CN101248064A - Nitrocatechol derivatives as COMT inhibitors - Google Patents
Nitrocatechol derivatives as COMT inhibitors Download PDFInfo
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- CN101248064A CN101248064A CNA2006800266140A CN200680026614A CN101248064A CN 101248064 A CN101248064 A CN 101248064A CN A2006800266140 A CNA2006800266140 A CN A2006800266140A CN 200680026614 A CN200680026614 A CN 200680026614A CN 101248064 A CN101248064 A CN 101248064A
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- oxadiazole
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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
Technical field
The present invention relates to the novel Nitrocatechol that replaces, its purposes in some nervus centralis of treatment and peripheral nervous system dysfunction and the pharmaceutical composition that comprises them.
Background technology
Although used many decades in clinical practice, levodopa (L-DOPA) remains the first-selected standard drug that is used for the Parkinson's disease symptom treatment.This promotes people to keep developing the strong interest of catechol-O-methyltransferase (COMT) inhibitor always, this exploitation is based on a kind of hypothesis, that is, the inhibition of this enzyme can provide clinical property improvement for the patient who suffers the Parkinson's disease misery, using L-DOPA and periphery amino acid decarboxylase (AADC) inhibitor to treat.Use the COMT inhibitor to be based on them and have the ability that metabolic levodopa oxygen position methyl changes into 3-O-methyl-levodopa (3-OMD) that reduces as the ultimate principle of L-DOPA/AADC therapy ancillary drug.Clinical property improvement of the time length of inductive levodopa shows as the transformation period in the short body of L-DOPA briefly, and the long transformation period of itself and 3-OMD forms contrast.In addition, 3-OMD and L-DOPA transport competitively and pass hemato encephalic barrier (BBB), and this means only has the actual arrival of the L-DOPA of the oral administration of minute quantity dosage action site, i.e. brain.Usually, with only within several years of beginning L-DOPA treatment under the situation of general dose, inductive L-DOPA clinical improvements can descend at the end of each cycle dose, cause the motor fluctuation of so-called " agent end phenomenon " pattern.People are described (Tohgi, H., et al., Neurosci.Letters, 132:19-22,1992) to the substantial connection between " agent end phenomenon " and the 3-OMD accumulation.By inference, this may be (Reches, the A.et al. that is caused by the L-DOPA brain penetrance that reduces due to the competition of the movement system of passing BBB because of 3-OMD, Neurology, 32:887-888,1982), perhaps say more simply, this is by the L-DOPA of available arrival brain less caused (Nutt, J.G., Fellman, J.H., Clin.Neuropharmacol., 7:35-49,1984).On effect, the inhibition of COMT has been protected L-DOPA to methylate by the oxygen position in avoiding outside peripheral tissues the metabolism loss to take place, so just have the L-DOPA that reproduces dosage, and average blood plasma L-DOPA concentration has raising.Except transhipment entered the competitiveness decline of brain, significantly the L-DOPA of this oral administration dosage of bigger per-cent can arrive action site.Like this, the COMT inhibition plays a part raising L-DOPA bioavailability and uses the L-DOPA of single dose to prolong the time length (Nutt, J.G., Lancet, 351:1221-1222,1998) of the sick effect of Kang Pajinsenshi.
The most effective COMT inhibitor of hitherto reported is 3,4-dihydroxyl-4 '-methyl-5-nitro phenyl benzophenone (tolcapone, Tolcapone, Australian Patent Au-B-69764/87), (E)-2-cyano group-N, N-diethyl-3-(3,4-dihydroxyl-5-nitrophenyl) acrylamide (Entacapone, Entacapone, German patent DE 3740383 A1) and BIA 3-202 (U.S. Pat 6512136), its all inhibition constant is all in lower nmole scope.Although their total substantially the same pharmacophoric groups, Tolcapone are different from Entacapone and BIA 3-202 part is that it more easily enters central nervous system (CNS) and can suppress COMT and the COMT of peripheral tissues in the brain.Can infer that if more significant inhibition COMT effect is to suppress L-DOPA to decompose in peripheral tissues, then the maincenter inhibition may be accessory.In fact, the use of not infiltrating the COMT inhibitor of brain under clinical corresponding dosage can be avoided the undesirable CNS side effect of these medicament potential.
Since these COMT inhibitor enter another serious problems that clinical practice has exposed, relate to the potential possibility that these xenobioticses based on Nitrocatechol can cause severe liver injury (hepatotoxicity).In fact, soon, after having reported several hepatotoxicity cases, having comprised three unfortunate cases dead because of fatal fulminant hepatitis, Tolcapone has withdrawed from market after it comes into operation.Now, Tolcapone can use in the patient of Parkinsonism, and these patients are unresponsive to other treatment, and periodic monitor liver function strictly, and it is costliness and inconvenience for the patient.Although the actual hepatotoxicity mechanism cause relevant with Tolcapone is still not exclusively clear, in vitro tests shows, Tolcapone may be metabolic be decomposed into active intermediate, and these active intermediates may form the covalency adducts with hepatic protein by inference, cause hepatocellular injury (Smith, K.S., et al., Chem.Res.Toxicol., 16:123-128,2003).
On the other hand, though the total identical Nitrocatechol pharmacophoric group of Entacapone and Tolcapone, itself and hepatotoxicity have nothing to do, and are considered to safe drugs usually.Yet unfortunately, Entacapone is obvious COMT inhibitor than Tolcapone poor efficiency, and the interior transformation period of body is very short.This means that the Entacapone acting duration is very limited, and therefore, each dose administration of the L-DOPA that this medicine must be taken with each patient with very high dosage.In this case, the clinical effectiveness of Entacapone has become a problem--in fact, research (Parashos in recent years, S.A.et al., Clin.Neuropharmacol., 27 (3): 119-123,2004) show that the major cause that stops the Entacapone treatment in the parkinsonian is felt to lack effect.
In a word, in the assisting therapy of handling the Parkinson disease symptoms, the clear and definite clinical requirement to safe and effective COMT inhibitor is arranged still.Preferred COMT inhibitor should have bigger effectiveness and longer COMT inhibition time length than Entacapone, can produce better clinical effectiveness like this.More preferably be different from Tolcapone, the COMT inhibitor should have the restricted path towards CNS,, preferably suppresses COMT of peripheral tissues rather than central COMT that is.More preferably the COMT inhibitor should merge above-mentioned feature, and should not have the possibility that causes hepatotoxicity as seeing from Tolcapone in addition.
We are surprised to find that, specific Nitrocatechol is very effective COMT inhibitor, and it is not or greatly reduce risk of toxicity.In addition, it is functional unexpectedly to check and verify its compound for the non-catechol substituent relevant with heterocycle, and this heterocycle has determined compound to lack toxic effect.
Up to now, prior art has only been reported a Nitrocatechol [1,2,4] embodiment of-oxadiazoles (embodiment 75, Australian Patent Au-B-69764/87), it is a 5-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl)-3-nitro pyrocatechol 1, it has chemical structure as follows:
This material is 3, two replacement-[1,2,4]-oxadiazoles of 5-, the Nitrocatechol pharmacophoric group that it has the methyl of the C-3 position that occupies Za Huan oxadiazole basic ring and is attached to the C-5 position.
We after deliberation as on the oxadiazole based compound 1 of stating, and find that it is medium activity (59% of contrast is referring to experimental section) in COMT inhibition test.Yet unfortunately, compound 1 has significant risk of toxicity (55% cell survival rate is referring to experimental section).In this case, this specific compound 1 can not be considered to represent adequate scheme, provides effectively and the problem that is occurred in the COMT inhibitor of clinical safety with solution.
