5- (trifluoromethyl) pyridine oxide, 1-oxide of (Z) -3- (l-cyano) -2- (3,4-dihydroxy-5-nitrophenyl) vinyl) -2-fluoropyridine, (Z) -4- (l-cyano-2- (3, -dihydroxy-5-nitrophenyl) vinyl) -2-fluoropyridine, 1-oxide of (Z) -2- (1-cyano-2- (3, 4-dihydroxy-5-nitrophenyl) vinyl) -6-fluoropyridine, 1-Oxide of (Z) -2-chloro-3- (l-cyano-2- (3, -dihydroxy-5-nitrophenyl) vinyl) -6-methylpyridine, 1-oxide of (Z) -2-bromo- 3- (l-cyano-2- (3, -dihydroxy-5-nitrophenyl) vinyl) -6-methylpyridine, and 1-oxide of (Z) -2-bromo-5-chloro-3- (l-cyano- 2- (3, 4-dihydroxy-5-nitrophenyl) vinyl) -4,6-dimethylpyridine. Preferred compounds of the above general formula (I) having as a central unit a furan-2,4-diyl or a 3-alkoxycarbonylfuran-2,4-diyl moiety, wherein alkoxy is represented by methoxy, ethoxy, n-propoxy and isopropoxy, include 3- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -4- (trifluoromethyl) pyridine 1-oxide, 1- (2-oxide) chloro-3- (4- (3, 4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -4,6-dimethylpyridine, 1-oxide. of 3- (4- (3, 4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2-methyl-6- (trifluoromethyl) pyridine, 5- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2- (trifluoromethyl) pyridine 1-oxide, 1-oxide - (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2-methyl-4- (trifluoromethyl) pyridine, 1-oxide of 3- (4- (3 , 4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 3-5-dichloro-4- (4- (3, 4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) furan-2-yl-1-oxide ) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 2-bromo-3- (4- (3,4-dihydroxy-5-nitrophenyl) furan-2-yl) -4-oxide, 5,6-trimethylpyridine, 2-chloro-3- (4- (3, 4-dihydroxy-5-nitrophenyl) furan-2-yl) -4,5,6-trimethylpyridine 1-oxide, 1-oxide - (4- (3, 4-dihydroxy-5-nitrophenyl) furan-2-yl) -2- (trifluoromethyl) pyridine, 2-5-dichloro-3- (4- (3,4-dihydroxy) -5-nitrophenyl) furan-2-yl) -4,6-dimethylpyridine, 1-oxide of 3- (4- (3, 4-dihydroxy-5-nitrophenyl) furan-2-yl) -5- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -oxide) -3- (ethoxycarbonyl) furan-2-yl) -2-fluoropyridine, 4- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -oxide 2-fluoropyridine, 2- (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -6-fluoropyridine 1-oxide, 2-chloro-3-oxide - (4- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -6-methylpyridine, 2-bromo-3- (4- (3, 4- dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -6-methylpyridine, and 1-oxide of 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 unit a 1H-imidazole-1,5-diyl portion include 3- (5- (3,4-dihydroxy-5-nitrophenyl) -lH-oxide -imidazol-1-yl) -4- (trifluoromethyl) pyridine, 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -1H-imidazol-1-yl) -4-oxide , 6-dimethylpyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -IH-imidazol-1-yl) -2-methyl-6- (trifluoromethyl) pyridine, 1-oxide 5- (5- (3, 4-dihydroxy-5-nitrophenyl) -lH-imidazol-1-yl) -2- (trifluoromethyl) pyridine, 3-5-dichloro-4- (5- (3-oxide , 4-dihydroxy-5-nitrophenyl) -1H-imidazol-1-yl) pyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -lH-imidazol-1-yl) - 1-oxide 2- (trifluoromethyl) pyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -lH-imidazol-1-yl) -5- (trifluoromethyl) pyridine 1-oxide, 1- 3-oxide (5- (3, 4-dihydroxy-5-nitrophenyl) -lH-imidazol-1-yl) -2-fluoropyridine, 2- (5- (3,4-dihydroxy-5-nitrophenyl) -lH-oxide -imidazol-1-yl) -6-fluoro pyridine, 2-chloro-3- (5- (3, 4-dihydroxy-5-nitrophenyl) -lH-imidazol-1-yl) -6-methylpyridine 1-oxide, and 2-bromo-3-oxide - (5- (3,4-dihydroxy-5-nitrophenyl) -lH-imidazol-1-yl) -6-methylpyridine. Preferred compounds of the above general formula (I) having as a central unit a portion isoxazole-3, 5-diyl include 3- (3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -4- (trifluoromethyl) pyridine 1-oxide, 2-chloro-1-oxide 3- (3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -4,6-dimethylpyridine, 3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazole-1-oxide -5-yl) -2-methy1-6- (trifluoromethyl) pyridine, 5- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2- (trifluoromethyl) pyridine 1-oxide , 5- (3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2-methyl-1-4- (trifluoromethyl) pyridine 1-oxide, 3- (3- (3-oxide , 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 1-oxide of 3,5-dichloro-4- (3- (3,4-dihydroxy) -5-nitrophenyl) isoxazol-5-yl) pyridine, 3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -6-methyl-2-phenyl-4- 1-oxide (trifluoromethyl) pyridine, 2-bromo-3- (3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -4,5,6-trimethylpyridine 1-oxide, 2-bromo-3- (3- (3,4-dihydroxy-5-nitrophenyl) chloro-3- (3- (3, 4-dihydroxy-5-nitrophenyl) isox azol-5-il) -4, 5, 6-trimethylpyridine, 3- (3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2- (trifluoromethyl) pyridine, 2-5-dichloro-3-1-oxide 3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -4,6-dimethylpyridine, 3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazole-5- 1-oxide il) -5- (trifluoromethyl) pyridine, 3- (3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2-fluoropyridine 1-oxide, 4- (3-) -oxide (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2-fluoropyridine, 1-oxide of 2- (3- (3, -dihydroxy-5-nitrophenyl) isoxazol-5-yl) -6 -fluoropyridine, 1-Oxide of 2-chloro-3- (3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -6-methylpyridine, 1-oxide of 2-bromo-3- (3- (3 , 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -6-methylpyridine, and 1-oxide of 2-bromo-5-chloro-3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazole -5-yl) -4,6-dimethylpyridine. Preferred compounds of the above general formula (I) having as a central unit a carbonyl moiety include 3- (3,4-dihydroxy-5-nitrobenzoyl) -4- (trifluoromethyl) pyridine 1-oxide, 1-oxide of 2 -chloro-3- (3,4-dihydroxy-5-nitrobenzoyl) -4,6-dimethylpyridine, 3- (3,4-dihydroxy-5-nitrobenzoyl) -2-methyl-6- (trifluoromethyl) pyridine, 5- (3,4-dihydroxy-5-nitrobenzoyl) -2- (trifluoromethyl) pyridine-1-oxide, 5- (3,4-dihydroxy-5-nitrobenzoyl) -2-methyl-4-oxide - (trifluoromethyl) pyridine, 3- (3,4-dihydroxy-5-nitrobenzoyl) -2,6-dimethyl-4- (trifluoromethyl) pyridine 1-oxide, 3-5-dichloro-4- ( 3,4-dihydroxy-5-nitrobenzoyl) pyridine, 3- (3,4-dihydroxy-5-nitrobenzoyl) -6-methy1-2-phenyl-4- (trifluoromethyl) pyridine-1-oxide, 1-oxide -bromo-3- (3,4-dihydroxy-5-nitrobenzoyl) -4,5,6-trimethylpyridine, 2-chloro-3- (3,4-dihydroxy-5-nitrobenzoyl) -4-oxide , 6-trimethylpyridine, 3- (3,4-dihydroxy-5-nitrob-1-oxide) enzoyl) -2- (trifluoromethyl) pyridine, 1-oxide of 2,5-dichloro-3- (3, 4-dihydroxy-5-nitr-obenzoyl) -4,6-dimethylpyridine, 1-oxide of 3- (3 , -dihydroxy-5-nitrobenzoyl) -5- (trifluoromethyl) pyridine, 3- (3,4-dihydroxy-5-nitrobenzoyl) -2-fluoropyridine 1-oxide, 4- (3,4-dihydroxy-5-nitrobenzoyl) -2-fluoropyridine-1-oxide 2- (3,4-dihydroxy-5-nitrobenzoyl) -6-fluoropyridine oxide, 2-chloro-3- (3,4-dihydroxy-5-nitrobenzoyl) -6-methylpyridine oxide, 1-oxide of 2-bromo-3- (3, 4-dihydroxy-5-nitrobenzoyl) -6-methylpyridine, and 1-oxide of 2-bromo-5-chloro-3- (3,4-dihydroxy-5-nitrobenzoyl) - 4, 6-dimethylpyridine. Preferred compounds of the above general formula (I) having an oxazole-2,4-diyl moiety as the main unit include 3- (4- (3,4-dihydroxy-5-nitrophenyl) oxazole-1-oxide. il) -4- (trifluoromethyl) pyridine, 1-oxy or 2-chloro-3- (4- (3, -dihydroxy-5-nitrophenyl) oxazol-2-yl) -4,6-dimethylpyridine, 1-oxide of 3- (4- (3, 4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -2-methyl-6- (trifluoromethyl) pyridine, - (4- (3,4-Dihydroxy-5-nitrophenyl) oxazol-2-yl) -2- (trifluoromethyl) pyridine 1-oxide, 5- (4- (3,4-dihydroxy) -oxide 5-nitrophenyl) oxazol-2-yl) -2-methyl-1-4- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl-1-oxide) -2 , 6-dimethyl-4- (trifluoromethyl) pyridine, 3-5-dichloro-4- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) pyridine, 1-oxide 3- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 2-bromo-3- (4-oxide - (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -4,5,6-trimethylpyridine, 2-chloro-3- (4- (3,4-dihydroxy-5-oxide) nitrophenyl) oxazol-2-yl) -4,5,6-trimethylpyridine, 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- (1-oxide 3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -5- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl-1-oxide) -2-fluoropyridine, 4- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -2-fluoropyridine, 1-oxide of 2- (4- (3, -dihydroxy) -5-nitrophenyl) oxazol-2-yl) -6-fluoropyridine, 2-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -6-methylpyridine 1-oxide , 2-bromo-3- (4- (3, 4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -6-methylpyridine 1-oxide, and 2-bromo-5-chloro-3-oxide - (4- (3,4-dihydroxy-5-nitrophenyl) oxazol-2-yl) -4,6-dimethylpyridine. Preferred compounds of the above general formula (I) having as a central unit a benzene-1,3-diyl moiety include 3- (3 ', 4'-dihydroxy-5'-nitrobiphenyl-3-yl-1-oxide) -4- (trifluoromethyl) pyridine, 5- (3 ', 4'-dihydroxy-5'-nitrobiphenyl-3-yl) -2- (trifluoromethyl) pyridine 1-oxide, 3,5-dichloro-1-oxide 4- (3 ', 4' -dihydroxy-5'-nitro-phenyl-3-yl) pyridine, 3- (3 ', 4'-dihydroxy-5'-nitrobiphenyl-3-yl) -2- ( trifluoromethyl) pyridine, and 3- (3 ', 4'-Dihydroxy-5'-nitrobiphenyl-3-yl) -5- (trifluoromethyl) pyridine-1-oxide. The preferred compounds of the general formula previous (I) having as a central unit a 1-Hp? razol-1, 5-d? o portion include 1-oxido of 3- (5- (3, 4-d? h? drox? -5 -nitrophenyl) -lH-p? razol-1-? l) -4- (tpfluorometll) pyridine, 5- (5- (3, 4-d? h? drox? -5-n? trofenil) 1-oxide) -lH-p? razol-1-? l) -2- (trifluoromethyl) pyridine, 1-oxido of 3,5-d? chloro-4- (5- (3, 4-d? h? drox? -5-n-trofenil) -lH-p? Razol-1-? L) pyridine, 1-oxido of 3- (5- (3, 4-d? H? Drox? -5-n? Trofen? l) -lH-p? razol-1-? l) -2- (trifluoromethyl) pyridine, 1-oxido of 3- (5- (3, 4-d? h? drox? -5-nitrophenyl) - lH-p? razol-1-? l) -5- (trifluoromethyl) pyridine, and 1-oxide of 4- (5- (3,4-d? h? drox? -5-n? trofenil) -lH- p? razol-1-? l) -2-fluoropyridine. Preferred compounds of the above general formula (I) having as a central unit a p? R? M? D? N-2, 4-d? Lo portion include 1-oxido of 3- (4- (3 , 4-d? H? Drox? -5-n? Trofenil) p? R? M? Dm-2-? L) -4- (trifluoromethyl) pyridine, 1-oxide of 2-chloro-3- (4- (3, 4-d? H? Drox? -5-n? Trofenil) pyrimidm-2-? L) -4,6-d? Met? Lp? R? D? Na, 1-oxido of 3- (4- (3, -d? H? Drox? -5-nitrophenyl) p? R? M? D? N-2-?) -2-met? L-6- (trifluoromethyl) pyridine, 1-ox 5- (4- (3, 4-d? -hydro? -5-nitrophenyl) p? r? m? dm-2-? l) -2- (trifluoromethyl) pyridine, 1-oxide of 5 - (4- (3, -d? H? Drox? -5-n? Trofenil) p? R? M? D? N-2-? L) -2-met? L-4- (trifluoromethyl) pyridine, 1-oxido of 3- (4- (3,4-d? H? Drox? -5-n? Trofenil) p? R? M? D? N-2-? L) -2, 6-dimeti1 -4- (trifluoromethyl) pyridine, 1-oxido of 3,5-d-chloro-4- (4- (3,4-d? H? Drox? -5-n? Trofenil) p? R? M ? dm-2-? l) piridma, 1-oxido of 3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 2-bromo-3- (4- ( 3, 4-dihydroxy-5-nitrophenyl) pyrimidin-2-yl) -4,5,6-trimethylpyridine, 2-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) pyrimidine 1-oxide) -2-yl) -4,5,6-trimethylpyridine, 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-dimethylpyridine, and 1-oxide of 3- (4- (3, -dihydroxy-5) -nitrophenyl) pyrimidin-2-yl) -5- (trifluoromethyl) pyridine. Preferred compounds of the above general formula (I) having as a central unit a 1H-pyrrole-2, 5-diyl portion include 3- (5- (3,4-dihydroxy-5-nitrophenyl) -l-1-oxide. -methyl-3- (ethoxycnyl) -lH-pyrrol-2-yl) -4- (trifluoromethyl) pyridine, 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) - 1-oxide 3- (5- (3,4-dihydroxy-5-nitrophenyl) -l-methyl- 3- (ethoxycnyl) -1-methyl-lH-pyrrol-2-yl) -4,6-dimethylpyridine, 1-oxide lH-pyrrol-2-yl) -2-methyl-6- (trifluoromethyl) pyridine, 5- (5- (3,4-dihydroxy-5-nitrophenyl) -l-ethyl-3- (ethoxycnyl) 1-oxide) -lH-pyrrol-2-yl) -2- (trifluoromethyl) pyridine, 5- (5- (3, 4-dihydroxy-5-nitrophenyl) -l-methyl-lH-pyrrol-2-yl-1-oxide) -2-methyl-4- (trifluoromethyl) pyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -l-methyl-1H-pyrrole-2-11) -2, 6- dimethyl-4- (trifluoromethyl) pyridine, 3-5-dichloro-4- (5- (3, 4- dihydroxy-5-nitrophenyl) -l-methyl-lH-pyrrol-2-yl) pyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -1-methyl-lH-pyrrole-1-oxide 2-yl) -6-methyl-2-phenyl-4- (trifluoromethyl) pyridine, 1-oxide of 2-bromo-3- (5- (3, -dihydroxy-5-nitrophenyl) -1-methyl-1H- pyrrol-2-yl) -4,5,6-trimethylpyridine, 2-chloro-3- (5- (3,4-dihydroxy-5-nitrophenyl) -l-methyl-lH-pyrrole-2-1-oxide) il) -4,5,6-trimethylpyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -l-methyl-lH-pyrrol-2-yl) -2- (trifluoromethyl) -l-oxide pyridine, 2-5-dichloro-3- (5- (3, 4-dihydroxy-5-nitrophenyl) -l-methyl-lH-pyrrol-2-yl) -4,6-dimethylpyridine 1-oxide, 1- 3- (5- (3, 4-dihydroxy-5-nitrophenyl) -l-methyl-lH-pyrrol-2-yl) -5- (trifluoromethyl) pyridine oxide, 3- (5- (3-oxide , 4-dihydroxy-5-nitrophenyl) -l-methyl-lH-pyrrol-2-yl) -2-fluoropyridine, 4- (5- (3,4-dihydroxy-5-nitrophenyl) -l- methyl-lH-pyrrol-2-yl) -2-fluoropyridine, 2- (5- (3,4-dihydroxy-5-nitrophenyl) -3- (ethoxycarbonyl) -l-methyl-lH-pyrrol-2-yl) -6-fluoropyridine 1-oxide, 1-oxide of 2 -chloro-3- (5- (3, 4-dihydroxy-5-nitrophenyl) -l-methyl-lH-pyrrol-2-yl) -6-methylpyridine, 1-oxide of 2-bromo-3- (5- (3, 4-dihydroxy-5-nitrophenyl) -1-methyl-lH-pyrrol-2-yl) -6-methylpyridine, and 1-oxide of 2-bromo-5-chloro-3- (5- (3, 4-dihydroxy-5-nitrophenol) -l-methyl-lH-pyrrol-2-yl) -4,6-dimethylpyridine. Preferred compounds of the above general formula (I) having as a central unit a 2H- portion tetrazol-2,5-diyl include 3- (5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl) -4- (trifluoromethyl) pyridine 1-oxide, 1-oxide - (5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl) -2- (trifluoromethyl) pyridine, 3-5-dichloro-4- (5- (3, 4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl) pyridine, 3- (5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl) -1-oxide - (trifluoromethyl) pyridine, and 3- (5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl) -5- (trifluoromethyl) pyridine-1-oxide. Preferred compounds of the above general formula (I) having as a central unit a 1,2,3-thiadiazol-4,5-diyl portion include 3- (4- (3,4-dihydroxy-5-) -oxide nitrophenyl) -1, 2, 3-thiadiazol-5-yl) -4- (trifluoromethyl) pyridine, 2-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) -1-oxide, 2, 3-thiadiazol-5-yl) -4,6-dimethylpyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2, 3-thiadiazol-5-yl-1-oxide) -2-methyl-6- (trifluoromethyl) pyridine, 5- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2, 3-thiadiazol-5-yl) -2- (trifluoromethyl) ) pyridine, 5- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2-methyl-4- (trifluoromethyl) pyridine 1-oxide, 1- 3- (4- (3, 4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine oxide, 1-oxide of 3 , 5-dichloro-4- (4- (3, 4-dihydroxy-5-nitrophenyl) -1,2, 3-thiadiazol-5-yl) pyridine, 1-oxide of 3- (4- (3, 4- dihydroxy-5-nitrophenyl) -1,2, 3-thiadiazol-5-yl) -6-methy1-2-phenyl-4- (trifluoromethyl) pyridine, 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 oxide, 3-oxide - (4- (3, -dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2- (trifluoromethyl) pyridine, 2-5-dichloro-3- (4-1-) (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -4,6-dimethylpyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1-oxide ) -1, 2, 3-thiadiazol-5-yl) -5- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazole-1-oxide -5-yl) -2-fluoropyridine, 4- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -2-fluoropyridine 1-oxide, 1- 2- (4- (3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -6-fluoropyridine oxide, 2-chloro-3- (4- ( 3,4-dihydroxy-5-nitrophenyl) -1,2,3-thiadiazol-5-yl) -6-methylpyridine, 2-bromo-3- (4- (3,4-dihydroxy-1-oxide) -nitrophenyl) -1,2, 3-thiadiazol-5-yl) -6-methylpyridine, and 1-oxide of 2-bromo-5-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) -1, 2, 3-thiadiazol-5-yl) -4,6-dimethylpyridine. Preferred compounds of the above general formula (I) having as a central unit a thiazol-2,4-diyl moiety include 3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazole-1-oxide) il) -4- (trifluoromethyl) pyridine, 2-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -4,6-dimethylpyridine 1-oxide, 1-oxide of 3- (- (3, 4-dihydroxy-5- nitrophenyl) thiazol-2-yl) -2-methyl-1-6- (trifluoromethyl) pyridine, 5- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -2- ( trifluoromethyl) pyridine, 5- (4- (3, 4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -2-methyl-4- (trifluoromethyl) pyridine 1-oxide, 3- (4-oxide - (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -2,6-dimethyl-4- (trifluoromethyl) pyridine, 3-5-dichloro-4- (4- (3, 4-dihydroxy-5-nitrophenyl) thiazol-2-yl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -6-methyl-2-phenyl -4- (trifluoromethyl) pyridine, 2-bromo-3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -4,5,6-trimethylpyridine 1-oxide, 1-oxide of 2-chloro-3- (4- (3, -dihydroxy-5-nitrophenyl) thiazol-2-yl) -4,5,6-trimethylpyridine, 3- (4- (3,4-dihydroxy) -oxide -5-nitrophenyl) thiazol-2-yl) -2- (trifluoromethyl) pyridine, 2-5-dichloro-3- (4- (3, 4-dihydroxy-5-nitrophenyl) thiazol-2-yl-1-oxide) ) -4, 6-dimethylpyridine, 3- (4- (3,4-dihydroxy-5-nitrophenol-1-oxide) l) thiazol-2-yl) -5- (trifluoromethyl) pyridine, 3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -2-fluoropyridine 1-oxide, 4- (4- (3,4-dihydroxy-5-) -oxide nitrophenyl) thiazol-2-yl) -2-fluoropyridine, 2- (3- (4,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -6-fluoropyridine 1-oxide, 2-chloro-1-oxide -3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) -6-methylpyridine, 2-bromo-3- (4- (3,4-dihydroxy-5-oxide) nitrophenyl) thiazol-2-yl) -6-methylpyridine, and 1-oxide of 2-bromo-5-chloro-3- (4- (3,4-dihydroxy-5-nitrophenyl) thiazol-2-yl) - 4, 6-dimethylpyridine.

In one embodiment, the compounds of the general formula (I) wherein the central unit consists of a 1,2,4-oxadiazo-3,5-diyl portion can be prepared by a process wherein a compound of the general formula IIA , IIB or IIC, IIA Iffi irc wherein R4, R5, Re and R7 are defined as in general formula I, subjected to a cyclization reaction comprising condensation and dehydration with a compound of general formula III (ip). wherein R8 and R9 independently represent hydrogen or suitable protecting groups for aromatic hydroxyl groups, under conditions suitable to produce oxadiazole derivatives of the formula IVA, IVB or IVC, followed by the removal of the hydroxyl protecting groups, to provide the compounds of the general formula I, wherein the central unit consists of a 1,2,4-oxadiazo-3,5-diyl portion. In another embodiment, the compounds of the general formula I wherein the central unit consists of a 1,2,4-oxadiazo-3,5-diyl portion can be prepared by a process wherein a compound of the general formula VA, VB or VC, VA VB C wherein R 4, R 5, R 7 and R 7 are defined as in the general formula I, is subjected to a cyclization reaction comprising condensation and dehydration with a compound of the general formula III under suitable conditions for produce oxadiazole derivatives of the formula VIA, VIB or VIC, VIA VIB VIC followed by oxidation of the nitrogen atom of the pyridyl to give a compound according to the formula IVA, IVB or IVC as shown above and finally, if necessary, removal of the hydroxyl protecting groups to provide the compounds of the general formula I, wherein the central unit consists of a 1, 2,4-oxadiazo-3, 5-diyl portion. Suitable protecting groups for aromatic hydroxyl groups are well known in the art. Examples of suitable protecting groups for aromatic hydroxyl groups include derivatives of methyl, ethyl, isopropyl, benzyl, 4-methoxybenzyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, tetrahydropyranyl, phenacyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, benzyloxycarbonyl, tert-butoxycarbonyl, ester, sulfonate, carbamate, phosphinate, acetal and ketal. • In a preferred embodiment, one of the groups R8 and Rg is hydrogen and the other is methyl. In a modality particularly preferred, R8 represents methyl and R9 represents hydrogen. In a preferred alternative embodiment, the protecting groups R8 and Rg are replaced with hydrogen or a group that is hydrolysable under physiological conditions. The protecting groups R8 and R9 can be removed independently from each other, in separate reaction steps or can be eliminated in the same reaction step. Likewise, the insertion of a group that is hydrolysable under physiological conditions can occur either in the same or in a subsequent reaction stage. In the present invention, suitable conditions for producing oxadiazole derivatives comprise conditions 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 to 99%, even more preferably 80 to 97%, and most preferably 85 to 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%. Following the teaching of the present invention, the skilled person can routinely determine the most suitable reaction conditions, to optimize the yield and purity of oxadiazole. The parameters that must be taken in consideration by the skilled person include, without restriction, reagents that effect condensation and dehydration agents, the choice of protecting groups R8 and Rg, solvent system, reaction temperature and reaction time and solubility of the reagents. The compound of the general formula III requires activation before condensation with a compound of the formula IIA-IIC or VA-VC. Suitable reagents for the activation of formula III include 1, 1-carbonyldiimidazole, thionyl chloride, sulfonyl chloride, N, N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide, phosgene, PC13, P0C13, PCI5, anhydrides, trichlorotriazine and chlorodimetoxitriazine and similar. Particularly preferable are 1,1-carbonyldiimidazole and thionyl chloride. In some cases, the same reagents can be used to effect the cyclization step consisting of condensation and dehydration. Alternative reagents for effecting condensation and / or dehydration include pyridine and tetrabutylammonium fluoride. Preferably, the dehydration can be carried out by thermal heating the reaction mixture, together with the aforementioned reagents. The compound of the 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 additional solvent. If preferred, the excess reagent can be removed, for example by distillation, and replaced with a solvent and another reagent such as pyridine to effect the steps of condensation and dehydration. Preferred solvent systems for activating the compound of the general formula III, and cyclization with compounds of the general formulas IIA-IIC or VA-VC are bipolar aprotic solvents including dimethylformamide, dimethyl sulfoxide, dimethylacetamide and N-methylpyrrolidinone. Dimethyl sulfoxide and dimethylacetamide are particularly preferred. Appropriate reaction temperatures and reaction times depend on the reactivity of the reagents used to effect 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 to 15 ° C, and more preferably in the range of 25 to 120 ° C. Preferably, the reaction time is in the range of 30 minutes to 24 hours, more preferably in the range from 1 hour to 18 hours, and more preferably from 2 to 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 conducted 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 product obtained. In an alternative preferred embodiment of the present invention, condensation and dehydration are conducted sequentially in the same vessel, without isolation of the O-acylated intermediates. In this particular embodiment, the reagents that effect the condensation and dehydration may be the same or different, but preferably identical. The amount of reagents that effect condensation and dehydration is not critical. Common amounts of reagents that effect condensation and dehydration include at least an amount of 1 mole, preferably 2.1 mole up to 5 mole, more preferably 2.2 to 4 mole, and most preferably from 2.3 mole to 3 mole, per mole of derivative of pyridine. In cases where the reagents effect the condensation and dehydration also serve as solvent or cosolvent, the excess amount can be much higher. As mentioned above, in preferred embodiments, the invention includes a step wherein the nitrogen atom of the pyridyl portion VIA, VIB or VIC is oxidized under conditions suitable to the corresponding pyridyl-N-oxide derivative IVA, IVB or IVC after the cyclization reaction. In the present invention, oxidative conditions suitable for producing the pyridyl-N-oxide comprise conditions that give the 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 from 92 to 99%, still more preferably from 94 to 98%, and most preferably from 95 to 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%. Following the teaching of the present invention, the skilled person can routinely determine the most suitable reaction conditions, to optimize the yield and purity of the pyridyl-N-oxide. The parameters that will be taken into consideration by the expert they include, without restriction, oxidizing agent, amount of oxidizing agent, choice of protecting groups, solvent system, reaction temperature and reaction time and solubility of reagents. Preferred oxidizing agents include hydrogen oxide, Mn02, peracetic acid, trifluoroperacetic acid, t-butylhydroperoxide, m-chloroperoxybenzoic acid, persulphuric acids, Oxone®, urea-hydrogen peroxide complex and trifluoroacetic anhydride, pyridinium chlorochromate and permanganate ions. Particularly preferred are the urea-hydrogen peroxide complex and the trifluoroacetic anhydride. The preferred amount of oxidizing agent is in the range of equimolar amounts to a 20-fold excess of the pyridine derivative. Preferably, the amount of oxidizing agent is in the range of an excess 1.2 times up to 10 times, more preferably excess 1.5 times up to 8 times and more preferably 2 times up to 5 times. Preferred solvent systems for conducting oxidation are solvents 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 ethers such as THF, 1,4-dioxane and ter- butyl methyl ether. The reaction temperatures and suitable reaction times depend on the reactivity of the oxidizing agent used. Preferably, the reaction temperature is in the range from 0 ° C to the boiling point of the solvent system used, more preferably in the range from 20 to 100 ° C, and most preferably in the range from 40 to 80 ° C. Preferably, the reaction time is in the range from 30 minutes to 24 hours, more preferably in the range from 1 hour to 18 hours, and most preferably from 2 to 6 hours. The oxidation of the nitrogen atom of the pyridyl can be carried out at any stage of the preparation process of compounds according to the general formula I. Preferably, the oxidation is conducted before the formation of the compounds of the formulas IIA-IIC, or alternatively after the formation of the oxadiazole ring as in the compounds of the VIA-VIC formulas. In another aspect of the invention, the compounds of the formulas IIA, IIB or IIC are prepared by reaction of the compounds of the general formula VIIA, VIIB or VIIC, VIIA VIIB VIIC with hydroxylamine in the presence of a chelating agent under suitable reaction conditions. In another aspect of the invention, the compounds of the formulas VA, VB or VC are prepared by reaction of the compounds of the general formula VIIIA, VIIIB or VIIIC, VIIIA VIIIB VIIIC with hydroxylamine in the presence of a chelating agent under suitable reaction conditions. In the present invention, suitable reaction conditions of the above reactions comprise conditions that give the amidoxime derivative in high yield and purity. Preferably, the yield of the desired amidoxime derivative is at least 70%, more preferably from 72 to 95%, even more preferably from 75 to 90%, and most preferably from 78 to 85%. Preferably, the purity of the amidoxime derivative. desired is at least 90%, more preferably at least 95%, even more preferably at least 96%, and most preferably at least 97%. Following the teaching of the present invention, the skilled person can routinely determine the most suitable reaction conditions to optimize the yield and purity of amidoxime. The parameters that must be taken into consideration by the skilled person include, without restriction, amount of hydroxylamine, choice of catalyst, nature of substituents R4 to R7, solvent system, reaction temperature and reaction time and reagent solubility. The preferred amount of hydroxylamine is in the range of equimolar amounts to a 50-fold excess of the pyridine derivative. Preferably, the amount of hydroxylamine is in the range of an excess of 1.2 times up to 20 times, more preferably excess of 1.5 times up to 10 times and most preferably excess of 3 times up to 5 times. Preferred chelating agents include 8-hydroxyquinoline, ortho-phenanthroline and hydrates and derivatives thereof. The preferred amount of chelating agent is in the range 0.1-10 mol%, more preferably 0.5-5 mol%, more preferably 0.75-3 mol% and most preferably 1-1.5 mol%. The solvent system is not limited particularly 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 from 0 ° C to the boiling point of the solvent system used, more preferably in the range from 20 to 100 ° C, and most preferably in the range from 40 to 80 ° C. Preferably, the reaction time is in the range from 30 minutes to 24 hours, more preferably in the range from 1 hour to 18 hours, and most preferably from 2 to 8 hours. For the preparation of pharmaceutical compositions of the general formula (I), the pharmaceutically acceptable, inert carriers are mixed with the active compounds. The pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules and capsules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be an encapsulation material. Preferably, the pharmaceutical preparation is. in a unit dosage form, for example packaged preparation, the package contains discrete quantities of the preparation as packaged tablets capsules and powders in vials or ampoules. The dosages may vary, depending on the requirement of the patient, the severity of the disease and the particular compound used, for convenience, the total daily dosage can be divided and administered in portions throughout the day. The determination of the appropriate dosage for a particular situation is within the experience of those in the medical art.