We are surprised to find that, if center ring is replaced (that is, pyridine N-oxides) with the pyridine ring that is oxidised form, the pyridine N-oxides that obtains demonstrates the toxicity that reduces greatly, perhaps even do not have a risk of toxicity, still might keep being better than simultaneously the COMT inhibition of Entacapone fully.If to C-3 position " switching ", the compound that obtains so common activity with regard to the COMT inhibition is lower Cong oxadiazole ring C-5 for the position Bei of Nitrocatechol pharmacophoric group.With regard to the COMT inhibition, wherein Nitrocatechol pharmacophoric group Fu Yu oxadiazole center ring C-2 position regional isomerism 1,3,4-oxadiazole class also is that activity is lower usually.For example, can consider the regional isomer 2 and 3 of the Xian You Ji Shu oxadiazole 1 estimated in our the also synthetic and body:
Though 2 and 3 with respect to 1 risk of toxicity that all presents reduction, with regard to the COMT inhibition, compound 2 only shows 79% of contrast, and compound 3 only is that to omit be 64%.Can reach a conclusion thus, Zhong in the Xin Bu oxadiazole ring correct heteroatoms positional alignment with add the functional combination of pyridine N-oxides, have unexpected decisive for obtaining synergy between the security that suppresses active and this class COMT inhibitor at high COMT.
Summary of the invention
Therefore, the present invention relates to the Nitrocatechol COMT inhibitor that do not have risk of toxicity or risk of toxicity to reduce greatly.In addition, confirmed to import the heterocyclic radical that is the N-oxidised form based on nitrogen, pyridine N-oxides for example, the result is unexpected, and it has determined the Nitrocatechol compound to lack toxic effect.We are surprised to find that further the compound of general formula I is the COMT inhibitor, and it has the characteristic of equilibrated biological activity, bioavailability and particularly security:
R wherein
1And R
2Be hydrogen independent of each other or low-grade alkane acidyl or aroyl group hydrolyzable under physiological condition, that randomly replace; X represents methylene radical; Y represents oxygen, nitrogen or sulphur atom; N represents numeral 0,1,2 or 3, and m represents numeral 0 or 1; R
3The pyridine N-oxides group of representative formula A, B or C, its by shown in unlabelled key be connected:
Wherein, R
4, R
5, R
6And R
7Represent hydrogen, C independently of one another
1-C
6Alkyl, C
1-C
6Alkylthio, C
1-C
6Alkoxyl group, C
6-C
12Aryloxy or C
6-C
12Thioaryl group, C
1-C
6Alkyloyl or C
7-C
13Aroyl group, amino, C
1-C
6Alkylamino, C
1-C
6Dialkylamino, C
3-C
12Naphthene amino, C
3-C
12Heterocycle alkylamino, C
1-C
6Alkyl sulphonyl, C
6-C
12Aryl sulfonyl, halogen, C
1-C
6Haloalkyl, trifluoromethyl, cyano group, nitro or heteroaryl groups; The perhaps two or more residue R that lump together
4, R
5, R
6And R
7Represent aliphatics or assorted aliphatics ring or aromatic series or heteroaromatic ring, and wherein P represents center cell, its preferably same flat unit, and further be preferably selected from following regional isomer: 1,3,4-oxadiazole-2,5-two replaces, 1,2,4-oxadiazole-3,5-two replaces, 4-methyl-4H-1,2,4-triazole-3,5-two replaces, 1,3,5-triazine-2,4-two replaces, 1,2,4-triazine-3,5-two replaces, 2H-tetrazolium-2,5-two replaces, 1,2,3-thiadiazoles-4,5-two replaces, 1-alkyl-3-(carbalkoxy)-1H-pyrroles-2, (wherein the representative of alkyl has methyl in 5-two replacements, ethyl, just-propyl group and normal-butyl and wherein the representative of alkoxyl group methoxyl group is arranged, oxyethyl group, positive propoxy and isopropoxy), 1-alkyl-1H-pyrroles-2, (wherein the representative of alkyl has methyl in 5-two replacements, ethyl, just-propyl group and normal-butyl), thiazole-2,4-two replaces, 1-H-pyrazoles-1,5-two replaces, pyrimidine-2,4-two replaces oxazole-2, and 4-two replaces, carbonyl, 1H-imidazoles-1,5-two replaces isoxazole-3,5-two replaces, furans-2,4-two replaces, 3-carbalkoxy furans-2, (wherein the representative of alkoxyl group has methoxyl group in 4-two replacements, oxyethyl group, positive propoxy and isopropoxy), benzene-1,3-two replaces, (Z)-1-cyano group-1,2-ethylidene-1,2-two replaces.
In above-mentioned qualification, the regional isomer of center cell both comprised and can partly exchange the regional isomer of realizing by Nitrocatechol, and comprising again can be by-(X) n-(Y) m-R
3Part exchanges and the regional isomer of realization.
Preferred C
1-C
6Alkyl residue represent methylidene, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group or hexyl.Preferred C
1-C
6The alkylthio residue is represented sulphomethyl, thio-ethyl, sulfo-n-propyl, sulfo-sec.-propyl, sulfo-normal-butyl, sulfo-n-pentyl and sulfo-n-hexyl.Preferred C
1-C
6Alkoxy residue representation methoxy, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy and tert.-butoxy.Preferred C
6-C
12The aryloxy residue is represented as can randomly substituted phenoxy group or naphthyloxy.Preferred C
6-C
12The thioaryl residue is represented as can randomly substituted thiophenyl and naphthalene sulfenyl.Preferred C
1-C
6The alkyloyl residue is represented methanoyl, ethanoyl, propionyl or butyryl radicals.Preferred C
7-C
13The aroyl residue is represented benzoyl and naphthoyl.Preferred C
1-C
6The alkylamino residue is represented methylamino-, ethylamino, n-propylamine base, isopropylamino and n-butyl amine base.Preferred C
1-C
6The dialkyl amido residue is represented dimethylamino, diethylin, two n-propylamine bases, two n-butyl amine bases, diisopropylaminoethyl, first and second amino, first third amino and b propylamido.Preferred C
3-C
12The cycloalkyl amino residue is represented pyrrolidyl, piperidino-(1-position only), cyclohexyl amino and dicyclohexylamine base.Preferred C
3-C
12The Heterocyclylalkyl amino residue is represented morpholino, 2,6-thebaine generation, 3,5-thebaine generation, piperazine generation, N methyl piperazine generation and N-ethyl piperazidine generation.Preferred C
1-C
6Alkyl sulphonyl or C
6-C
12The aryl sulfonyl residue is represented methylsulfonyl, ethylsulfonyl, benzenesulfonyl and tosyl group.Preferred halogen residue is represented chloro, bromo, iodo and fluoro.Preferred C
1-C
6Haloalkyl is represented chloromethyl, methyl fluoride, dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl.Preferred heteroaryl residue is represented pyridyl, pyrimidyl, isoxazolyl, oxazolyl, Yi oxadiazole Ji, oxadiazole base, triazolyl and tetrazyl.If the two or more residue R that lump together
4, R
5, R
6And R
7Represent aliphatics or assorted aliphatics ring or aromatic series or heteroaromatic ring, the then preferred basic residue that merges is indolizine base, isoindolyl, indyl, indazolyl, purine radicals, quinolizinyl, naphthyridine base, isoquinolyl and quinolyl.