MATERIALS AND METHODS COMT activity assay in mice Liver samples from 60-day-old NMRI mice weighing 20-30 g (Harlan-Interfauna Ibérica, Barcelona, Spain) were used in all experiments, ten were maintained per cage under controlled environmental conditions ( cycle of 12 light / dark hours and room temperature of 24 ° C). The tissues perfused in saline, obtained from mice anesthetized with pentobarbitone (60 mg / kg) were used in the experiments. The tissues were immediately removed and homogenized in 5 mM phosphate buffer, pH 7.8 and stored at -80 ° C.

The activity of COMT was evaluated by the ability to methylate adrenaline to metanephrine, as previously described (Vieira-Coelho, M.A., Soares-da-Silva, P., Brain Res, 1999, 821, 69-78). The aliquots of 0.5 ml of hepatic homogenates were preincubated for 20 minutes with 0.4 ml of phosphate buffer (5 mM); after this, 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, the methyl donor (250 μM). The incubation medium also contained pargyline (100 μM), MgCl2 (100 μM) and EGTA (1 mM). Preincubation and incubation were carried out at 37 ° C under light protection conditions with continuous agitation and without oxygenation. At the end of the incubation period, the tubes were transferred to ice and the reaction was stopped by the addition of 200 μl of 2 M perchloric acid. The samples were then centrifuged (200 xg, 4 minutes, 4 ° C), and 500 μl Aliquots of the supernatant were filtered in 0.22 μm pore size Spin-X filter tubes (Costar) were used for the. metanephrine assay by high pressure liquid chromatography, with electrochemical detection. In the experiments designed to evaluate the effects of the test compounds on hepatic COMT, the test d-e compounds (in 5% carboxymethylcellulose) were given by gastric tube to mice fasting, overnight.

Subsequently, at defined intervals, the livers were removed and used to determine COMT activity as described above.

Test of COMT activity in rats The livers of 60-day-old male rats, males weighing 240-260 g (Harlan-Interfauna Ibérica, Barcelona, Spain), were kept two per cage under controlled environmental conditions (12-hour cycle). light / dark and room temperature of 24 ° C) were used in all experiments. After decapitation, the organs were immediately removed and homogenized in 5 mM phosphate buffer pH 7.8. The COMT activity was evaluated for the ability to methylate adrenaline to metanephrine. Aliquots of 0.5 ml of liver homogenates were preincubated for 20 minutes with 0.4 ml of phosphate buffer (5 mM); after this, 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), the methyl donor; the incubation medium also contained pargyline (100 μM), MgCl2 (100 μM) and EGTA (1 mM). Preincubation and incubation were carried out at 37 ° C under light protection conditions, with continuous agitation and without oxygenation. - In experiments designed to evaluate the oral bioavailability of the test substances, the compounds were administered by gastric tube to rats fasting overnight. After this, at defined intervals, the animals were sacrificed by decapitation and the livers were removed and used to determine COMT activity as described above. At the end of the incubation period (5 minutes) the tubes were transferred to ice and the reaction was stopped by the addition of 200 μl of 2 M perchloric acid. The samples were then centrifuged (200xg, 4 minutes, 4 ° C), and aliquots of 500 μl of the supernatant were filtered in 0.22 μm pore size Spin-X filter tubes (Costar) were used for the metanephrine assay. The metanephrine assay was carried out by means of high pressure liquid chromatography with electrochemical detection. The lower limits for the detection of metanephrine ranged from 350 to 500 fmol (from 0.5 to 1.0 pmol / mg protein / h).

Levels of L-DOPA and 3-O-methyl-L-DOPA in plasma They were administered orally to rats fasting overnight, topalcona, entacapone and compounds of the general formula I (all at 3 mg / kg) or vehicle ( 0.5% carboxymethylcellulose, 4 ml / kg). Some, 6 or 23 hours later, the rats were orally administered L-DOPA (12 mg / kg) plus benserazide (3 mg / kg) or vehicle (0.5% of carboxymethylcellulose, 4 ml / kg). One hour later the rats were anesthetized with sodium pentobarbitone (60 mg / kg, i.p.), the blood was collected through the vena cava and the whole brain was rapidly removed. The blood samples were centrifuged for 15 minutes at 3,000 g (4 ° C) and the plasma samples were stored at -80 ° C until the L-DOPA and 3-O-methyl-L-DOPA assay. All animal interventions were performed in accordance with the European Directive number 86/609, and the rules of the "Guide for the care and use of laboratory animals", 7th edition, 1996, Institute for Animal Research of Laboratory (ILAR), Washington, DC.

Assay of L-DOPA and catechol derivatives L-DOPA and 3-0-methyl-L-DOPA in blood samples were tested by HPLC with electrochemical detection, as previously described (Soares-da-Silva et al., Brain Res. 2000; 863: 293-297). In brief, aliquots of 20 μl were injected into the chromatograph. The chromatographic system consisted of a pump (Gilson 307) and an ODS2 column of 5 μm stainless steel (Biophase; Bioanalytical Systems, West Lafayette, IN) of 25 cm length and 4.6 mm diameter; the samples were injected by means of an automatic sample injector (Gilson 231) connected to a diluent. Gilson (Gilson 401). The mobile phase was a degassed solution of citric acid (0.1 mM); 0.5 mM sodium octyl sulfate; 0.1 M sodium acetate; Na2EDTA 0.17 mM; 1 mM dibutylamine and methanol (10% v / v), adjusted to pH 3.5 with 2 M PCA and pumped at a rate of 1.0 ml / min. "1 The detection was carried out electrochemically with a glassy carbon electrode, an electrode of Ag / AgCl reference and an amperometric detector (Gilson 142), the detector cell was operated at 0.75 V. The current produced was monitored using the Gilson Unipoint HPLC software.

Cellular toxicity The method that detects the cellular toxicity of a test substance was according to that described by Pedrosa and Soares-da-Silva (Br. J. Pharmacol., 137, 1 1305-1313, 2002). Briefly, 2A Neuro mouse neuroblastoma cells were seeded in 96 well plates in 200 μl per well of cell culture culture medium (CMA), under a humid atmosphere of C02 / air (5% / 95%) at 37 ° C. The controls of the test system before the incubations consisted of a morphological control (light microscope) of the cultured cells: coupling, dispersion and density. Five days after sowing (24 hours after the cells became confluent); the test compounds were incubated for 24 hours with cultured cells. Cultures without test article or ethanol are They ran in parallel as negative and positive controls. All incubations contained the same percentage of solvent, necessary for the test compound. Cell viability was measured using calcein-AM (Molecular Probes, Eugene, OR, USA). Membranal permeable calcein-AM, a non-fluorescent dye, is taken and converted by intracellular esterases to membranal impermeable calcein, which emits green fluorescence. After treatment with the test article or vehicle for 24 hours, the cells were washed twice with Hanks medium (composition of the medium, in mM: NaCl, 137, KCl, 5, MgSO4, 0.8, Na2HP04, 0.33, KH2P04, 0.44, CaCl2, 0.25, MgCl2, 1.0, Tris HCl, 0.15 and sodium butyrate, 1.0, pH = 7.4) and loaded with 2 μM calcein-AM in Hanks medium, at room temperature for 30 minutes. The florescence is measured at excitation of 485 nm and emission wavelengths of 530 nm in a multiplat reader. To determine the minimum staining for calcein-AM (calceinmina), eight wells were treated with ethanol, 30 minutes before the addition of calcein-AM. Subsequently, the percentage viability is calculated as [(calceínarauestra-calceínam? N) / (calceínacontroi-calceínam? N)] xlOO.

Results Table 1 shows the effects of standard inhibitors of COMT, tolcapone and entacapone, and the compounds of general formula I after COMT activity in mouse liver three hours after its oral administration (3 mg / kg). Table 1 also shows cell viability after 24 hours of exposure to tolcapone, entacapone and the compounds of general formula I (all at 30 μM) in Neuro 2 A cells.

Table 1. COMT activity in mouse liver (% control) after administration (oral) of 3 mg / kg of listed compounds and viability of Neuro 2A cells (% of viable cells) Note: * represents the coupling point of the pyridine N-oxide substituent to the molecule.

It was also discovered that the compounds of the general formula I are potent COMT inhibitors in rat liver, the maximum inhibitory effect is achieved within 1 hour up to 3 hours after their oral administration (Table 2). The maximum inhibitory effect of entacapone (Ent) and tolcapone (Tole) was observed within 1 hour after the administration (Table 2). Nine hours after administration, entacapone lacks COMT inhibitory effects and tolcapone produces minimal inhibitory effects (~ 16% inhibition), while compounds of general formula I continue to inhibit COMT activity by 22% to 90%. % of control levels (Table 2).

Table 2. COMT activity in rat liver (% control) after administration (oral) of 3 mg / kg of listed compounds.

Compound Time (h) 1 3 6 9 Entacapone 32.0 74.5 95.2 100.0 Tolcapone 18.3 28.6 56.8 83.9 18 5.2 19.9 43.0 57.4 59 1.2 18.5 39.7 56.4 30 6.3 34.8 41.2 54.5 41 21.2 9.3 18.8 39.7 42 3.6 6.1 12.3 30.9 43 16.1 30.6 64.3 77.9 45 1.1 1.2 3.8 8.9 47 10.6 4.0 3.8 8.2 Table 3 shows the percentage changes in the plasma levels of L-DOPA and 3-0-methyl-L-DOPA (3-OMD) of rats treated with L-DOPA plus benserazide at 2 hours after the administration of entacapone, tolcapone and compounds of the general formula I ( 3 mg / kg). L-DOPA plus benserazide were administered 1 hour before the collection of the plasma samples. This time point was chosen because it represents the traax for L-DOPA. As can be seen, the compounds of the general formula I produce significant increases in plasma L-DOPA, accompanied by a marked decrease in plasma 3-0-methyl-L-DOPA.

Table 3. Effect of listed compounds (3 mg / kg, oral administration) after changes (% control) in plasma levels of L-DOPA and 3-O-methyl-L-DOPA (3-OMD) of rats treated with L -DOPA plus benserazide.

Compound L-DOPA 3-OMD L-Dopa / 3-OMD increase% reduction Entacapone 68.5 -55.6 3.8 Tolcapona 202.4 -89.0 27.6 18 61.4 -63.9 4.5 29 105.1 -80.7 10.6 30 103.5 -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_L9 Conclusion The compounds of the general formula I are very potent catechol-O-methyltransferase (COMT) inhibitors, with significantly reduced toxicity. The compounds of the general formula I have potentially valuable pharmaceutical properties in the treatment of some disorders of the central and peripheral nervous system, where the inhibition of 0-methylation of catecholamines can be of therapeutic benefit, such as sleep disorders, Parkinson's disease and parkinsonian disorders, restless legs syndrome, gastrointestinal alterations, states of edema formation and hypertension. The possibility of using a long-acting, potent inhibitor with an improved safety profile opens new perspectives in the treatment of Parkinson's disease and parkinsonian disorders, gastrointestinal disorders, edema formation states and hypertension by improving the safety of the patients. Nitrocatecholic COMT inhibitors, while improving or maintaining the duration and selectivity of COMT inhibition. This is particularly important when you think about the treatment of patients affected by 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 described herein is exemplified by the following preparation examples, which should not be considered as limits of the scope of the description. Alternative routes and similar structures may be apparent to those skilled in the art.

Example 1 3-Nitro-5- [3- (l-oxy-pyridin-4-yl) - [1,2,4-oxadiazol-5-yl] -benzene-1,2-diol (compound 4, Table 1 ) a) To a stirred solution of 4-dibenzyloxy-5-nitrobenzoic acid (0.5 g, 1.32 mmol) in dimethylformamide (5 mL) at room temperature, 1, 1-carbonyldiimidazole (0.246 g, 1.52 mmol) was added in one portion. . After stirring for one hour, N '-hydroxypyridine-4-carboximidamide (0.208 g, 1.52 mmol) is added in one portion and the resulting mixture is stirred at room temperature overnight. The mixture is then stirred at 110 ° C for three hours and then allowed to cool to room temperature. The mixture is emptied on 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 leave a solid residue that was recrystallized from ethanol. 4- [5- (3, 4-Bis-benzyloxy-5-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl] -pyridine was obtained as a beige solid (0.395 g, 62%). b) 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 m-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 30 minutes, after which it was cooled again in an ice water bath. Subsequently, m-chloroperoxybenzoic acid (0.17 g, 1.03 mmol) was added and the mixture was allowed to stir at room temperature for one and one-half hour. Water (20 ml) was added and the organic phase was separated and washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried (Na 2 SO), filtered and evaporated to leave a yellow oil. The addition of diethyl ether caused the formation of a precipitate which was filtered and recrystallized from a dichloromethane / isopropanol mixture. 1-oxide of 4- [5- (3,4-Bis-benzyloxy-5-nitro-phenyl) - [1,2,4] oxadiazol-3-yl] -pyridine was obtained as white crystals (0.239 g, 70 %). c) A solution of above dibenzyl ether (0.232 g, 0.468 mmol) in dichloromethane (5 ml) was cooled to -78 ° C with stirring under argon atmosphere and treated with tribromide of boron (0.586 g, 2.34 mmol) per drip. The resulting dark purple suspension was allowed to stir at room temperature for one hour, before cooling again to -78 ° C. The mixture is quenched by the careful addition of methanol. After stirring at room temperature for one hour, the volatile materials were evaporated and the residue was treated with ethanol / toluene and re-evaporated. The yellow residue was triturated with boiling ethanol and filtered while still hot to give the title present as a yellow solid (0.102 g, 69%) with m.p. 280-282 ° C.

Example 2 3-Nitro-5- [3- (l-oxy-iridin-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, 1022 mmol) in dimethylformamide (5 ml) at room temperature, 1, 1-carbonyldiimidazole was added. (0.174 g, 1073 mmol) in one portion. The resulting mixture was stirred for ninety minutes, after which time N'-hydroxypyridine-3-carboximidamide 1-oxide (0.156 g, 1022 mmol) was added in one portion. 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, washed with water, then dried in water. the air and recrystallized from diethyl ether. 3-[5- (3,4-dimethoxy-5-nitro-phenyl- [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 dimethyl ether above (0.153 g, 0.445 mmol) in dichloromethane (10 mL) at -78 ° C under an argon atmosphere, boron tribromide (0.445 g, 1.779 mmol) was added dropwise. . The reaction mixture was allowed to warm to room temperature and stirred for ninety minutes before carefully draining it over water (100 ml). After stirring for twenty minutes, the mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated. 2-Methoxy-3-nitro-5- [3- (1-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -phenol was obtained as a yellow solid (0.12 g, 82%). c) A stirred solution of the above methyl ether (0.108 g, 0.327 mmol) in 1,2-dichloroethane (10 mL) at room temperature under argon atmosphere was treated with aluminum chloride (0.087 g, 0.654 mmol) followed by pyridine. (0.207 g, 2.62 mmol) per drop. The mixture was then heated to reflux for seven hours, then aluminum chloride (0.087 g, 0.654 mmol) and pyridine (0.207 g, 2.62 mmol) were added and the mixture was stirred at reflux for another seven hours. The mixture was allowed to cool to Room temperature, and it was drained over cold 1 N hydrochloric acid (30 ml). The resulting precipitate was precipitated, washed with water and dried at 50 ° C under vacuum. The desired product was obtained as an orange solid (0.075 g, 72%) with m.p. 278-280 ° C.

Example 3 3-Nitro-5- [3- (l-oxy-iridin-2-yl) - [1,2,4] oxadiazol-5-yl] -benzene-1,2-diol (compound 6, Table 1) a) To a stirred solution of 3,4-dimethoxy-5-nitrobenzoic acid (1.0 g, 4.40 mmol) in dimethylformamide (10 mL) at room temperature, 1,1-carbonyldiimidazole (0.821 g, 5.06 mmol). The resulting yellow mixture was allowed to stir for ninety minutes, then N'-hydroxypyridine-2-carboximidamide 1-oxide (0.775 g, 5.06 mmol) was added in one portion. The resulting mixture was stirred at room temperature overnight and then poured into water (100 ml). The resulting precipitate was filtered, washed with water and then taken up in dichloromethane (30 ml). The organic layer was washed with water and brine, dried (Na 2 SO 4), filtered and evaporated to leave a white solid (1.37 g, 86%). b) To a stirred suspension of the solid obtained above (1365 g, 3.77 mmol). in tetrahydrofuran (14 ml) at room temperature under argon atmosphere, added a 1 N solution of tetrabutylammonium fluoride in tetrahydrofuran (3.8 ml3.8 mmol). The resulting light yellow solution was allowed to stir at room temperature for seven hours, during which time a new precipitate formed. The mixture was filtered and the solid was washed with several portions of cold tetrahydrofuran. 1-Oxide of 2- [5- (3,4-dimethoxy-5-nitro-phenyl) - [1,2,4] oxadiazol-3-yl] -pyridine was obtained as a white solid (0.97 g, 75% ). c) To a stirred suspension of the dimethyl ether obtained above (0.961 g, 2.79 mmol) in dichloromethane (15 ml) at -78 ° C under an argon atmosphere, boron tribromide (3.5 g, 13.97 mmol) was added dropwise. The resulting purple suspension was allowed to stir at room temperature for seven hours, before cooling in an ice / water bath. The mixture is carefully quenched by the addition of methanol. The resulting yellow mixture was allowed to stir at room temperature for one hour, before the precipitate was filtered and washed with methanol. The solid was triturated with boiling ethanol and filtered while it was customer. After drying, the desired compound was obtained as an orange solid (0.712 g, 81%) with m.p. 168 ° C.

Example 4 5- (5-Methyl- [1,2,4] oxadiazol-3-yl) -3-nitro-benzene-l, 2-diol (compound 2, Table 1) a) To a stirred solution of 3,4-bis-benzyloxy-N '-hydroxy-5-nitro-benzamidine (1.0 g, 2.54 mmol) in dimethylformamide (5 ml) at room temperature, added 1, 1-carbonyldiimidazole (0.494 g, 3048 mmol) in one portion and the mixture was stirred at room temperature for ninety minutes. Subsequently, acetic acid (0.184 g, 3067 mmol) was added dropwise and the mixture was allowed to stir for two hours at room temperature, then at 155 ° C for three hours. The mixture was allowed to cool to room temperature and was poured into ice water (100 ml). Brine (10 mL) was added and the resulting precipitate was removed by filtration, washed with water and dried in air. The solid was dissolved in dichloromethane (20 ml) and a spatula tip of activated charcoal was added. After stirring for twenty minutes, the suspension was filtered through diatomaceous earth and the filtrate was evaporated to leave a yellow oil, which solidified upon standing. 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) To a stirred solution of the solid obtained previously (0.128 g, 0.307 mmol) in dichloromethane (15 ml) at -78 ° C under argon atmosphere, boron tribromide was added (0.318 g, 1269 mmol) per drop. The resulting purple suspension was allowed to stir at room temperature for one hour, then cooled again to -78 ° C. The mixture was quenched by the careful addition of 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%) with m.p. 169.8-172 ° C.

Example 5 5- (5-Methyl- [1, 3,] oxadiazol-2-yl) -3-nitro-benzene-1,2-diol (compound 3, Table 1) a) To a stirred solution of acid 3, 4-dimethoxy-5-nitrobenzoic acid (0.438 g, 1.93 mmol) in tetrahydrofuran (10 mL) at room temperature, 1,1-carbonyldiimidazole (0.343 g, 2.12 mmol) was added in one portion and the mixture was stirred at room temperature for one hour, then at 70 ° C for two hours, then acetic hydrazide (0.157 g, 2.12 mmol) was added. The resulting product was stirred at room temperature for thirty minutes, then at 70 ° C for two hours. After cooling to room temperature, the mixture was poured onto ice-water (100 ml) and the precipitate was filtered 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 allowed to cool to room temperature. The solution was emptied on ice-water (200 ml), causing the formation of a white precipitate. This was extracted with dichloromethane, and the organic extracts were washed with water and brine, then dried, filtered and evaporated to leave a white solid. Recrystallization from dichloromethane / petroleum ether gave 2- (3,4-dimethoxy-5-nitro-phenyl) -5-methy1- [1,3,4] oxadiazole as white crystals (0.151 g, 56%). c) To a stirred solution of the solid obtained above (0.145 g, 0.547 mmol) in dichloromethane (10 ml) at -78 ° C under an argon atmosphere, boron tribromide (0.685 g, 2.74 mmol) was added dropwise. The resulting purple suspension was allowed to stir at room temperature overnight, 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 volatiles were evaporated. Toluene (20 ml) was added to the residue and re-evaporated. The residue was triturated with boiling ethanol and filtered while hot. to give the desired product as an orange solid (0.107 g, 82%) with m.p. 245-246 ° C.

Example 6 5- [3- (3,5-Dichloro-l-oxy-pyridin-4-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-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) at room temperature was added in one portion 1.1- carbonyldiimidazole (0.246 g, 1.52 mmol), and the mixture was stirred for ninety minutes, then 3, 5-dichloro-N'-hydroxy-1-oxyisonicotinamidine (0.337 g, 1.52 mmol) was added in one portion. The resulting mixture was stirred at room temperature overnight and then emptied onto ice-water (100 ml). Brine (10 mL) was added and the precipitate was filtered, washed with water and dissolved in 30% isopropanol / dichloromethane. The dichloromethane was distilled and the resulting isopropanol suspension was stored at 0 ° C for one hour. The solid was filtered, washed with cold isopropanol and dried. to leave 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) were dissolved in dimethylformamide. (10 ml), stirred at 100 ° C for -nueve hours, then at room temperature overnight. The The resulting mixture was poured into ice-water (100 ml) and then acidified to pH 1-2 by the dropwise addition of 2N hydrochloric acid. The yellow precipitate that formed was filtered, washed with water and dissolved in water. % isopropanol / dichloromethane (50 ml). The organic phase was dried, filtered and evaporated to dryness. The residue was chromatographed on silica gel using a solvent mixture of ethyl acetate / petroleum ether (1: 1). 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-oxy-pyridin-4-yl) - [ 1, 2, 4] oxadiazol-5-yl] -6-nitro-phenol as a yellow solid (0.263 g, 49%). c) To a stirred suspension of the solid obtained above (0.24 g, 0.505 mmol) in dichloromethane (5 ml) a -78 ° C under argon atmosphere, boron tribromide was added (0.371 g, 1.5 mmol) per drop. The resulting purple suspension was allowed to stir 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%) with m.p. 252-253 ° C.

Example 7 5- [3- (2-Chloro-1-oxo-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) at room temperature, 1,1-carbonyldiimidazole was added in one portion ( 0.246 g, 1.52 mmol) and the mixture was stirred for one hour, then 2-chloro-N '-hydroxy-1-oxy-isonicotinamidine (0.284 g, 1.52 mmol) was added in one portion. The resulting mixture was stirred at room temperature for thirty minutes, then at 140 ° C for four hours. After cooling a. At room temperature, the mixture was poured into water (100 ml) and acidified to pH 1-2 by the dropwise addition of 2N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine. , then dried, filtered and evaporated to leave an orange solid which was recrystallized from dichloromethane / isopropanol to give 4- [5- (3,4-bis-benzyloxy-5-nitro-phenyl) -oxide] - [1, 2, 4] oxadiazol-3-yl] -2-chloro-pyridine as pale orange crystals (0.265 g, 38%). b) To a stirred solution of the solid obtained above (0.25 g, 0.471 mmol) in dichloromethane (5 ml) at -78 ° C under an argon atmosphere, boron tribromide (0.59 g, 2.36 mmol) was added dropwise. The dark purple suspension The resulting mixture was allowed to stir 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 reevaporated. The residue was triturated with boiling ethanol and filtered while hot to give the desired product as yellow crystals (0.12 g, 72%) that decomposed at a temperature higher than 300 ° C.

EXAMPLE 8 2-5-Dichloro-3- (5- (3,4-dihydroxy-2-nitrophenyl) -1,2,4-oxadiazol-3-yl) -4,6-dimethylpyridine a) A a stirred suspension of 3-hydroxy-4-methoxy-2-nitrobenzoic acid (0.900 g, 4.22 mmol) in N, N-dimethylacetamide (10.35 ml) at room temperature, added 1, 1-carbonyldiimidazole (1540 g, 9.506 mmol ) in 7.65 ml of V, N-dimeti lacetamide by drip. After stirring for three hours, (Z) -2,5-dichloro- was added. '-hydroxy-4,6-dimethylnicotinimidamide (1.19 g, 5.107 mmol) in 2.7 ml of N,? 7-dimethylacetamide in one portion. The resulting mixture was stirred for one hour and forty-five minutes. Then it was heated at 135 ° C for one hour. The reaction mixture was poured over ice / HCl 2? The precipitate is filtered, 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 as a yellow solid (0.317 g, 18%). b) To a stirred suspension of the solid obtained above (0.315 g, 0.766 mmol) in dichloromethane (4.3 ml) at room temperature, addition complex of hydrogen peroxide-urea (0.231 g, 2.451 mmol) was added. The resulting suspension was cooled to 0 ° C and trifluoroacetic anhydride (0.483 g, 2.30 mmol) was added dropwise. The mixture was allowed to stir at room temperature for 24 hours, then water was added and stirred for one hour. The precipitate was filtered, washed with water and dried. The crude product was chromatographed in dichloromethane / methanol (99: 1) mixture. Evaporation of the pure fractions gave 2, 5-dichloro-3- (5- (3-hydroxy-4-methoxy-2-nitrophenyl) -1,2,4-oxadiazol-3-yl) -1-oxide , 6-dimethylpyridine as yellow crystals (0.195 g, 59%). c) To a stirred suspension of the solid obtained above (0.143 g, 0.335 mmol) in N-methylpyrrolidone (2.5 ml) at 0 ° C under an argon atmosphere, aluminum chloride (0.056 g, 0.42 mmol) was added in one portion, followed by the addition of pyridine. (0.106 g, 1.34 mmol). The resulting solution was heated at 60 ° C for 25 minutes, after cooled again to room temperature and was emptied over ice / 2N HCl mixture. After stirring at room temperature for 45 minutes, the precipitate was filtered, washed with water and dried under vacuum. The crude product was recrystallized from a dichloromethane / isopropanol mixture. After drying, the desired product was obtained as yellow crystals (0.101 g, 73%) with m.p. 230 ° C (decomposes).

Examples 9-17 By applying the technique described above and related procedures, known to those skilled in the art and using the appropriate N-hydroxy-1-oxy-isonicotinamidines, the following compounds were prepared: 3-Nitro-5- [3- (1-oxy-2-phenyl-pyridin-4-yl) - [1, 2, 4] oxadiazol-5-yl] -benzene-1,2-diol, with mp 264-264.8 ° C (compound 9, Table 1) 5- [3- (2-Furan-3-yl-l-oxy-pyridin-4-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, with mp 304-305 ° C (compound 10, Table 1) 5- [3- (2-Morpholin-4-yl-l-oxy-pyridin-4-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, with mp 277-280 ° C (compound 11, Table 1) - - - 3-Nitro-5- [3- (l-oxy-2-thiomorpholin-4-yl-pyridin-4- il) - [1, 2,4] oxadiazol-5-yl] -benzene-1,2-diol, with mp 260-262 ° C (compound 12, Table 1) 3-Nitro-5- [3- (l -oxi-2-phenylsulfanyl-pyridin-4-yl) - [1, 2,4] oxadiazol-5-yl] -benzene-1,2-diol, with mp 299-301 ° C (compound 13, Table 1) 3-Nitro-5- [3- (1-oxy-2- phenoxy-pyridin-4-yl) - [1,2,4-oxadiazol-5-yl] -benzene-1,2-diol, with mp 245-246 ° C (compound 14, Table 1) 5- [3- (2,6-Dimethyl-l-oxy-pyridin-4-yl) - [1,4,2-oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol with mp 280-282 ° C (compound 15, Table 1) 5- [3- (2-Methanesulfonyl-1-oxy-pyridin-4-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro -benzene-1, 2-diol with mp 282-285 ° C (compound 16, Table 1) 5- [3- (2-Methylsulfanyl-1-oxy-pyridin-4-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol with mp 239-240 ° C (compound 17, Table 1) EXAMPLE 18 3-Nitro-5- [3- (1-oxy-4-trifluoromethyl-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -benzene-1,2-diol (compound 18, Table 1) a) To a solution of 3, -dibenzyloxy-5-nitrobenzoic acid (0.291 g, 0.769 mmol) in dimethylformamide (5 ml) at room temperature, 1, 1-carbonyldiimidazole was added. (0.131 g, 0.808 mmol) in one portion. After stirring for 90 minutes, N '-hydroxy-1-oxy-4-trifluoromethyl-nicotinamidine (0.17 g, 0.769 mmol) was added in one portion. The resulting mixture was stirred for 2 hours and then emptied onto ice-water (100 ml). The precipitate was filtered, washed with water and dried in air to give a white solid (0.192 g, 43%). b) To a stirred solution of the solid obtained above (0.192 g, 0.33 mmol) in tetrahydrofuran (10 ml) at room temperature, under an argon atmosphere, a 1 N solution of tetrabutylammonium fluoride in tetrahydrofuran (1.2 ml, 1.2 mmol) was added. ) by drip. 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 (Na2SO4), filtered and evaporated. The residue was chromatographed on silica gel using a solvent mixture of dichloromethane / methanol (99: 1) 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 solid obtained above (0.09 g, 0.16 mmol) in dichloromethane (5 ml) a - 78 ° C under an argon atmosphere, boron tribromide (0.16 g, 0.64 mmol) was added dropwise. The resulting purple suspension was allowed to stir at room temperature for 1 hour, then cooled again to -78 ° C and carefully quenched by the addition of water. After stirring at room temperature for 1 hour, the precipitate was filtered, washed with water and dried at 50 ° C under vacuum to provide the desired compound as yellow crystals (0.048 g, 79%) with mp 239-240 ° C .