The preferred center unit is selected from the heteroaromatic five-ring that comprises 1～4 heteroatoms N, O and S.More preferably center cell P is selected from following regional isomer: 1,3,4-oxadiazole-2,5-two replaces, 1,2,4-oxadiazole-3,5-two replaces, 4-methyl-4H-1,2,4-triazole-3,5-two replaces, 1,3,5-triazine-2,4-two replaces, 1,2,4-triazine-3,5-two replaces, 2H-tetrazolium-2,5-two replaces, 1,2,3-thiadiazoles-4,5-two replaces, 1-alkyl-3-(carbalkoxy)-1H-pyrroles-2,5-two replaces, wherein the representative of alkyl has methyl, ethyl, n-propyl and normal-butyl, and wherein the representative of-oxyl has methoxyl group, oxyethyl group, positive propoxy and isopropoxy, 1-alkyl-1H-pyrroles-2,5-two replaces, wherein the representative of alkyl has methyl, ethyl, n-propyl and normal-butyl, thiazole-2,4-two replaces, 1H-pyrazoles-1,5 two replaces oxazole-2, and 4-two replaces, carbonyl, 1H-imidazoles-1,5-two replaces isoxazole-3,5-two replaces, furans-2,4-two replaces, 3-carbalkoxy furans-2,4-two replaces, wherein the representative of-oxyl has methoxyl group, oxyethyl group, positive propoxy and isopropoxy.
Most preferably center cell P is selected from 1,3,4-oxadiazole-2, and 5-two replacements and 1,2,4-oxadiazole-3,5-two replaces.
Preferably has center cell 1,2,4-oxadiazole-3, compound shown in the dibasic above-mentioned general formula of 5-(I) comprises 5-[3-(3,5-two chloro-1-oxygen-pyridin-4-yls)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-chloro-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-morpholine-4-base-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 3-nitro-5-[3-(1-oxygen-4-trifluoromethyl-pyridin-3-yl) [1,2,4] oxadiazole-5-yl]-benzene-1, the 2-glycol, 5-[3-(4-bromo-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-chloro-6-methyl isophthalic acid-oxygen-pyridin-3-yl)-[1,2,4] oxadiazoles-5-base 1-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-morpholine-4-base-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 3-nitro-5-[3-(1-oxygen-6-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl] benzene-1, the 2-glycol, 5-[3-(2-methyl isophthalic acid-oxygen-6-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(6-methyl isophthalic acid-oxygen-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2,6-dimethyl-1-oxygen-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-methyl isophthalic acid-oxygen-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(6-methyl isophthalic acid-oxygen-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-bromo-6-methyl isophthalic acid-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-bromo-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-bromo-4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-chloro-4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2,5-two chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-bromo-5-chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, and 3-nitro-5-[3-(1-oxygen-2-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1, the 2-glycol, 3-[3-(3,4-dihydroxyl-5-nitrophenyl)-[1,2,4] oxadiazole-5-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, (3-(3 for 2-chloro-3-, 4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl)-4,6-lutidine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-(3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5--yl) pyridine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, (3-(3 for 2-bromo-3-, 4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl)-4,5,6-trimethylpyridine 1-oxide compound, (3-(3 for 2-chloro-3-, 4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl)-4,5,6-trimethylpyridine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-(3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl)-4,6-lutidine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-5 (trifluoromethyl) pyridine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-2-fluorine pyridine 1-oxide compound, 4-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-2-fluorine pyridine 1-oxide compound, 2-[3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-6-fluorine pyridine 1-oxide compound, 2-chloro-3-(3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl]-6-picoline 1-oxide compound, (3-(3 for 2-bromo-3-, 4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl)-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-(3-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-oxadiazole-5-yl)-4,6-lutidine 1-oxide compound.
Preferably has center cell 1,3,4-oxadiazole-2, compound shown in the dibasic above-mentioned general formula of 5-(I) comprises 3-, and (5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, (5-(3 for 2-chloro-3-, 4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-4,6-lutidine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3, (5-(3 for 5-two chloro-4-, 4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, (5-(3 for 2-bromo-3-, 4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-4,5,6-trimethylpyridine 1-oxide compound, (5-(3 for 2-chloro-3-, 4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-4,5,6-trimethylpyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2, (5-(3 for 5-two chloro-3-, 4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-4,6-lutidine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-2-fluorine pyridine 1-oxide compound, 4-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-2-fluorine pyridine 1-oxide compound, 2-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-6-fluorine pyridine 1-oxide compound, (5-(3 for 2-chloro-3-, 4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-6-picoline 1-oxide compound, 2-bromo-3-(5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-(5-(3,4-dihydroxyl-5-nitrophenyl)-1,3,4-oxadiazole-2-yl)-4,6-lutidine 1-oxide compound.
Preferably has center cell 4-methyl-4H-1,2,4-triazole-3, the compound of the dibasic above-mentioned general formula of 5-(I) comprises 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4-(trifluoromethyl) pyridine 1-oxide compound, (5-(3 for 2-chloro-3-, 4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4,6-lutidine 1-oxide compound, (5-((3 for 3-, 4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, (5-(3 for 3-, 4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-(5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4,5,6-trimethylpyridine 1-oxide compound, 2-chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-4,5,6-trimethylpyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2, (5-(3 for 5-two chloro-3-, 4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-4,6-lutidine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-2-fluorine pyridine 1-oxide compound, 4-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-2-fluorine pyridine 1-oxide compound, 2-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 4-methyl-4H-1,2,4-triazole-3-yl]-6-fluorine pyridine 1-oxide compound, (5-(3 for 2-chloro-3-, 4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl)-6-picoline 1-oxide compound, 2-bromo-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-yl]-4,6-lutidine 1-oxide compound.
Preferably has center cell 1,3,5-triazine-2, compound comprises 3-[4-(3 shown in the dibasic above-mentioned general formula of 4-(I), 4-dihydroxyl-5-nitrophenyl)-1,3,5-triazine-2-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazine-2-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazine-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazine-2-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazine-2-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazines-2-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazine-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, and 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazine-2-yl]-5-(trifluoromethyl) pyridine 1-oxide compound.
Preferably has center cell 1,2,4-triazine-3, compound comprises 3-[5-(3 shown in the dibasic above-mentioned general formula of 5-(I), 4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 4-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-2-fluorine pyridine 1-oxide compound, and 2-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl]-6-fluorine pyridine 1-oxide compound.
Preferably has center cell (Z)-1-cyano group-1,2-ethylidene (cyanoethen)-1, compound comprises (Z)-3-[1-cyano group-2-(3 shown in the above-mentioned general formula (I) of 2-two replacement parts, 4-dihydroxyl-5-nitrophenyl) vinyl]-4-(trifluoromethyl) pyridine 1-oxide compound, (Z)-2-chloro-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-4,6-lutidine 1-oxide compound, (Z)-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, (Z)-5-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-2-(trifluoromethyl) pyridine 1-oxide compound, (Z)-5-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, (Z)-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, (Z)-3,5-two chloro-4-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl] pyridine 1-oxide compound, (Z)-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, (Z)-2-bromo-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-4,5,6-trimethylpyridine 1-oxide compound, (Z)-2-chloro-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-4,5,6-trimethylpyridine 1-oxide compound, (Z)-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-2-(trifluoromethyl) pyridine 1-oxide compound, (Z)-2,5-two chloro-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-4,6-lutidine 1-oxide compound, (Z)-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-5-(trifluoromethyl) pyridine 1-oxide compound, (Z)-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-2-fluorine pyridine 1-oxide compound, (Z)-4-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-2-fluorine pyridine 1-oxide compound, (Z)-2-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-6-fluorine pyridine 1-oxide compound, (Z)-2-chloro-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-6-picoline 1-oxide compound, (Z)-2-bromo-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-6-picoline 1-oxide compound, and (Z)-2-bromo-5-chloro-3-[1-cyano group-2-(3,4-dihydroxyl-5-nitrophenyl) vinyl]-4,6-lutidine 1-oxide compound.