Examples 19-35 By applying the technique described above and related procedures, known to those skilled in the art and using the appropriate N '-hydroxy-1-oxy-isonicotinamidines, the following compounds were prepared: 5- [3- (5-Bromo-l-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, with mp, 258-260 ° C (compound 19, Table 1) 5- [3- (6-Methyl-l-oxy-pyridin-3-yl) - [1,2,2] oxadiazol-5-11] -3-nitro-benzene-l, 2-diol , with pf 325-326 ° C (compound , Table 1) 5- [3- (4-Methyl-l-oxy-pyridin-3-yl) - [1,2,] oxadiazol-5-yl] -3-nitro-benzene-1, -2- diol, with pf 297 ° C (compound 21, Table 1) 3-Nitro-5- [3- (1-oxy-5-phenyl-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -benzene-1, 2-diol, with m.p. 288-289 ° C (compound 22, Table 1) 5- [3- (6-Chloro-1-oxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro -benzene-l, 2-diol, with mp 268-270 ° C (composite 23, Table 1) 5- [3- (2-Chloro-1-oxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-2, diol, with pf 265-267 ° C (composite 24, Table 1) 5- [3- (2-Chloro-6-methyl-1-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene l, 2-diol, with pf 218-220 ° C (compound 25, Table 1) 5- [3- (2-Morpholin-4-yl-l-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, with mp 175-177 ° C (compound 26, Table 1) 5- [3- (6-Methylsulfanyl-1-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro -benzene-l, 2-diol, with mp 264-66 ° C (compound 27, Table 1) 3-Nitro-5- [3- (1-oxy-6-trifluoromethyl-pyridin-3-yl) - [1,2,4-oxadiazol-5-yl] -benzene-l, 2-diol, with mp . 269.5-71.3 ° C (compound 28, Table 1) 5- [3- (2-Methyl-1-oxy-6-trifluoromethyl-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, with mp 240-42 ° C (compound 29, Table 1) 5- [3- (6-Methyl-1-oxy-4-trifluoromethyl-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, with m.p. 250-252.5 ° C (compound 30, Table 1) 5- [3- (2,6-Dimethyl-l-oxy-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazole-5- il] -3-nitro-benzene-l, 2-diol, with mp 252-253 ° C (compound 31, Table 1) 5- [3- (2-Methyl-1-oxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazole- 5-yl] -3-nitro-benzene-l, 2-diol, with mp 256-256.5 ° C (compound 32, Table 1) 5- [3- (6-Methyl-1-oxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazole- 5-yl] -3-nitro-benzene-l, 2-diol, with mp 237-239 ° C (compound 33, Table 1) 3-Nitro-5- [3- (1-oxy-quinolin-4-yl) - [1, 2,4] oxadiazol-5-yl] -benzene-1 , 2-diol, with mp 306-307 ° C (compound 34, Table 1) 3-Nitro-5- [3- (1-oxy-quinolin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -benzene-1 , 2-diol, with mp 276-277 ° C (compound 35, Table 1) 3-Nitro-5- [3- (l-oxy-2-trifluoromethyl-pyridin-3-yl) - [1,2, 4] oxadiazol-5-yl] -benzene-l, 2-diol, with mp 253-254 ° C (compound, Table 1) Example 36 5- [3- (2-Bromo-6-methyl-1-oxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-2 -diol (compound 36, Table 1) a) To a stirred solution of 3,4- acid dibenzyloxy-5-nitrobenzoic acid (1355 g, 3.576 mmol) in dimethylformamide (10 mL) at room temperature, added 1, 1-carbonyldiimidazole (0.667 g, 4.113 mmol) in one portion. After stirring for 90 minutes, 2-bromo-N1-hydroxy-6-methylnicotinamidine (0.946 g, 4.113 mmol) was added and the mixture was stirred overnight, then it was poured into water (100 ml). Brine (10 mL) was added and the precipitate was filtered, washed with water and dissolved in dichloromethane (50 mL). The organic layer was washed with water and brine, then dried (Na2SO4), filtered and evaporated to leave a white foam (1.91 g, 90%). b) To a solution of the solid obtained above (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 3 hours, then it was allowed to cool to room temperature. It was emptied onto ice-water (150 ml) and acidified to pH 1-2 by the dropwise addition of 2N hydrochloric acid. The mixture was extracted with dichloromethane and the organic extracts were washed with water and brine, then dried (Na2SO4). ), filtered and evaporated to leave an orange solid. Recrystallization from dichloromethane / ethanol gave 3- [5- (3,4-bis-benzyloxy-5-nitro-phenyl) - [1,4,2] oxadiazol-3-yl] -2-bromo-6- methy1- pyridine as an orange solid (0.702 g, 38%). c) To a stirred solution of the solid obtained above (0.609 g, 1063 mmol) in dichloromethane (15 ml) at room temperature, urea-hydrogen peroxide addition complex (0.525 g, 5.579 mmol) was added. The resulting suspension was cooled to 0 ° C and trifluoroacetic anhydride (1.12 g, 5.314 mmol) was added dropwise. The mixture was allowed to stir at room temperature for 5 hours, then the insoluble material was filtered and washed with a small volume of dichloromethane. The combined filtrate was stirred with a 10% aqueous solution of sodium metabisulfite (10 mL) for 15 minutes to destroy the excess peroxides, then the phases were separated. The organic phase was washed with water, a saturated aqueous solution of sodium bicarbonate, water again and brine, and then dried (Na2SO4), filtered and evaporated to leave a white solid. Recrystallization twice from dichloromethane / ethanol gave 3- [5- (3,4-bis-benzyloxy-5-nitro-phenyl) - [1,2,4] oxadiazol-3-yl] -oxide. 2-bromo-6-methy1-pyridine as white crystals (0.344 g, 55%). d) To a stirred solution of the solid obtained above (0.337 g, 0.572 mmol) in dichloromethane (10 ml) at -78 ° C under an argon atmosphere, boron tribromide (0.717 g, 2.86 mmol) was added dropwise. The resulting golden suspension was stirred at room temperature for 1 hour, then cooled again to -78 ° C and quenched by the addition of methanol. After stirring at temperature environment for 1 hour, the solvents evaporated. Ethanol (5 ml) and toluene (20 ml) were added to the residue and reevaporated. The residue was stirred in boiling ethanol and filtered while hot. After drying, the desired compound was obtained as orange crystals (0.187 g, 80%) with m.p. 246-247 ° C.

Examples 37-41 By applying the technique described above and related procedures, known to those skilled in the art and using the appropriate N'-hydroxy nicotinamidines, the following compounds were prepared: 5- [3- (2-Chloro -4,6-dimethyl-l-oxy-pyridin-3-yl) - [1,4,2-oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, with mp 234-235 ° C (compound 37, Table 1) 5- [3- (2-Bromo-4,6-dimethyl-l-oxy-pyridin-3-yl) - [1,2,4] oxadiazole-5- il] -3-nitro-benzene-l, 2-diol, with mp 205-207 ° C (compound 38, Table 1) 3-Nitro-5- [3- (1'-oxy-pyridin-3-ylmethyl) - [1,2,2] oxadiazol-5-yl] -benzenediol, with pf 232 ° C (compound 39, Table 1) 3-Nitro-5- [3- (1'-oxy-6-trifluoromethyl-pyridin-3-ylmethyl) - [1, 2, 4] oxadiazol-5-yl] - benzene-1, 2-diol, - with pfl95.2 ° C (compound 43, Table 1) 3-Nitro-5- [3- (1'-oxi-5-trifluoromethyl-pyridin-2-yloxymethyl) - [1, 2, 4] oxadiazol-5-yl] -benzene-1,2-diol, with m.p. 222 ° C (compound 44, Table 1) Example 42 5- [3- (2-Bromo-4,5,6-trimethyl-l-oxy-pyridin-3-yl) - [1,4,2-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) at room temperature, 1, 1-carbonyldiimidazole (0.465 g, 2.87 mmol) was added. ) in one portion, and the resulting mixture was stirred for 2 hours, then 2-bromo-N '-hydroxy-4,5,6-trimethyl-nicotinamidine (0.74 g, 2.87 mmol) was added in one portion. The resulting mixture was allowed to stir at room temperature overnight, and then it was poured into water (150 ml). Brine (10 ml) was added, and the resulting precipitate was filtered and washed with water. The solid was dissolved in dichloromethane (50 ml) and the organic phase was washed with water and brine, then dried, filtered and evaporated to leave an off white solid (1.40 g, 91%). b) To a stirred solution of the solid obtained above (1.39 g, 2.245 mmol) in tetrahydrofuran (20 ml) at room temperature, under an argon atmosphere, added a 1 N 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 leave a brown oil. Addition of dichloromethane (4 ml) and diethyl ether (4 ml) caused the formation of a precipitate, which was filtered and recrystallized from isopropanol. 3- [5- (3,4-Bis-benzyloxy-5-nitro-phenyl) - [1,4,2-oxadiazol-3-yl] -2-bromo-4,5,6-trimethyl-pyridine was obtained 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, urea-hydrogen peroxide complex (1.018 g, 10.82 mmol) was added in one portion. 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 15 minutes and then allowed to stir at room temperature overnight. The insoluble material was filtered and washed with a small volume of dichloromethane. The combined filtrate was stirred with a 10% aqueous solution of sodium metabisulfite for 15 minutes and then the phases were separated. The organic phase was washed with water, a saturated aqueous solution of sodium bicarbonate, water again and brine, then dried, filtered and evaporated to leave a pale orange foamy solid. This solid was subjected to chromatography on silica gel using a mixture of petroleum ether / ethyl acetate (1: 1) as eluent. The homogeneous product containing the fractions was combined and evaporated. 3-[5- (3, -Bis-benzyloxy-5-nitro-phenyl) - [1, 2, 4] oxadiazol-3-yl] -2-bromo-4,5,5-6-oxide was obtained trimethyl-pyridine as a pale yellow foamy solid (0.342 g, 54%). d) To a stirred solution of the solid obtained above (0.325 g, 0.527 mmol) in dichloromethane (10 ml) at -78 ° C under an argon atmosphere, boron tribromide was added. (0.66 g, 2.633 mmol) per drop. The resulting dark purple suspension was allowed to stir at room temperature for 1 hour, then cooled again to -78 ° C and carefully quenched by the dropwise addition of methanol. After stirring at room temperature for 1 hour, the solvents were removed by evaporation. Toluene (-20 ml) and ethanol (5 ml) were added to the residue and reevaporated. The resulting yellow solid was triturated with boiling ethanol (15 ml) and filtered while hot. The desired product was obtained as a yellow solid (0.172 g, 75%) with m.p. 242-243 ° C. - - - Examples 43-46 By applying the technique described above and the related procedures, known to those skilled in the art and using the appropriate N'-hydroxy nicotinamidine, the following compounds were prepared: 5- [3- (2-Chloro 4, 5, 6-trimethyl-1-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitrobenzene-l, 2-diol, with mp 246-247.3 ° C (compound 41, Table 1) 5- [3- (2, 5-Dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl) - [1,2,4] oxadiazole- 5-yl] -3-nitrobenzene-l, 2-diol, with mp 237-240 ° C (compound 45, Table 1) 3-Nitro-5- [3- (4, 5, 6-trimethyl-1-oxy-pyridin-3-yl) - [1,2,4] oxadiazole- 5-yl] -benzene-1,2-diol, with mp 255-256 ° C (compound 46, Table 1) 5- [3- (2-Bromo-5-chloro-4,6-dimethyl-1-oxy-pyridin-3-yl) - [1, 2, 4] oxadiazol-5-yl] -3-nitrobenzene-l, 2-diol, with mp 227-228 ° C (compound 47, Table 1) Example 47 As an example of the general formula (I) having a 2H-pyrazole-1, 5-diyl portion as the central unit, 3-nitro-5- [2- (l-oxy-2-trifluoromethyl-pyridine was prepared -3-yl) -2H-pyrazol-3-yl] -benzene-1,2-diol by the following procedure: a) To a stirred solution of 1- (3,4-dimethoxy-5-nitro-phenyl) -3-dimethylamino-prop-2-en-l-one (0.5 g, 1.79 mmol) and (2-trifluoromethyl-pyridine) -3-yl) -hydrazine (0.33 g, 1.87 mmol) in ethanol (10 mL) were added 10 drops of concentrated hydrochloric acid and the mixture was heated to reflux for 2 hours. The mixture was allowed to cool to room temperature and the resulting precipitate was filtered, 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 was added urea-hydrogen peroxide complex (0.26 g, 2.76 mmol) in one portion, followed by trifluoroacetic anhydride (0.53 g, 2.52 mmol) per drop. The resulting mixture was allowed to stir at room temperature overnight and then the insoluble material was filtered. The filtrate was washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated to leave 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 3- [5- (3, -dimethoxy-5-nitro-phenyl) -pyrazol-1-yl] -2-trifluoromethyl-pyridine 1-oxide (0.3 g, 0.73 mmol) in aqueous hydrobromic acid to 48% (10 mi) stirred at 140 ° C for one hour and then allowed to cool to room temperature. The mixture was emptied onto ice-water (100 ml) and the resulting yellow precipitate was filtered, washed with water and dried to give 3-nitro-5- [2- (1-oxy-2-trifluoromethyl-pyridin-3 -yl) -2H-pyrazol-3-yl] -benzene-1,2-diol, 0.16 g (57%).

Example 48 As an example of a compound of the general formula (I) having a 1,3,4-oxadiazol-2,5-diyl portion as the central unit, 3-nitro-5- [5- (1-) oxy-2-trifluoromethyl-pyridin-3-yl) - [1,3,4] oxadiazol-2-yl] -benzene-1,2-diol by the following procedure: a) A mixture of 3,4-dimethoxy acid -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) at reflux for three hours and then cooled to room temperature. 2-Trifluoromethyl-nicotinic acid hydrazide (0.53 g, 2.57 mmol) was added in one portion and the yellowish mixture was stirred at reflux overnight and then allowed to cool to room temperature. The mixture was poured into ice water (100 ml) and the copious precipitate was filtered, washed with water and dried to give N '- (3,4-dimethoxy-5-nitro-benzoyl) -hydrazide. 2-trifluoromethyl-nicotinic acid, 0.71 g (73%). b) A suspension of N '- (3,4-dimethoxy-5-nitro-benzoyl) -hydrazide of 2-trifluoromethyl-nicotinic acid (0.60 g, 1.44 mmol) in phosphorus oxychloride (10 ml) was stirred at 130 °. C for three hours, becoming a pale yellow solution. The mixture was allowed to cool to room temperature and then emptied onto ice-water (200 ml). The white precipitate was filtered, washed with water and dried to give 3- [5- (3,4-dimethoxy-5-nitro-phenyl) - [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) - [1,4,4] oxadiazol-2-yl] -2-trifluoromethyl-pyridine (0.45 g, 1.13 mmol) in dichloromethane (10 ml) cooled in an ice-water bath was added urea-hydrogen peroxide complex (0.23 g, 2.45 mmol) in one portion, followed by trifluoroacetic anhydride (0.47 g, 2.24 g). mmol) by drip. The resulting mixture was allowed to stir at room temperature overnight and then the insoluble material was filtered. The filtrate was washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated to leave an off white solid. Recrystallization from ethanol gave 3- [5- (3,4-dimethoxy-5-nitro-phenyl) - [1,3,4] oxadiazol-2-yl] -2-trifluoromethyl-pyridine 1-oxide. 0.39 g (83%). d) A suspension of 3- [5- (3,4-dimethoxy-5-nitro-phenyl) - [1,3,4] oxadiazol-2-yl] -2-trifluoromethyl-1-oxide. 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 allowed to cool to room temperature. 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-oxy-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 of a compound of the general formula (I) having a pyrimidin-2,4-diyl moiety as a central unit, 3-nitro-5- [2- (l-oxy-2-trifluoromethyl- pyridin-3-yl) -pyrimidin-4-yl] -benzene-1,2-diol by the following procedure: a) A stirred suspension of 1- (3,4-dimethoxy-5-nitro-phenyl) -3- dimethylamino-prop-2-en-l-one (0.28 g, 1.0 mmol), l-oxy-2-trifluoromethyl-nicotinamidine (0.31 g, 1.5 mmol) and potassium tert-butoxide (0.17 g, 1.5 mmol) in ethanol absolute (5 ml) was heated at 80 ° C in a sealed tube for one hour and then allowed to cool to room temperature.

The mixture was poured into ice water (100 ml) and the resulting precipitate was filtered, washed with water and dried to give 4- (3, 4-dimethoxy-5-nitro-phenyl) -2- (1-oxy-2-trifluoromethyl-pyridin-3-yl) -pyrimidine, 0.31 g (73%). b) a suspension of 4- (3,4-dimethoxy-5-nitro-phenyl) -2- (l-oxy-2-trifluoromethyl-pyridin-3-yl) -pyrimidine (0.25 g, 0.59 mmol) in hydrobromic acid 48% (5 mL) was stirred at 140 ° C for four hours and then allowed to cool to room temperature. The mixture was poured onto ice-water (100 ml) and the resulting filtrate was filtered, washed with water and dried to give 3-nitro-5- [2- (1-oxy-2-trifluoromethyl-pyridine-3- il) -pyrimidin-4-yl] -benzene-1,2-diol, 0.21 g (90%).

Example 50 As an example of the compound of the general formula (I) having a benzene-1,3-diyl moiety as a central unit, 5-nitro-3 '- (1-oxy-6-trifluoromethyl-pyridine-2 was prepared -yl) -biphenyl-3,4-diol by the following procedure: a) to a stirred solution of 4-benzyloxy-3-methoxyphenylboronic acid (1.0 g, 3.87 mmol) and 2- (3-bromo) -oxide phenyl) -6-trifluoromethyl-pyridine (1.12 g, 3.52 mmol) in toluene (10 ml) and ethanol (1 ml) at room temperature under argon atmosphere, 2 N aqueous sodium carbonate solution (5.41 ml, 10.82 g. mmol) followed by tetrakis (triphenylphosphine) palladium (0.22 g, 0.19 mmol). The resulting mixture was stirred at 90 ° C for two hours and then it was allowed to cool 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 left a brown oil which was chromatographed on silica gel (petroleum ether / ethyl acetate, 9: 1) to give 2- (4'-benzyloxy-3'-methoxybiphenyl- 1-oxide. 3-yl) -6-trifluoromethyl-pyridine as a 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 a bath of ice-water was added a 30% solution of hydrogen bromide in acetic acid (4 mL, 20 mmol) per drop. The resulting solution was allowed to stir at room temperature for six hours, then it was emptied onto 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 left a brown oil which was subjected to chromatography on silica gel (petroleum ether / ethyl acetate, 4: 1) to give 3-methoxy-3 '- (1-oxy-6-trifluoromethyl-pyridine. -2-il) -biphenyl-4-ol as a clear oil, -0.57 g (65%). c) To a solution of 3-methoxy-3 '- (1-oxy-6-trifluoromethyl-pyridin-2-yl) -biphenyl-4-ol (0.50 g, 1.38 mmol) in acetic acid (10 ml) at room temperature At room temperature, 60% nitric acid (0.12 ml, 1.52 mmol) was added per drip. The resulting mixture was allowed to stir for 30 minutes, then it was emptied onto ice-water (100 ml) and the resulting precipitate was filtered, washed with water and dried. After chromatography on silica gel (petroleum ether / ethyl acetate, 2: 1), 5-methoxy-3-nitro-3 '- (1-oxy-6-trifluoromethyl-pyridin-2-yl) was obtained. -biphenyl-4-ol as a yellow solid, 0.34 g (60%). d) To a stirred solution of 5-methoxy-3-nitro-3 '- (1-oxy-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, added aluminum chloride (0.123 g, 0.922 mmol) in one portion, followed by pyridine (0.233 g, 2.95 mmol) per drop. The resulting red suspension was stirred at 80 ° C for two hours, then cooled to room temperature and poured into 2N aqueous hydrochloric acid (100 ml). The precipitate was filtered, washed with water and dried to give 5-nitro-3 '- (1-oxy-6-trifluoromethyl-pyridin-2-yl) -biphenyl-3,4-diol, 0.17 g, (59 %).

Example 51 As an example of a compound of the formula (I) having a carbonyl portion as the central unit, (3,4-dihydroxy-5-nitro-phenyl) - (1-oxy-2-trifluoromethyl-pyridin-3-yl) -methanone was prepared by 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 an argon atmosphere, 2N butyllithium solution in hexanes (3.75) was added. mi, 7.5 mmol) by drip. The resulting mixture was allowed to stir for one hour, then 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 allowed to reach room temperature in two hours, then was poured over cold 2N aqueous hydrochloric acid (150 ml). The mixture was extracted with diethyl ether, and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent left a brown oil which was chromatographed on silica gel (petroleum ether / ethyl acetate, 2: 1) to give (4-benzyloxy-3-methoxy-phenyl) - (2-trifluoromethyl-pyridine -3-yl) -metanone, 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 a water bath. ice-water, urea-hydrogen peroxide complex was added (0.85 g, 9.08 mmol) in one portion, followed by trifluoroacetic anhydride (1.73 g, 8.26 mmol) per drop. The resulting mixture was allowed to stir at room temperature overnight, then the more soluble material was filtered and washed with dichloromethane (5 ml). The combined filtrate was washed with water and brine, then dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent left an orange solid which was recrystallized from ethanol to give (4-benzyl) -3-methoxy-phenyl) - (1-ox-2-tpfluoromethyl-pyr-dm-3) -? l) -metanone, 1.0 g (60%). c) To a stirred solution of (4-benzyl) -3-methox? -phenyl) - (1-ox? -2-tr? fluoromet? lp? pd? n -3? l) -methanone (0.95) g, 2.36 mmol) in dichloromethane cooled in an ice-water bath, a 30% solution of hydrogen bromide in acetic acid (3.54 mL, 17.7 mmol) was added dropwise. The resulting solution was allowed to stir at room temperature overnight, then was emptied on 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 left a brown oil which was subjected to chromatography on silica gel (petroleum ether / ethyl acetate, 1: 1) to give (4-hydroxy? -3-methox? -phen?) - (l-ox? -2-tr? fluoromet? lp? r? dm-3-? l) -methanone as a colorless solid, 0.59 g (80%). d) To a solution of (4-hydroxy-3-methoxy-phenyl) - (1-oxy-2-trifluoromethyl-pyridin-3-yl) -methanone (0.50 g, 1.59 mmol) in acetic acid (10 ml) a At room temperature, 60% nitric acid (0.14 ml, 1.75 mmol) was added per drip. The resulting mixture was allowed to stir for 30 minutes, then it was emptied onto ice-water (100 ml) and the resulting precipitate was filtered, washed with water and dried. Recrystallization from ethanol gave (4-hydroxy-3-methoxy-5-nitro-phenyl) - (1-oxy-2-trifluoromethyl-pyridin-3-yl) -methanone as a yellow solid, 0.33 g (58%) ). e) To a stirred solution of (4-hydroxy-3-methoxy-5-nitro-phenyl) - (1-oxy-2-trifluoromethyl-pyridin-3-yl) -methanone (0.30 g, 0.84 mmol) in 1, 2-Dichloroethane (10 mL) cooled in an ice-water bath, aluminum chloride (0.14 g, 1.05 mmol) was added in one portion, followed by pyridine (0.26 g, 3.35 mmol) per drop. The resulting red suspension was stirred at 80 ° C for two hours, then cooled to room temperature and poured into 2N aqueous hydrochloric acid (100 ml). The precipitate was filtered, washed with water and dried to give (3,4-dihydroxy-5-nitro-phenyl) - (1-oxy-2-trifluoromethyl-pyridin-3-yl) -methanone, 0.19 g, ( 66%).

Example 52 As a. example of a compound. of the general formula (I) having a portion (Z) -1-cyanoethen-l, 2-diyl as a central unit, 3- (3,4-dihydroxy-5-nitro-phenyl) -2- (l-oxy-6-trifluoromethyl-pyridin-3-yl) -acrylonitrile was prepared by the following procedure: a) A suspension of vanillin (1.0 g, 6.57 mmol), (l-oxy-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 at reflux for 48 hours and then allowed to cool to room temperature. The resulting precipitate was filtered, washed with water and dried. Recrystallization from isopropanol afforded 3- (4-hydroxy-3-methoxy-phenyl) -2- (1-oxy-6-trifluoromethyl-pyridin-3-yl) -acrylonitrile as white crystals, 0.95g (43%) . b) To a solution of 3- (4-hydroxy-3-methoxy-phenyl) -2- (l-oxy-6-trifluoromethyl-pyridin-3-yl) -acrylonitrile (0.90 g, 2.68 mmol) in acetic acid ( 20 ml) 60% nitric acid (0.23 ml, 2.95 mmol) was added per drip. The resulting mixture was allowed to stir at room temperature for 30 minutes, then was poured into ice-water (100 ml). The precipitate-yellow was filtered, washed with water and dried. The recrystallization from. isopropanol provided 3- (4-hydroxy-3-methoxy-5-nitro-phenyl) -2- (l-oxy-6-trifluoromethyl-pyridin-3-yl) -arylonitrile as a yellow solid, 0.63 g, (62%) ). c) To a stirred solution of 3- (-hydroxy-3-methoxy-5-nitro-phenyl) -2- (l-oxy-6-trifluoromethyl-pyridin-3-yl) - Acrylonitrile (0.55 g, 1.44 mmol) in 1,2-dichloroethane (10 mL) cooled in an ice-water bath, added aluminum chloride (0.24 g, 1.80 mmol) in one portion, followed by pyridine (0.46 g, 5.77 mmol) by drip. The resulting red suspension was stirred at 80 ° C for two hours, then cooled to room temperature and poured into 2N aqueous hydrochloric acid (100 ml). The precipitate was filtered, washed with water and dried to give 3- (3,4-dihydroxy-5-nitro-phenyl) -2- (l-oxy-6-trifluoromethyl-pyridin-3-yl) -acrylonitrile, 0.32 g (60%).

Example 53 As an example of a compound of the general formula (I) having an lH-imidazole-1, 5-diyl portion as the central unit, 2- (5- (3,4-dihydroxy) -oxide was prepared 5-nitrophenyl) -lH-imidazol-1-yl) -5- (trifluoromethyl) pyridine by the following procedure: a) To a stirred solution of 2-amino-5- (trifluoromethyl) pyridine 1-oxide (0.445 g, 2.5 mmol) in a mixture of ethanol (12.5 ml) and acetic acid (0.25 ml) at room temperature, 3,4-dimethoxy-5-nitrobenzaldehyde (0.53 g, 2.5 mmol) was added. The reaction was heated to reflux temperature for two hours, then the ethanol was evaporated. The oily residue was dissolved in a mixture of. methanol (17 ml) and 1,2-dimethoxyethane (7.5 ml), then added in one portion 1- (isocyanomethylsulfonyl) -4-methylbenzene (TOSMIC) (0.73 g, 3.75 mmol) and potassium carbonate (0.69 g, 5 mmol). The resulting mixture was stirred at reflux temperature for three hours. The reaction was evaporated to dryness and then taken up in dichloromethane (50 ml). The organic phase was washed with water (50 ml) and then dried over anhydrous magnesium sulfate, filtered and evaporated to leave a brown oil. Column chromatography on silica gel (petroleum ether / ethyl acetate, 9: 1) gave 2- (5- (3,4-dimethoxy-5-nitrophenyl) -lH-imidazol-1-yl-1-oxide ) -5- (trifluoromethyl) pyridine, 0.56 g (55%). b) 2- (5- (3,4-Dimethoxy-5-nitrophenyl) -1H-imidazol-1-yl) -5- (trifluoromethyl) pyridine 1-oxide (0.41 g, 1 mmol) was heated to 140 °. C in 48% aqueous hydrogen bromide (6 ml) for 2.5 hours. The dark homogenous solution was cooled to room temperature and the volatile materials were removed by evaporation to leave a light brown crystalline solid which was dried over P205 under vacuum. Trituration of the resulting solid with diethyl ether gave 2- (5- (3,4-dihydroxy-5-nitrophenyl) -lH-imidazol-1-yl) -5- (trifluoromethyl) pyridine 1-oxide as a yellow crystalline solid. , 0.27 g (71%).

Example 54 As an example of a compound of the formula general (I) having an isoxazo-3, 5-diyl portion as the central unit, 3- (3- (3, 4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2-oxide 1-oxide was prepared (trifluoromethyl) pyridine by the following procedure: a) To a stirred suspension of (E) -3- (3- (3,4-dimethoxy-5-nitrophenyl) acryloyl) -2- (trifluoromethyl) pyridine 1-oxide ( 1.19 g, 3 mmol) in ethanol (15 mL) was added 50% aqueous hydroxylamine solution (0.74 mL, 4.5 mmol) and the mixture was heated to 80 ° C. After stirring for 1 hour, a fine precipitate was separated from the reaction mixture. After cooling to room temperature, the yellow precipitate was filtered, washed with ethanol and dried under vacuum to give 3- (3- (3,4-dimethoxy-5-nitrophenyl) -5-hydroxy-4-oxide. , 5-dihydroisoxazol-5-yl) -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 at 70 ° C. To the resulting suspension was added trifluoroacetic acid (0.74 g, .6.5 mmol) per drop. After 10 minutes, the reaction was evaporated to dryness and the residue was recrystallized from isopropanol to give 3- (3- (3, 4-dimethoxy-5-nitrophenyl) isoxazol-5-yl-1-oxide) - (trifluoromethyl) pyridine, 1.27 g (62%). c) 3- (3- (3,4-Dimethoxy-5-) 1-oxide nitrophenyl) isoxazol-5-yl) -2- (trifluoromethyl) pyridine (0.81 g, 2 mmol) was taken up in dichloromethane (15 ml) and the yellowish suspension was cooled to -78 ° C under an argon atmosphere, then boron tribromide (4.5 g, 18 mmol) was added dropwise. The reddish reaction mixture was allowed to warm to room temperature and stirred for 18 hours, then carefully poured into ice-water (100 ml) and allowed to stir for 1 hour. The yellow precipitate was filtered, washed with water and dried over P2Os under vacuum. Trituration with boiling ethanol gave 3- (3- (3,4-dihydroxy-5-nitrophenyl) isoxazol-5-yl) -2- (trifluoromethyl) pyridine 1-oxide as a yellow solid, 0.49 g (64%). ).