Preferably has center cell furans-2,4-two replaces part or 3-carbalkoxy furans-2,4-two replaces part, and (wherein the representative of alkoxyl group has methoxyl group, oxyethyl group, positive propoxy and isopropoxy) above-mentioned general formula (I) shown in compound comprise 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-and 3-(ethoxycarbonyl) furans-2-yl]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-and 3-(ethoxycarbonyl) furans-2-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[4-(3,4-dihydroxyl-5-nitrophenyl)-and 3-(ethoxycarbonyl) furans-2-yl] pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) furans-2-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl) furans-2-yl]-4,5,6-trimethylpyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) furans-2-yl]-4,5,6-trimethylpyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) furans-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) furans-2-yl]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) furans-2-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-2-fluorine pyridine 1-oxide compound, 4-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-2-fluorine pyridine 1-oxide compound, 2-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-6-fluorine pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-6-picoline 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-and 3-(ethoxycarbonyl) furans-2-yl]-4,6-lutidine 1-oxide compound.
Preferably has center cell 1H-imidazoles-1, compound comprises 3-[5-(3 shown in the above-mentioned general formula (I) of 5-two replacement parts, 4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 1H-imidazoles-1-yl]-4,6-lutidine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 1H-imidazoles-1-yl] pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-2-fluorine pyridine 1-oxide compound, 2-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-6-fluorine pyridine 1-oxide compound, 2-chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-6-picoline 1-oxide compound, and 2-bromo-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl]-6-picoline 1-oxide compound.
Preferably has center cell isoxazole-3, compound comprises 3-[3-(3 shown in the above-mentioned general formula (I) of 5-two replacement parts, 4-dihydroxyl-5-nitrophenyl)-isoxazole-5-bases]-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-[3-(3,4-dihydroxyl-3-nitrophenyl) isoxazole-5-base]-4,6-lutidine 1-oxide compound, 3-[3-(3,4-dihydroxyl-3-nitrophenyl) isoxazole-5-base]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base] pyridine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-4,5,6-trimethylpyridine 1-oxide compound, (3-(3 for 2-chloro-3-, 4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-4,5,6-trimethylpyridine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-4,6-lutidine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-2-fluorine pyridine 1-oxide compound, 4-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-2-fluorine pyridine 1-oxide compound, 2-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-6-fluorine pyridine 1-oxide compound, 2-chloro-3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-6-picoline 1-oxide compound, 2-bromo-3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5]-4,6-lutidine 1-oxide compound.
Have preferably that compound comprises 3-(3 shown in the above-mentioned general formula (I) of center cell carbonyl moiety, 4-dihydroxyl-5-oil of mirbane formyl)-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-(3,4-dihydroxyl-5-oil of mirbane formyl)-4,6-lutidine 1-oxide compound, 3-(3,4-dihydroxyl-5-oil of mirbane formyl)-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-(3,4-dihydroxyl-5-oil of mirbane formyl)-2-(trifluoromethyl) pyridine 1-oxide compound, 5-(3,4-dihydroxyl-5-oil of mirbane formyl)-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-(3,4-dihydroxyl-5-oil of mirbane formyl)-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-(3,4-dihydroxyl-5-oil of mirbane formyl) pyridine 1-oxide compound, 3-(3,4-dihydroxyl-5-oil of mirbane formyl)-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-(3,4-dihydroxyl-5-oil of mirbane formyl)-4,5,6-trimethylpyridine 1-oxide compound, 2-chloro-3-(3,4-dihydroxyl-5-oil of mirbane formyl)-4,5,6-trimethylpyridine 1-oxide compound, 3-(3,4-dihydroxyl-5-oil of mirbane formyl)-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-(3,4-dihydroxyl-5-oil of mirbane formyl)-4,6-lutidine 1-oxide compound, 3-(3,4-dihydroxyl-5-oil of mirbane formyl)-5-(trifluoromethyl) pyridine 1-oxide compound, 3-(3,4-dihydroxyl-5-oil of mirbane formyl)-2-fluorine pyridine 1-oxide compound, 4-(3,4-dihydroxyl-5-oil of mirbane formyl)-2-fluorine pyridine 1-oxide compound, 2-(3,4-dihydroxyl-5-oil of mirbane formyl)-6-fluorine pyridine 1-oxide compound, 2-chloro-3-(3,4-dihydroxyl-5-oil of mirbane formyl)-6-picoline 1-oxide compound, 2-bromo-3-(3,4-dihydroxyl-5-oil of mirbane formyl)-6-picoline 1-oxide compound, and 2-bromo-5-3-(3,4-dihydroxyl-5-oil of mirbane formyl)-4,6-lutidine 1-oxide compound.
Preferably has Zhong heart Dan Yuan oxazole-2, compound comprises 3-[4-(3 shown in the above-mentioned general formula (I) of 4-two replacement parts, 4-dihydroxyl-5-nitrophenyl)-oxazoles-2-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl] pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-4,5,6-trimethylpyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-4,5,6-trimethylpyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-21-fluorine pyridine 1-oxide compound, 4-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-2-fluorine pyridine 1-oxide compound, 2-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-6-fluorine pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-6-picoline 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-4,6-lutidine 1-oxide compound.
Preferably has center cell benzene-1,3-two replace compound shown in the above-mentioned general formula (I) of part comprise 3-(3 ', 4 '-dihydroxyl-5 '-nitrobiphenyl-3-yl)-4-(trifluoromethyl) pyridine 1-oxide compound, 5-(3 ', 4 '-dihydroxyl-5 '-nitrobiphenyl-3-yl)-2-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-(3 ', 4 '-dihydroxyl-5 '-nitrobiphenyl-3-yl) pyridine 1-oxide compound, 3-(3 ', 4 '-dihydroxyl-5 '-nitrobiphenyl-3-yl)-2-(trifluoromethyl) pyridine 1-oxide compound, and 3-(3 ', 4 '-dihydroxyl-5 '-nitrobiphenyl-3-yl)-5-(trifluoromethyl) pyridine 1-oxide compound.
Preferably has center cell 1H-pyrazoles-1, compound comprises 3-[5-(3 shown in the above-mentioned general formula (I) of 5-two replacement parts, 4-dihydroxyl-5-nitrophenyl)-the 1H-pyrazol-1-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-the 1H-pyrazol-1-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[5-(3,4-dihydroxyl-5-nitrophenyl)-and the 1H-pyrazol-1-yl] pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-the 1H-pyrazol-1-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-the 1H-pyrazol-1-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, and 4-[5-(3,4-dihydroxyl-5-nitrophenyl)-1H-pyrazol-1-yl]-2-fluorine pyridine 1-oxide compound.
Preferably has center cell pyrimidine-2, compound comprises 3-[4-(3 shown in the above-mentioned general formula (I) of 4-two replacement parts, 4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base] pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-4,5,6-trimethylpyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-4,5,6-trimethylpyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-4,6-lutidine 1-oxide compound, and 3-[4-(3,4-dihydroxyl-5-nitrophenyl) pyrimidine-2-base]-5-(trifluoromethyl) pyridine 1-oxide compound.