Example 55 As an example of a compound of the general formula (I) having a furan-2,4-diyl portion as the central unit, 3- (4- (3,4-dihydroxy-5-) -oxide was prepared nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2- (trifluoromethyl) pyridine by the following procedure: a) To a stirred solution of 3- (3-ethoxy-3-oxopropanoyl) -2-oxide - (trifluoromethyl) pyridine (1.39 g, 5 mmol) in pyridine (25 ml) was added 2-bromo-l- (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 emptied onto 6 N aqueous HCl. (100 mi) The precipitate was filtered, washed with water and dried over P2Os under vacuum. The solid was recrystallized from dichloromethane / isopropanol to give 3- (4- (3,4-dimethoxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2- (trifluoromethyl) -oxide. crude pyridine, 1.05 g (43%). b) 3- (4- (3,4-Dimethoxy-5-nitrophenyl) -3- (ethoxycarbonyl) furan-2-yl) -2- (trifluoromethyl) pyridine 1-oxide (482 mg, 1 mmol) it was taken up in dichloromethane (8 ml). The yellowish suspension was cooled to -78 ° C under argon atmosphere, and boron tribromide (0.85 ml, 9 mmol) was added dropwise. The reddish reaction mixture was allowed to warm to room temperature and was stirred for 18 hours, and then carefully poured into ice-water (100 ml) and stirred for 1 hour. The yellow precipitate was filtered, washed with water and dried over P2 5 under vacuum. 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 of a compound of the general formula (I) having an oxazole-2,4-diyl moiety as a central unit, 3- (4- (3,4-dihydroxy-5-) -oxide was prepared nitrophenyl) oxazol-2-yl) -2- (trifluoromethyl) pyridine by 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) were added 3-oxide carbamoyl-2- (trifluoromethyl) pyridine (3.40 g, 16.5 mmol) and boron trifluoride etherate (0.18 ml, 15 mmol). The resulting yellow solution was heated to reflux for 18 hours and then cooled or 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. 1-Oxide of 3- (4- (3,4-dimethoxy-5-nitrophenyl) oxazol-2-yl) -2- (trifluoromethyl) pyridine was obtained by column chromatography on silica gel (petroleum ether / acetate ethyl, 2: 1) 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 taken up in dichloromethane (25 ml) . The yellowish suspension was cooled to -78 ° C under an argon atmosphere, and boron tribromide (2.55 ml, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. This was carefully poured into ice-water (100 ml) and stirred for 1 hour. The resulting yellow precipitate was filtered, washed with water and dried over P205 under vacuum. 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 of a compound of the general formula (I) having a 1,2,4-triazin-3,5-diyl portion as the central unit, 3- (5- (3-1-oxide) was prepared , -dihydroxy-5-nitrophenyl) -1,2, 4-triazin-3-yl) -2- (trifluoromethyl) pyridine by the following procedure: a) To a stirred solution of 1-oxide of (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 to 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) 3- (5- (3,4-dimethoxy-5-nitrophenyl) -1, 2-triazine-1-oxide 3-yl) -2- (trifluoromethyl) pyridine (1.27 g, 3 mmol) was taken up in dichloromethane (25 ml). The yellowish solution was cooled to -78 ° C under an argon atmosphere, and boron tribromide (2.55 ml, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. This was carefully poured into ice-water (100 ml) and stirred for 1 hour. The yellow precipitate was filtered, washed with water and dried over P205 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) -oxide. ) pyridine as a yellow solid, 0.84 g (71%).

Example 58 As an example of a compound of the general formula (I) having a 1,3,5-triazin-2,4-diyl portion as the central unit, 3- (4- (3-1-oxide) was prepared , 4-dihydroxy-5-nitrophenyl) -1, 3, 5-triazin-2-yl) -2- (trifluoromethyl) pyridine by the following procedure: a) To a solution of (E) -N- ((dimethylamino) Methylene) -3,4-dimethoxy-5-nitrobenzamide (1.12 g, 4 mmol), ethanol (30 mL) was added 3-carbamidoyl-2- (trifluoromethyl) pyridine 1-oxide (0.82 g, 4 mmol). The reaction mixture was heated to reflux for 5 hours. This was cooled to room temperature and the solvent was removed by evaporation. The residue was dissolved in dichloromethane / isopropanol mixture (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) -l, 3,5-triazin-2-yl) -2- (trifluoromethyl) 1-oxide. pyridine, 1.27 g (75%). b) A 1-oxide portion of 3- (4- (3,4-dimethoxy-5-nitrophenyl) -1,3,5-triazin-2-yl) -2- (trifluoromethyl) pyridine (1269 g, 3) mmol) was taken up in dichloromethane (25 ml). The yellowish solution was cooled to -78 ° C under an argon atmosphere, and boron tribromide (2.55 ml, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours and then carefully vacuum in ice-water (100 ml) and stirred for 1 hour. The yellow precipitate was filtered, washed with water and dried over P2Os under vacuum. Recrystallized from a dichloromethane-ethanol mixture gave 3- (4- (3,4-dihydroxy-5-nitrophenyl) -1, 335-triazin-2-yl) -2- (trifluoromethyl) pyridine-1-oxide. as a yellow solid, 1.07 g (90%).

Example 59 As an example of. a Compound of the general formula (I) having a portion of pyrrole-2, 5-diyl as central unit, 5- (3,4-dihydroxy-5-nitrophenyl) -l-methyl-2- (2-trifluoromethyl-1-oxypyridin-3-yl) -lH-pyrrole-3-ethyl acid ethyl ester was prepared carboxylic acid by 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) at room temperature was added 3-Oxo-3- (l-oxy-2-trifluoromethyl-pyridin-3-yl) -propionic acid ethyl ester (1.39 g, 5 mmol). The reaction mixture was heated to reflux for 2 hours, then 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) in one portion, followed by 1- (3, -bis-benzyloxy-5-nitro-phenyl) -2-bromine. Ethanone (2.51 g, 5.50 mmol) and the mixture was stirred at 100 ° C. Once the starting material was not detectable by TLC, the reaction mixture was allowed to warm to room temperature and was emptied - over 1 N aqueous hydrochloric acid (100 ml). The resulting precipitate was filtered, washed with water and dried. The residue was subjected to silica gel chromatography. The homogeneous fractions were combined and evaporated to give 5- (3,4-bis-benzyloxy-5-nitro-phenyl) -l-methyl-2- (2-trifluoromethyl-1-oxy-pyridin-3-ethyl ester. -yl) -lH-pyrrole-3-carboxylic acid, 2.41 g (79%). b) A solution of 5- (3,4-) ethyl ester bis-benzyloxy-5-nitro-phenyl) -l-methyl-2- (2-trifluoromethyl-1-oxy-pyridin-3-yl) -lH-pyrrole-3-carboxylic acid (0.2 g, 0.30 mmol) in dichloromethane (10 ml) was cooled to -78 ° C with stirring and treated under argon atmosphere, with boron tribromide (0.30 g, 1.21 mmol). The resulting dark purple suspension was allowed to stir at room temperature for 1 hour, before being cooled again to -78 ° C. The mixture is quenched by the careful addition of methanol. After stirring at room temperature for 30 minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for 30 minutes. The resulting solid was filtered, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- (3,4-dihydroxy-5-nitro-phenyl) -l-methyl-2-ethyl ester. - (L-oxy-2-trifluoromethyl-pyridin-3-yl) -lH-pyrrole-3-carboxylic acid as a yellow solid, 0.13 g (93%).

Example 60 As an example of a compound of the general formula (I) having a 2H-tetrazole-2,5-diyl portion as the central unit, 5- [2- (5-trifluoromethyl-1-oxy-pyridine- 2-yl) -2H-tetrazol-5-yl] -3-nitrobenzene-1,2-diol by 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 to yield 5- (3,4-bis-benzyloxy-5-nitro-phenyl) -2H-tetrazole, 0.53 g (87%). b) 2-Chloro-5-trifluoromethyl-1-oxy-pyridine (0.20 g, 1.00 mmol) was added to a stirred suspension of 5- (3,4-bis-benzyloxy-5-nitro-phenyl) -2H-tetrazole (0.4 g, 1.00 mmol) and potassium carbonate (0.14 g, 1 mmol) in acetonitrile (10 mi) The reaction mixture was stirred at room temperature until completion, then diluted with dichloromethane and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, to leave a crude residue which was recrystallized from a dichloromethane / isopropanol mixture to give 2- [5- (3, 4- bis-benzyloxy-5-nitro-phenyl) -tetrazol-2-yl] -5-trifluoromethyl-1-oxy-pyridine, 0.40 g (71%). c) A solution of 2- [5- (3,4-bis-benzyloxy-5-nitro-phenyl) -tetrazol-2-yl] -5-trifluoromethyl-1-oxy-pyridine (0.282 g, 0.5 mmol) in dichloromethane (15 ml) was cooled to -78 ° C with stirring under argon atmosphere, and treated, with boron tribromide (1.00 g, 4.00 mmol) per drop. The purple suspension The resulting dark was allowed to stir at room temperature for 1 hour, before being cooled again to -78 ° C. The mixture is quenched by the careful addition of methanol. After stirring at room temperature for 30 minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for 30 minutes. The resulting solid was filtered, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- [2- (5-trifluoromethyl-1-oxy-pyridin-2-yl) -2H-tetrazole- 5-yl] -3-nitrobenzene-1,2-diol as a yellow solid, 0.17 g, (90%).

Example 61 As an example of a compound of the general formula (I) having a 1,3-thiazol-2,4-diyl portion as the central unit, 5- [2- [2- (trifluoromethyl) -1 was prepared -oxi-pyridin-3-yl] - [l, 3] -thiazol-4-yl] -3-nitrobenzene-1,2-diol by the following procedure: a) A mixture of 2- (trifluoromethyl) -1- oxy-pyridine-3-carbothioamide (0.24 g, 1.10 mmol) and 1- [3, -bis (benzyloxy) -5-nitrophenyl] -2-bromoethanone (0.50 g, 1.10 mmol) was heated to reflux overnight in ethanol absolute (5 mi). After cooling to room temperature, the reaction mixture was poured into water (50 ml). The resulting precipitate was filtered, washed with water (25 ml) and dried. Recrystallized from dichloromethane / isopropanol gave 3- [4- (3, 4- bis-benzyloxy-5-nitro-phenyl) - [1,3] -thiazol-2-yl] -2-trifluoromethyl-1-oxy-pyridine, 0.55 g (87%). b) a solution of 3- [4- (3,4-bis-benzyloxy-5-nitro-phenyl) - [1,3] -thiazol-2-yl] -2-trifluoromethyl-1-oxy-pyridine (0.15) g, 0.26 mmol), in dichloromethane (10 mL) was cooled to -78 ° C and treated under argon atmosphere, with boron tribromide (0.26 g, 1.03 mmol). The resulting dark purple suspension was allowed to stir at room temperature for 1 hour, before being cooled again to -78 ° C. The mixture is quenched by the careful addition of methanol. After stirring at room temperature for 30 minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for 30 minutes. The resulting solid was filtered, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- [2- [2- (trifluoromethyl) -1-oxy-pyridin-3-yl] - [1] , 3] -thiazol-4-yl] -3-nitrobenzene-l, 2-diol as a yellow solid, 0.09 g (87%).

Example 62 As an example of a compound of the general formula (I) having a portion of 1,2,4-triazole-3,5-diyl as the central unit, 5- [4-methyl-5- (2-trifluoromethyl) was prepared -l-oxy-pyridin-3-yl) -4 H- [1, 2, 4] triazol-3-yl] -3-nitro-benzene-1,2-diol by the following procedure: a) To a solution stirred from 3,4- chloride dimethoxy-5-nitro-benzoyl (0.50 g, 2.04 mmol) in dichloromethane (10 mL) at 0 ° C, methylamine (1.02 mL, 2.04 mmol, 2 M in THF) was added dropwise. The reaction mixture was stirred at room temperature until all the 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 leave a crude residue which was recrystallized from a dichloromethane / isopropanol mixture to give 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) in portions. After the addition was completed, the reaction mixture was heated to reflux until complete disappearance of the starting material. Evaporation to dryness resulted in a crude solid which was washed with diethyl ether, yielding 3,4-dimethoxy-N-methyl-5-nitro-benzimidoyl chloride, 0.37 g (85%). c) A mixture of 2-trifluoromethyl-1-oxy-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 acid dilute hydrochloric The resulting precipitate was collected, washed with water and dried to yield 3- (2H-tetrazol-5-yl) -2-trifluoromethyl-1-oxy-pyridine, 0.52 g (90%). d) 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 -oxi-pyridine (0.23 g, 1 mmol) in anhydrous pyridine (3 ml), preheated to 50 ° C. The resulting mixture was carefully heated to 75-90 ° C and maintained at this temperature until nitrogen evolution 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 provide 3- [5- (3,4-dimethoxy-5-nitro-phenyl) -4-methyl-4H- [1,2,4] triazol-3-yl] -2- trifluoromethyl-1-oxy-pyridine, 0.25 g (59%). e) 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-oxy-pyridine (0.20 g, 0.47 mmol) in dichloromethane (20 mL) at -78 ° C under argon atmosphere, boron tribromide (0.47 g, 1.88 mmol) was added dropwise. The resulting dark purple suspension was allowed to stir at room temperature for 7 hours, before it was cooled in an ice-water bath. The mixture is quenched by the careful addition of methanol. After shaking at room temperature for 30 minutes, the volatiles were evaporated and the residue was stirred with 2N hydrochloric acid (5 ml) for 30 minutes. The resulting solid was filtered, washed with water (25 ml) and then with cold isopropanol (5 ml) to give, after drying, 5- [4-Methyl-5- (2-trifluoromethyl-l-oxy-pyridin-3 -yl) -4H- [1, 2, 4] triazol-3-yl] -3-nitro-benzene-1,2-diol which was obtained as an orange solid, 0.16 g (86%).

Example 63 An example of a compound of the general formula (I) having a 1,2,3-thiadiazol-4,5-diyl portion as the central unit was prepared 5- [5- (2-trifluoromethyl-1- oxy-pyridin-3-yl) - [1,2,3] thiadiazol-4-yl] -3-nitrobenzene-1,2-diol by the following procedure: a) A mixture of 1- (3, -bis- benzyloxy-5-nitro-phenyl) -2- (2-trifluoromethyl-1-oxy-pyridin-3-yl) -ethanone (0.50 g0.93 mmol), ethyl carbazate (0.11 g, 1.06 mmol) and p-toluenesulfonic acid (4 mg) in toluene (10 mL) was heated 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 to yield N '- [1 -. 3, 4-bis-benzyloxy-5-nitro-phenyl) -2- (2-trifluoromethyl-1-oxy-pyridin-3-yl) -ethylidene] - Hydrazincarboxylic acid, 0.49 g (84%). b) A mixture of N '- [l- (3,4-bis-benzyloxy-5-nitro-phenyl) -2- (2-trifluoromethyl-1-oxy-pyridin-3-yl) -ethylidene ethyl ester ] -hydrazincarboxylic acid (0.40 g, 0.64 mmol), in thionyl chloride (2 mL) was heated to reflux until no more initial material was detected by TLC. The excess solvent was removed and the residue was purified by chromatography on silica gel using a dichloromethane / ethanol mixture as eluent. The homogeneous fractions were combined and evaporated to give 3- [4- (3,4-bis-benzyl i-5-nitro-phenyl) - [1,2,3] thiadiazol-5-yl] -2-trifluoromethyl- 1-oxy-pyridine, 0.19 g (51%). c) A solution of 3- [4- (3,4-bis-benzyloxy-5-nitro-phenyl) - [1, 2, 3] thiadiazol-5-yl] -2-trifluoromethyl-1-oxy-pyridine ( 0.15 g, 0.26 mmol) in dichloromethane (10 mL) was cooled to -78 ° C with stirring and treated under argon atmosphere, with boron tribromide (0.26 g, 1.03 mmol). The resulting dark purple suspension was allowed to stir at room temperature for 1 hour, before cooling again to -40 ° C. The mixture is quenched by the careful addition of methanol.