Preferably has center cell 1H-pyrroles-2, compound comprises 3-[5-(3 shown in the above-mentioned general formula (I) of 5-two replacement parts, 4-dihydroxyl-5-nitrophenyl)-1-methyl-3-(ethoxycarbonyl)-1H-pyrroles-2-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 3-(ethoxycarbonyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-4,6-lutidine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-ethyl-3-(ethoxycarbonyl)-1H-pyrroles-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 1-methyl isophthalic acid H-pyrroles-2-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 1-methyl isophthalic acid H-pyrroles-2-yl] pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 1-methyl isophthalic acid H-pyrroles-2-yl]-4,5,6-trimethylpyridine 1-oxide compound, 2-chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 1-methyl isophthalic acid H-pyrroles-2-yl]-4,5,6-trimethylpyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 1-methyl isophthalic acid H-pyrroles-2-yl]-4,6-lutidine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-2-fluorine pyridine 1-oxide compound, 4-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-2-fluorine pyridine 1-oxide compound, 2-[5-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-6-fluorine pyridine 1-oxide compound, 2-chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-6-picoline 1-oxide compound, 2-bromo-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl isophthalic acid H-pyrroles-2-yl]-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 1-methyl isophthalic acid H-pyrroles-2-yl]-4,6-lutidine 1-oxide compound.
Preferably has center cell 2H-tetrazolium-2, compound comprises 3-[5-(3 shown in the above-mentioned general formula (I) of 5-two replacement parts, 4-dihydroxyl-5-nitrophenyl)-2H-tetrazolium-2-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 5-[5-(3,4-dihydroxyl-5-nitrophenyl)-2H-tetrazolium-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[5-(3,4-dihydroxyl-5-nitrophenyl)-and 2H-tetrazolium-2-yl] pyridine 1-oxide compound, 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-2H-tetrazolium-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, and 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-2H-tetrazolium-2-yl]-5-(trifluoromethyl) pyridine 1-oxide compound.
Preferably has center cell 1,2,3-thiadiazoles-4, compound comprises 3-[4-(3 shown in the above-mentioned general formula (I) of 5-two replacement parts, 4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl] pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-4,5,6-trimethylpyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-4,5,6-trimethylpyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-2-fluorine pyridine 1-oxide compound, 4-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-2-fluorine pyridine 1-oxide compound, 2-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-6-fluorine pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-6-picoline 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,2,3-thiadiazoles-5-yl]-4,6-lutidine 1-oxide compound.
Preferably has center cell thiazole-2, compound comprises 3-[4-(3 shown in the above-mentioned general formula (I) of 4-two replacement parts, 4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-4-(trifluoromethyl) pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-2-methyl-6-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 5-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-2-methyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-2,6-dimethyl-4-(trifluoromethyl) pyridine 1-oxide compound, 3,5-two chloro-4-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl] pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-6-methyl-2-phenyl-4-(trifluoromethyl) pyridine 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-4,5,6-trimethylpyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-4,5,6-trimethylpyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2,5-two chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-4,6-lutidine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-5-(trifluoromethyl) pyridine 1-oxide compound, 3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-2-fluorine pyridine 1-oxide compound, 4-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-2-fluorine pyridine 1-oxide compound, 2-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-6-fluorine pyridine 1-oxide compound, 2-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-6-picoline 1-oxide compound, 2-bromo-3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-6-picoline 1-oxide compound, and 2-bromo-5-chloro-3-[4-(3,4-dihydroxyl-5-nitrophenyl) thiazol-2-yl]-4,6-lutidine 1-oxide compound.
In one embodiment; center cell comprises 1; 2; 4-oxadiazole-3; the compound that 5-two replaces the general formula I of part can prepare by following method: general formula is that the compound of IIA, IIB or IIC and the compound of general formula III are being suitable for producing under the condition that chemical formula is IVA, IVB or IVC De oxadiazole derivative; the annulation that comprises condensation and dehydration reaction; then remove hydroxyl protecting group; thereby obtain center cell and comprise 1; 2; 4-oxadiazole-3,5-two replaces the compound of the general formula I of part
Wherein, R
4, R
5, R
6And R
7As defined in the general formula I, R
8And R
9Represent hydrogen or the suitable blocking group that is used for the aromatic hydroxyl group independently of one another.
In another embodiment, center cell comprises 1,2,4-oxadiazole-3, and the compound that 5-two replaces the general formula I of part can prepare by following method:
General formula is that the compound of the compound of VA, VB or VC and general formula III produces under the condition that chemical formula is VIA, VIB or VIC De oxadiazole derivative being suitable for, and comprises the annulation of condensation and dehydration, then; pyridyl nitrogen-atoms generation oxidation; thereby obtain the compound that meets Formula I VA, IVB or IVC as implied above, last, in case of necessity; remove hydroxyl protecting group; obtain its center unit pack and draw together 1,2,4-oxadiazole-3; 5-two replaces the compound of the general formula I of part
Wherein, R
4, R
5, R
6And R
7As defined in the general formula I.
The suitable blocking group that is used for the aromatic hydroxyl group is well known to those skilled in the art.The suitable example that is used for the blocking group of aromatic hydroxyl group comprises that methyl, ethyl, sec.-propyl, phenmethyl, 4-methoxybenzyl, methoxyl methyl, benzyloxymethyl, methoxy (ethoxy) methyl, THP trtrahydropyranyl, phenacyl, allyl group, trimethylsilyl, tertiary butyl diformazan are for silyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl, ester, sulfonate (ester), carbamate, phosphinate, acetal and ketal derivatives.
In preferred embodiment, radicals R
8And R
9One of be hydrogen, and and another is a methyl.In especially preferred embodiment, R
8Represent methylidene, and R
9Represent hydrogen.
In alternative preferred implementation, blocking group R
8And R
9Be replaced by hydrogen or hydrolyzable group under physiological condition.Blocking group R
8And R
9Can be removed independently of one another in isolating reactions steps, perhaps they can be removed in same reactions steps.Similarly, the insertion of hydrolyzable group can occur in same reactions steps under physiological condition, perhaps occurs in the subsequent reaction step.
In the present invention, the condition that is suitable for Sheng Chan oxadiazole derivative comprises the condition Dao the oxadiazole derivative with higher yields and purity De.Preferred Yu Qi De oxadiazole derivative yield is at least 70%, more preferably 75～99%, and further preferred 80～97%, and most preferably 85～95%.Preferred Yu Qi De oxadiazole derivative purity is at least 90%, more preferably at least 95%, further preferably at least 99%, and most preferably at least 99.5%.Under instruction of the present invention, those skilled in the art can determine only reaction conditions usually, so that Youization oxadiazole yield and purity.The parameter that those skilled in the art takes in includes but not limited to, influences the reagent of condensation reaction and dehydrated reagent, protecting group R
8And R
9Selection, solvent system, temperature of reaction and reaction times and agent dissolves.
The compound of general formula III with Formulae II A-IIC or VA-VC condensation before need the activation.The suitable agent that is used for the compound activating of Formulae II I comprises 1,1-N,N'-carbonyldiimidazole, thionyl chloride, SULPHURYL CHLORIDE, N, N '-dicyclohexyl carbon imide, I-hydroxybenzotriazole and N-(3-dimethylaminopropyl)-N '-ethyl carbon imide, phosgene, PCl
3, POCl
3, PCl
5, acid anhydrides, three chloro triazines and chloro dimethoxy-triazine etc.Particularly preferably be 1,1-N,N'-carbonyldiimidazole and thionyl chloride.Under some situation, can use identical reagent effectively to finish into the ring step, this step comprises condensation and dehydration.The pack selected that is effective to condensation and/or dehydration is drawn together pyridine and tetrabutylammonium fluoride.Preferably effectively finish dehydration by reacting by heating mixture and mentioned reagent.
The compound of general formula III can be in suitable solvent or is not needed additional solvent and activate such as thionyl chloride with excessive reagent.Preferably, for example can remove excessive reagent then, and replace such as pyridine, thereby effectively finish condensation and dehydrating step with solvent and another kind of reagent by distillation.Be preferred for activating the solvent system of the compound of general formula III, and the solvent system that is used for the compound Cheng Huan of the compound of general formula III and general formula I IA-IIC or VA-VC is dipolar aprotic solvent, comprises dimethyl formamide, methyl-sulphoxide, N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone.Particularly preferably be methyl-sulphoxide and N,N-DIMETHYLACETAMIDE.
Suitable reaction temperature and reaction times are depended on the employed reagent react that is effective to condensation and dehydration reaction.Preferable reaction temperature 0 ℃ to the scope of solvent for use system boiling point, more preferably 20～150 ℃, and most preferably 25～120 ℃.The preferred reaction time in 30 minutes to 24 hours scope, more preferably 1～18 hour, and most preferably 2～6 hours.
In alternative preferred implementation, condensation and dehydration reaction are carried out when organic or inorganic alkali exists.Suitable preferred bases comprises triethylamine, Tributylamine, 2,6-lutidine, N-methylmorpholine, pyridine, imidazoles, N-Methylimidazole and 4-Dimethylamino pyridine.Particularly preferred alkali comprises pyridine, N-Methylimidazole and 4-Dimethylamino pyridine.
In a kind of preferred implementation of the present invention, condensation and dehydration are carried out in two isolating reactions steps.In this specific embodiment, can use different condensations and dehydrated reagent and solvent system, to optimize products therefrom yield and purity.
In alternative preferred implementation of the present invention, condensation is carried out in identical container in regular turn with dehydration, need not separate O-acidylate intermediate.In this specific embodiment, the reagent that is effective to condensation and dehydration can be identical or inequality, but preferably identical.
The reagent content that is effective to condensation and dehydration is not a crucial factor.The typical content that is effective to condensation and dehydrated reagent is, for every mol pyridine derivate, comprises the reagent of 1mol at least, is preferably 2.1mol～5mol, more preferably 2.2～4mol, and 2.3mol～3mol most preferably.The reagent that is effective to condensation and dehydration therein also is used as under the situation of solvent or solubility promoter, and it can be excessive greatly.
As mentioned above, in a preferred embodiment, the nitrogen-atoms that the present invention includes wherein pyridyl part of V IA, VIB or VIC oxidized step under appropriate condition, thus behind annulation corresponding to pyridyl-N-oxidized derivatives IVA, IVB or IVC.
In the present invention, the oxidizing condition that is suitable for producing pyridyl-N-oxide compound comprises the condition that obtains pyridyl-N-oxidized derivatives with higher yields and purity.
Pyridyl-N-oxidized derivatives the yield of preferred expection is at least 90%, more preferably 92～99%, and further preferred 94～98%, and most preferably 95～97%.Pyridyl-N-oxidized derivatives the purity of preferred expection is at least 90%, more preferably at least 95%, further preferably at least 99%, and most preferably at least 99.5%.Under instruction of the present invention, those skilled in the art can determine only reaction conditions usually, so that optimize pyridyl-N-oxide compound yield and purity.The parameter that those skilled in the art takes in includes but not limited to selection, solvent system, temperature of reaction and reaction times and the agent dissolves of oxygenant, oxygenate content, protecting group.
Preferred oxidant comprises hydrogen peroxide.MnO
2, peracetic acid, trifluoroperacetic acid, t-butyl hydroperoxide.Metachloroperbenzoic acid, persulfuric acid, Oxone , perhydrit mixture and trifluoroacetic anhydride (TFAA), pyridinium chlorochromate and permanganate ion.Preferred especially perhydrit mixture and trifluoroacetic anhydride (TFAA).
Preferred oxidant content pyridine derivate etc. molar content to the excessive 20 times scope.Excessive 1.2 times～10 times of preferred oxidant content, more preferably excessive 1.5 times～8 times, and most preferably excessive 2 times～5 times.
The solvent system that is preferred for carrying out oxidizing reaction is to oxygenant inert solvent.Preferred especially halogenated solvent is such as methylene dichloride, chloroform, chlorobenzene and tetracol phenixin; Aromatic solvent such as benzene and toluene, alkane such as hexanaphthene and normal hexane; And ethers is such as tetrahydrofuran (THF), 1,4-dioxane and t-butyl methyl ether.
Suitable reaction temperature and reaction times are depended on the reactivity of used oxygenant.Preferable reaction temperature at 0 ℃ to the scope of solvent for use system boiling point, more preferably at 20～100 ℃, and most preferably 40～80 ℃.The preferred reaction time in 30 minutes to 24 hours scope, more preferably 1 hour～18 hours, and most preferably 2～6 hours.
The oxidation of pyridyl nitrogen-atoms can be carried out according to any stage of the method for the compound of general formula I in preparation.Preferred oxidation is to carry out before the compound formation of Formulae II A-IIC, perhaps selects as another kind of, carries out after the oxadiazole ring forms in the change compound of chemical formula VIA-VIC.
In the present invention is aspect another, by under proper reaction conditions when sequestrant exists, compound and the azanol of general formula VIIA, VIIB or VIIC react, and prepare the compound that chemical formula is IIA, IIB or IIC.
In the present invention aspect another, by under proper reaction conditions when sequestrant exists, general formula is that compound and the azanol of VIIIA, VIIIB or VIIIC reacts, and prepares the compound that chemical formula is VA, VB or VC.
In the present invention, the suitable reaction conditions of above-mentioned reaction comprises the condition that obtains amidoxim (amidoxime) derivative with higher yields and purity.The amidoxim derivative yield of preferred expection is at least 70%, more preferably 72～95%, and further preferred 75～90%, and most preferably 78～85%.The amidoxim derivative purity of preferred expection is at least 90%, more preferably at least 95%, further preferably at least 96%, and most preferably at least 97%.Under instruction of the present invention, those skilled in the art can determine only reaction conditions usually, so that optimize amidoxim yield and purity.The parameter that those skilled in the art takes in includes but not limited to hydroxylamine content, selection of catalysts, substituent R
4～R
7Character, solvent system, temperature of reaction and reaction times and agent dissolves.
The content of preferred azanol pyridine derivate etc. molar content to excessive 50 times scope.Excessive 1.2 times～20 times of the content of preferred azanol, more preferably excessive 1.5 times～10 times, and most preferably excessive 3 times～5 times.
Preferred sequestrant comprises oxine, o-phenanthroline and its hydrate and their derivative.The content of preferred sequestrant is in 0.1～10mol% scope, more preferably 0.5～5mol%, more preferably 0.75～3mol%, and 1～1.5mol% most preferably.
Solvent system is not particularly limited, and comprises: water; Alcohol is such as methyl alcohol, ethanol or Virahol; Ether, such as tetrahydrofuran (THF) or 1, the 4-dioxane; And dipolar aprotic solvent, such as methyl-sulphoxide etc.; The perhaps mixture of these solvents.
Preferable reaction temperature 0 ℃ to the scope of solvent for use system boiling point, more preferably 20～100 ℃, and most preferably 40～80 ℃.The preferred reaction time in 30 minutes to 24 hours scope, more preferably 1 hour～18 hours, and most preferably 2～8 hours.