After stirring at room temperature for 30 minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for 30 minutes. He The resulting solid was filtered, washed with water - (25 ml) and then with cold isopropanol (5 ml) to give 5- [5- (2- trifluoromethyl-1-oxy-pyridin-3-y1) - [1,2,3] thiadiazol-4-yl] -3-nitrobenzene-1,2-diol as a yellow solid, 0.09 g (89%).

Example 64 As an example of a compound of the general formula (I) having a 1,2,4-oxadiazol-3, 5-diyl portion as the central unit, 5- [5- [2- (trifluoromethyl) was prepared -l-oxypyridin-3-yl] - [1,2,4] -oxadiazol-3-yl] -3-nitrobenzene-1,2-diol by the following procedure: a) To a stirred solution of 2-trifluoromethyl acid -nicotinic acid (0.38 g, 2 mmol) in dimethylformamide (10 ml) at room temperature, 1, 1-carbonyldiimidazole (0.34 g, 2.10 mmol) was added in one portion. The resulting yellow mixture was allowed to stir for 90 minutes, subsequently 3,4-bis (benzyloxy) -N'-hydroxy-5-nitrobenzamidine (0.79 g, 2 mmol) was added in one portion. The reaction mixture was stirred at room temperature for two hours and then poured into water (100 ml). The resulting precipitate was filtered, washed with water and dried. After recrystallization from dichloromethane / isopropanol, 3,4-bis (benzyloxy) -5-nitro-N '- (2- (trifluoromethyl) nicotinoyloxy) benzimidamide was obtained as a yellow solid, 0.88 g (78%). b) To a stirred solution of the solid obtained above (0.26 g, 0.46 mmol) in tetrahydrofuran (15 ml) at room temperature, under an argon atmosphere, a 1 N solution of tetrabutylammonium fluoride (0.7 ml, 0.7 mmol) was added. The resulting light yellow solution was allowed to stir at room temperature for 4 hours. Additional tetrabutylammonium fluoride (0.7 mmol) was added and the reaction mixture was allowed to stir for 15 hours at room temperature and then 10 hours at 55 ° C. After cooling to room temperature, the reaction mixture was poured into water (150 ml). The resulting precipitate was filtered, washed with water and dried. The crude product was subjected to chromatography on silica gel using dichloromethane as eluent. The homogeneous fractions were combined and evaporated to provide 3- [3- [3,4-bis (benzyloxy) -5-nitrophenyl] - [1,2,4] -oxadiazol-5-yl] -2- (trifluoromethyl) pyridine as an 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, was added a complex of urea-hydrogen peroxide (0.28 g, 3 mmol) and trifluoroacetic anhydride (0.43 ml, 3.00 mmol). After the reaction mixture had been stirred at room temperature for 60 hours, the solid residues were filtered. The organic phase was then treated successively with an aqueous solution of Na2S20d (0.6 g, 3.45 mmol, dissolved in 20 ml of water), 0.4 N hydrochloric acid (20 ml), a saturated solution of NaHCO3 (20 ml), water (20 ml) and brine (20 mi). 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 eluent. The homogeneous fractions were combined and evaporated, and the residue was recrystallized from dichloromethane / isopropanol to provide 3- [3- [3,4-bis (benzyloxy) -5-nitrophenyl] - [1,2,4] - Oxadiazol-5-yl] -2- (trifluoromethyl) -1-oxy-pyridine as a yellow solid, 0.23 g (68%). d) A solution of 3- [3- [3, 4-bis (benzyloxy) -5-nitrophenyl] - [1,2,4] -oxadiazol-5-yl] -2- (trifluoromethyl) -1-oxy- pyridine (0.10 g, 0.18 mmol) in dichloromethane (5 mL) was cooled to -78 ° C with stirring, under an argon atmosphere, and treated with boron tribromide (0.18 g, 0.74 mmol) per drop. The resulting dark purple suspension was allowed to stir at room temperature for 1 hour, before being cooled again to -78 ° C. The mixture is quenched by the careful addition of methanol. After stirring at room temperature for 30 minutes, the volatiles were evaporated and the residue was stirred with 2 N hydrochloric acid (5 ml) for 30 minutes. The resulting solid was filtered, washed with water (25 ml) and then with cold isopropanol (5 ml) to give 5- [5- [2- (trifluoromethyl) -l-oxypyridin-3-yl] - [1, 2]. , 4] -oxadiazol-3-yl] -3-nitrobenzene-l, 2-diol as a yellow solid, 0.06 g (88%).

Claims (24)

1. Compound of the formula (i; (i) wherein R x and R 2 are independently of each other hydrogen or a group that is hydrolysable under physiological conditions, optionally substituted alkanoyl or lower aroyl; X represents a methylene group; Y represents an oxygen, nitrogen or sulfur atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a pyridine N-oxide group according to formula A, B or C, which is connected as indicated by the unmarked link: wherein R 4, R 5, R 6 and R 7 independently represent hydrogen, alkyl of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 6-12 carbon atoms or a thioaryl group of 6-12 carbon atoms, alkanoyl of 1-6 carbon atoms or aroyl group of 7-13 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms, cycloalkylamino of 3-12 carbon atoms or heterocycloalkylamino of 3-12 carbon atoms, alkylsulfonyl of 1-6 carbon atoms or arylsulfonyl of 6-12 carbon atoms, halogen, haloalkyl of 1-6 carbon atoms, trifluoromethyl, cyano, nitro or a heteroaryl group; or wherein two or more of the residues R4, R5, R6 and R7 taken together represent aliphatic or heteroaliphatic rings or aromatic or heteroaromatic rings and wherein P represents a central unit, which is preferably selected from the regioisomers of 1, 3, 4 -oxadiazol-2,5-diyl, 1, 2, 4-oxadiazol-3, 5-diyl, 4-methyl-4H-l, 2,4-triazol-3, 5-diyl, 1, 3, 5-triazin -2,4-diyl, 1, 2,4-triazin-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, l-alkyl-3 - (alkoxycarbonyl) -lH-pyrrole-2, 5-diyl, wherein alkyl is represented by methyl, ethyl, n-propyl and n-butyl and wherein alkoxy is represented by methoxy, ethoxy, n-propoxy and isopropoxy, - l-alkyl-lH-pyrrole-2, 5-diyl, wherein alkyl is represented by methyl, ethyl, n-propyl and n-butyl, t-azol-2, 4-dial, 1-Hp? razol-l, 5-dnlo, p? r? m? d? n-2, 4-dial, oxazole -2, 4-dial, carbonyl, 1H-? M? Dazol-1, 5-dial,? -soxazol-3, 5-dial, furan-2, 4-dial , 3-alkoxycarbonylfuran-2,4-dial, wherein alkoxy is represented by methoxy, ethoxy, n-propoxy and isopropoxy, benzene-1,3-dial and (Z) -1-c? Anoete -l, 2-dial and wherein the regioisomers of the central unit include both regioisomers realizable by exchange of the nitrocatechol portion and the - (X) n- (Y) m-R3 portion.
2. 2. Compound according to claim 1, comprising 5- [3- (3,5-d? Chloro-l-ox? -p? R? Dm-4-? L) - [1,2,4] oxad? Azole 5-? L] -3-n? Tro-benzene-l, 2-d? Ol, 5- [3- (2-chloro-l-ox? -p? R? Dm-4-? L) - [ l, 2,4] oxad? azole-5-? l] -3-n? trobenzene-1,2-d? ol, 5- [3- (2-morpholm-4? ll-ox? -p? pd? n-4-yl) - [1, 2, 4] oxad? azole-5? l] -3-n? tro-benzene-l, 2-diol, 3-n? tro-5- [3 - (l-ox? -4-tr? fluoromet? lp? r? dm-3-? l) - [1,2,4] oxadiazol-5? l] -benzene-1,2-d? ol, 5- [3- (4-bromo-l-ox? -p? R? D? N -3? L) - [1,2,4] oxad? Azole-5-? L] -3-n? tro-benzene-l, 2-diol, 5- [3- (2-chloro-6-met? ll-ox? -p? r? d? n -3?) - [1,2,4] oxad? azole-5-? l] -3-n? tro-benzene-1,2-d? ol, 5- [3- (2-morpholine? 4-? ll-ox? -p? r? dm-3-yl) - [1, 2, 4] oxad? azole-5? l] -3-n? tro-benzene-1, 2-diol, 3-n? tro-5- [3- ( l-ox? -6-tr? fluoromethyl-pyridin-3-ll) - [1,2,4] oxadiazol-5? l] -benzene-1,2-d? ol, 5- [3- (2 -met? ll-ox? -6-tr? fluoromethyl-p? pdm-3-? l) - [1,2,4] oxad? azole-5? l] -3-n? tro-benzene , 2-diol, 5- [3- (6-Methyl-l-oxy-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol , 5- [3- (2,6-dimethyl-l-oxy-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro-benzene, 2-diol, 5- [3- (2-methyl-l-oxy-6-phenyl-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitro -benzene-1, 2-diol, 5- [3- (6-methyl-1-oxy-2-phenyl-4-trifluoromethyl-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl ] -3-nitro-benzene-l, 2-diol, 5- [3- (2-bromo-6-methyl-l-oxy-pyridin-3-yl) - [1,2,4] oxadiazole-5- il] -3-nitro-benzene-1,2-diol, 5- [3- (2-chloro-4, 6-dimethyl-l-oxy-pyridin-3-yl) - [1, 2,4] oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, 5- [3- (2- bromo-4,6-dimethyl-l-oxy-pyridin-3-yl) - [1,2,4-oxadiazol-5-yl] -3-nitro-benzene-l, 2-diol, 5- [3- (2-bromo-4, 5,6-trimethyl-l-oxy-pyridin-3-yl) - [1, 2,4] oxadiazol-5-yl] -3-nitrobenzene-l, 2-diol, 5- [3- (2-Chloro-4,5,6-trimethyl-l-oxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-1,2-diol , 5- [3- (2, 5-dichloro-4,6-dimethyl-l-oxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3-nitrobenzene-1, 2-diol, 5- [3- (2-bromo-5-chloro-4,6-dimethyl-l-oxy-pyridin-3-yl) - [1,2,4] oxadiazol-5-yl] -3 -nitrobenzene-1, 2-diol and 3-nitro-5- [3- (1-oxy-2-trifluoromethyl-pyridin-3-y1) - [1,2,4] oxadiazol-5-yl] -benzene 1,2-diol.
3. 3. Method of treatment of a subject affected by some disorders of the central nervous system and peripheral, wherein a reduction in O-methylation of catecholamines may be of therapeutic benefit, such as Parkinson's disease and parkinsonian disorders, gastrointestinal disorders, edema formation states and hypertension, which comprises administering to the subject, an amount of a compound according to claim 1 or 2, effective to treat the diseases of the subject.
4. 4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or 2, in combination with a pharmaceutically acceptable carrier.
5. 5. Use of a compound according to claim 1 or 2, in the manufacture of a medicament for treating a subject affected by central or peripheral nervous system disorder.
6. 6. Use of a compound according to claim 1 or 2, in the manufacture of a medicament for treating mood disorders, Parkinson's disease and parkinsonian disorders, restless legs syndrome, gastrointestinal disorders, state of edema formation and hypertension.
7. 7. Use of a compound according to claim 1 or 2, in therapy.
8. 8. Use of a compound according to claim 1 or 2, for use in the manufacture of a medicament for use as a COMT inhibitor.
9. 9. Process for the preparation of compounds according to formula I, comprising the steps wherein a compound of formula IIA, IIB or IIC, HA IIB IIC, wherein R 4, R 5, Re and R as defined in general formula I in claim 1, is cyclized with a compound of formula III, (neither), wherein R8 and Rg independently from each other represent hydrogen or suitable protecting groups for aromatic hydroxyl groups, under conditions suitable to produce oxadiazole derivatives of the formula IVA, IVB or IVC, optionally followed by the removal of the protective groups Re and Rg.
10. 10. Process for the preparation of compounds according to formula I, comprising the steps wherein a compound of the formula VA, VB or VC, VA VB VC, where R4, R5, R and R7 are defined as in. the general formula I according to claim 1 is subjected to a cyclization reaction with a compound of the general formula III under conditions suitable to produce oxadiazole derivatives of the formula VIA, VIB or VIC, VIA VIB VIC followed by oxidation of the nitrogen atom of the pyridyl to give a compound according to the formula IVA, IVB or IVC, optionally followed by removal of the protective groups R8 and / or R9.
11. 11. Process according to claim 9 or 10, wherein the compound of formula III is activated by reaction with thionyl chloride or 1,1-carbonyldiimidazole.
12. 12. Process according to any of claims 9 to 11, wherein the cyclization step consists of condensation and the dehydration is conducted sequentially in a reaction in a vessel.
13. 13. Process according to any of claims 9 to 12, wherein the cyclization step is carried out in the presence of a suitable organic base.
14. Process according to claim 13, wherein the cyclization step is carried out in the presence of pyridine.
15. 15. Process according to any of claims 9 to 14, wherein the groups Rs and Rg are independently of each other or are removed together and replaced with hydrogen or a group that is hydrolysable under physiological conditions.
16. 16. Process according to any of claims 9 to 15, wherein Rg and Rg of the compound of the formula III independently represent methyl or hydrogen.
17. 17. Process according to claim 16, wherein the methyl group is removed by reaction with aluminum chloride and pyridine in N-methylpyrrolidinone.
18. 18. Process according to any of claims 9 to 17, wherein the condensation and dehydration are carried out in a bipolar aprotic solvent.
19. 19. Process according to claim 18, wherein the condensation and dehydration are carried out in dimethylacetamide, N-methylpyrrolidinone or sulfoxide of dimethyl.
20. 20. Process according to any of claims 10 to 19, wherein the nitrogen atom of the pyridyl of the oxadiazolyl compound of the formula VIA, VIB or VIC is oxidized by hydrogen peroxide, peracetic acid, trifluoroperacetic acid or urea-hydrogen peroxide and anhydride complex trifluoroacetic.
21. 21. Process according to any of claims 9 and 11 to 19, wherein the compound of the formula IIA, IIB or IIC is obtained by the reaction of the compound VIIA, VIIB or VIIC, respectively, VIA VIB VIC wherein R 4, R 5, R 6 and -R 7 are defined as in general formula I in claim 1, with hydroxylamine in the presence of a chelating agent under conditions suitable to produce derivatives of amidoxime.
22. 22 Process according to any of the claims 10 to 19, wherein the compound of the formula VA, VB or VC is obtained by the reaction of the compound VIIIA, VIIIB or VIIIC, respectively, VIIIA VIIIB VIIIC wherein R 4 R 5, R 6 and R 7 are as defined in general formula I according to claim 1, with hydroxylamine in the presence of a chelating agent under conditions suitable to produce amidoxime derivatives.
23. 23. Process according to claim 19 or 20, wherein the chelating agent is selected from the group consisting of 8-hydroxyquinoline, ortho-phenanthroline and hydrates or derivatives thereof.
24. 24. Process for the preparation of compounds according to formula I comprising the oxidation of the respective pyridine compound to the pyridine N-oxide compound.