As for preparation of drug combination shown in the general formula (I), the inert pharmaceutically acceptable carrier is mixed mutually with this active compound.This pharmaceutically acceptable carrier can be solid or liquid.The solid form goods comprise pulvis, tablet, discrete particles and capsule.Solid carrier can be one or more materials, and it also can be used as thinner, sweetener, solubilizing agent, lubricant, suspension agent, tackiness agent or tablet disintegrant; It also can coating material.
The preferred agents preparation is unit dosage form, for example is packaged preparation, and this packing is to contain the preparation of dispersion amount such as packaged tablet, capsule and pulvis in bottle or ampoule.
Depend on that the patient requires, the specific compound of the severity of disease and use, dosage can change.For simplicity, every day, total dose can five equilibrium and in whole part administration on daytime.Determine that for specific situation suitable dosage is known by the technician of pharmacy field.
Embodiment
Material and method
The active test of mouse COMT
In all experiments, use take from 60 days big, heavy 20-30g, at controllable environment bar 1 (12h illumination/dark cycle, 24 ℃ of room temperatures) every cage keeps ten NMRI mouse (Harlan-Interfauna Iberica under, Barcelona, Spain) liver sample.In experiment, use by the acquisition of Sodital (60mg/kg) anesthetized mice, the dabbling tissue of physiological saline.Take out tissue and homogenate in 5mM, pH7.8 phosphate buffered saline buffer immediately, and-80 ℃ of storages.
By the method for describing in the past (Vieira-Coelho, M.A., Soares-da-Silva, P., Brain Res., 1999,821,69-78), become the ability of metanephrine by the suprarenin that methylates, estimate the COMT activity.With the 0.5ml liver homogenate liquid of five equilibrium 0.4ml phosphate buffered saline buffer (5mM) pre-incubation 20min; Thereafter, in the presence of the methyl donor S-of saturation concentration adenosine-L-methionine(Met) (250 μ m), with reaction mixture suprarenin (500 μ m; 0.1mL) hatch 10min.This is hatched medium and also contains pargyline (100 μ m), MgCl
2(100 μ m) and EGTA (1mM).Carry out under pre-incubation and the condition that is incubated in 37 ℃, lucifuge, continuous oscillation and do not have oxidation to take place.At the incubation period end, change test tube over to ice bath, and cross the chloric acid termination reaction by the 2M that adds 200 μ l.Then with the centrifugal (200 * g of sample, 4min, 4 ℃), and the filtering five equilibrium supernatant liquor of Spin-X chimney filter (Costar) of 500 μ l via hole diameters sizes, 0.22 μ m is used for the metanephrine test, this test is undertaken by the high pressure lipuid chromatography (HPLC) that has Electrochemical Detection.
In being designed for of the experiment of evaluation tested compounds, tested compounds (in 5% carboxymethyl cellulose) is supplied with the mouse of going on a hunger strike and spending the night by stomach tube to the influence of liver COMT.After this, at the interval that limits, take out liver and be used for by determining the COMT activity as mentioned above.
The active test of rat COMT
In all experiments, use take from 60 days big, heavy 240-260g, at controllable environment condition (12h illumination/dark cycle, 24 ℃ of room temperatures) every cage keeps two male Wistar rat (Harlan-Interfauna Iberica under, Barcelona, Spain) liver.After decaptitating, take out internal organs and homogenate in the pH7.8 of 5mM phosphate buffered saline buffer immediately.Become the ability of metanephrine to estimate the COMT activity by the suprarenin that methylates.With the five equilibrium liver homogenate liquid of 0.5ml 0-4ml phosphate buffered saline buffer (5mM) pre-incubation 20min; At the methyl donor S-of saturation concentration adenosine-L-methionine(Met) (500 μ m) when existing, use suprarenin (1000 μ ms thereafter; 0.1mL) incubation reaction mixture 5min; Hatch medium and also contain pargyline (100 μ m), MgCl
2(100 μ m) and EGTA (1mM).Carry out under pre-incubation and the condition that is incubated in 37 ℃, lucifuge, continuous oscillation and do not have oxidation to take place.
In being designed for the tested material oral administration biaavailability of evaluation, compound is supplied with the rat of going on a hunger strike and spending the night by stomach tube.After this, at the interval that limits,, take out liver and be used for by determining the COMT activity as mentioned above by animal being killed by detruncation.At incubation period (5min) end, test tube is changed over to ice bath and crosses the chloric acid termination reaction by the 2M that adds 200 μ l.Be used for the metanephrine test then with sample centrifugal (200 * g, 4min, 4 ℃), and with branch supernatant liquors such as the filtering 500 μ l of via hole diameter size 0.22 μ mSpin-X chimney filter (Costar).Utilization has the high pressure lipuid chromatography (HPLC) test metanephrine of Electrochemical Detection.The lower range that detects metanephrine is 350～500fmol (0.5～1.0pmol/mg albumen/h).
L-DOPA and 3-O-methyl-L-DOPA level in the blood plasma
(0.5% carboxymethyl cellulose 4ml/kg) is administered orally in the rat of going on a hunger strike and spending the night with the compound (all being 3mg/kg) of Tolcapone, Entacapone and general formula I or remedium constituens.1,6 or 23h after, add the following hydrazine of hydroxyl (3mg/kg) or (0.5% carboxymethyl cellulose 4ml/kg) is administered orally in the rat of going on a hunger strike and spending the night with remedium constituens with L-DOPA (12mg/kg).After one hour, rat is collected blood by Vena cava, and takes out whole brain fast with sodium pentobarbital (injection in the 60mg/kg, abdomen) anesthesia.Blood sample 3, the centrifugal 15min of 000g (4 ℃), and with plasma sample-80 ℃ storage until L-DOPA and 3-O-methyl-L-DOPA test.According to European command N o.86/609 and " be concerned about and use laboratory animal guide " (7th version, 1996, Institute for Laboratory Animal Research (ILAR), Washington, DC) article and carrying out all animals participate in all.
L-DOPA and catechol derivatives test
(Soares-da-Silva et al., Brain Res., 2000 as previously mentioned; 863:293-297), measure L-DOPA and 3-O-methyl-L-DOPA in the blood sample by the HPLC that has Electrochemical Detection.In brief, 20 μ l aliquots containigs are injected into chromatographic instrument.This chromatographic system comprises the stainless steel 5 μ m ODS2 post (Biophase of pump (Gilson 307) and long 25cm, diameter 4.6 mM; Bioanalytical Systems, West Lafayette, Indiana); Use is connected to automatic sample syringe (Gilson 231) injected sample on the Gilson diluter (Gilson 401).Moving phase is the 0.1mM citric acid solution of the degassing; 0.5mM sodium octyl sulfate; 0.1M sodium-acetate; 0.17mM Na2EDTA; 1mM dibutylamine and methyl alcohol (10%v/v) are adjusted to pH3.5 with it and with 1.0ml min with the PCA of 2 M
-1Speed pump into.Detector (Gilson 142) with glassy carbon electrode, Ag/AgCl reference electrode and measurement electric current carries out Electrochemical Detection; Under 0.75V, operate detector cell.The electric current that uses the monitoring of Gilson Unipoint HPLC software to produce.
Cytotoxicity
This detects the toxic method of tested object cell plastid, can be undertaken by the method (Br.J.pharmacol., 137,11305-1313,2002) that Pedrosa and Soares-da-Silva describes.In brief, in 96 orifice plates, every hole 200 μ L cell attachment substratum (CMA) are at CO with neural 2A (Neuro 2A) mouse neuroblastoma cell inoculation
2Cultivate during following 37 ℃ of the moist environment of/air (5%/95%).The control of test macro before hatching comprises the Morphology Control (light microscope) of culturing cell: adhere to, expansion and density.(after cell becomes fusion 24h) after the inoculation 5 days, hatch tested compounds 24h with cultured cells.With the culture of no tester or ethanol as negative control with positive control is parallel tests.All hatch the required solvent of the tested compounds that contains same percentage.
Use fluorexon AM (Molecular Probes, Eugene, Oregon, the U.S.) to measure cell survival rate.After birth perviousness fluorexon AM, no fluorochrome is absorbed and be converted into the impervious fluorexon of cytolemma by the esterase in the born of the same parents, and it launches green fluorescence.Handling back 24h with test article or remedium constituens, cell is used Hanks ' medium (media compositions, the mM:NaCl of unit, 137; KCl, 5; MgSO
4, 0.8; Na
2HPO
4, 0.33; KH
2PO
4, 0.44; CaCl
2, 0.25; MgCl
2, 1.0; Tris.HCl, 0.15 and Sodium propanecarboxylate, 1.0, pH=7.4) washed twice, and load in Hanks ' medium with 2 μ m fluorexon AM, at room temperature be incubated 30min.In many plates reading machine, measure fluorescence in 485nm excitation wavelength and 530nm transmitted wave strong point.For determining the minimum dyeing of fluorexon AM (fluorexon), Ethanol Treatment 30min was used in eight holes before adding fluorexon AM.Use formula then
[(fluorexon
Sample-fluorexon
Min)/(fluorexon
Contrast-fluorexon
Min)] * 100 calculating percentage survival rates.
Test-results
Table 1 has shown that the compound of standard C OMT inhibitor Tolcapone and Entacapone and general formula I is to their the active influence of liver COMT behind mouse oral (3mg/kg) 3h.Table 1 has also shown the cell survival rate of Neuro 2A cellular exposure behind compound (all the being 30 μ m) 24h of Tolcapone, Entacapone and general formula I simultaneously.
The cell survival rate (% viable cell) of table 1 mouse liver COMT activity (% contrast) and Neuro 2A behind the listed compound of administration 3mg/kg (oral)
Annotate:
*Represent the tie point of pyridine N-oxides substituting group and this molecule
Experiment finds that also the compound of general formula I is effective inhibitor of rat liver COMT, obtains maximum inhibition effect (table 2) behind their oral administrations in 1h～3h.After administration, observe the maximum suppression effect (table 2) of Entacapone (Ent) and Tolcapone (Tolc) in the 1h.In administration after 9 hours, Entacapone no longer includes COMT inhibition effect, and Tolcapone produces minimum inhibition effect (～16% inhibition), otherwise the compound of general formula I can continue to keep the active inhibition level (table 2) of COMT of contrast 22%～90%.
Table 2 behind the listed compound of administration 3mg/kg (oral), rat liver COMT activity (% contrast).
| Compound | Time (h) | |||
| 1 | 3 | 6 | 9 | |
| Entacapone Tolcapone 18 29 30 41 42 43 45 47 | 32.0 18.3 5.2 1.2 6.3 21.2 3.6 16.1 1.1 10.6 | 74.5 28.6 19.9 18.5 34.8 9.3 6.1 30.6 1.2 4.0 | 95.2 56.8 43.0 39.7 41.2 18.8 12.3 64.3 3.8 3.8 | 100.0 83.9 57.4 56.4 54.5 39.7 30.9 77.9 8.9 8.2 |
Table 3 shown with back 2 hours of the compound administration (3mg/kg) of Entacapone, Tolcapone and general formula I, adds the percentage ratio of L-DOPA and the variation of 3-O-methyl-L-DOPA (3-OMD) level in the rat plasma of following hydrazine processing of hydroxyl with L-DOPA.1h administration L-DOPA adds the following hydrazine of hydroxyl before plasma sample is collected.Select this time point to be because it has represented the t of L-DOPA
MaxAs observable, the compound of general formula I produces the remarkable increase of L-DOPA in the blood plasma, follows the obvious decline of 3-O-methyl-L-DOPA in the blood plasma.
Listed compound (the 3mg/kg of table 3; Oral administration) to adds the influence that L-DOPA and 3-O-methyl-L-DOPA (3-OMD) level in the rat plasma that following hydrazine of hydroxyl handle change (% contrast) with L-DOPA.
| Compound | L-DOPA % improves | 3-OMD % reduces | L-DOPA/3-OMD |
| Entacapone Tolcapone 18 29 30 41 42 43 45 47 | 68.5 202.4 61.4 105.1 103.5 95.2 30.7 74.9 100.8 102.9 | -55.6 -89.0 -63.9 -80.7 -75.0 -72.3 -43.4 -48.3 -54.3 -58.5 | 3.8 27.6 4.5 10.6 8.1 7.1 2.3 3.4 4.4 4.9 |
Conclusion
The compound of general formula I is very effective catechol-O-methyltransferase (COMT) inhibitor, and toxicity obviously reduces.The compound of general formula I has potential valuable drug characteristic, can be used for the treatment of some nervus centralis and peripheral nervous system dysfunction, wherein, the methylated inhibition in catecholamine oxygen position has the treatment of being beneficial to, and this dysfunction is such as being mood dysfunction, Parkinson's disease and forming situation and hypertension like parkinsonian dysfunction, restless leg syndrome, gastrointestinal dysfunction, edema.Use effectively by improving the security of Nitrocatechol COMT inhibitor, improve simultaneously or keep time length and COMT inhibition selectivity, making, long-term role, have the new prospect that the possibility of the inhibitor that improves security features has been showed following disease treatment: Parkinson's disease and form situation and hypertension like parkinsonian dysfunction, gastrointestinal dysfunction, edema.Owing to can be used for the treatment of for a long time, suffer the Parkinson's disease misery when expecting treating, when taking L-DOPA and adding the patient of the AADC of peripheral tissues inhibitor, this is even more important.
The present invention discloses following preparation embodiment at this, it must not be considered as limiting the scope of the invention.To those skilled in the art, selectable path and similar structures can be conspicuous.
Embodiment 1
3-nitro-5-[3-(1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol (compound 4, table 1)
A) at room temperature, to 3 of stirring, 4-two benzyloxies-5-nitrobenzoic acid (0.5g 1.32mmol) adds 1 part 1 in the solution in dimethyl formamide (5mL), and the 1-N,N'-carbonyldiimidazole (0.246g, 1.52mmol).After stirring 1 hour, (0.208g 1.52mmol), and at room temperature stirs the mixture that obtains and to spend the night to add 1 part of N '-pyridone-4-carboxylic Imidamide (carboximidamide).Then this mixture was stirred three hours down at 110 ℃, make it be cooled to room temperature then.This mixture is poured on the ice-water bath (100mL), and with 20% Virahol/dichloromethane extraction.Organic extract liquid water and salt water washing, dry then (Na
2SO
4), filter, evaporation, remaining solid residue is used ethyl alcohol recrystallization.Obtain beige solid 4-[5-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-pyridine (0.395g, 62%).
B) the above-mentioned pyridine compounds that will stir (0.331g, 0.689mmol) solution in methylene dichloride (15mL) cools off in ice-water bath, and the portion-wise addition metachloroperbenzoic acid (0.179g, 1.03mmol).The mixture that stirring obtains under the cooling 30 minutes at room temperature stirred 30 minutes then, subsequently it was cooled off in ice-water bath once more.(0.17g 1.03mmol), at room temperature stirred the mixture one and a half hours then to add metachloroperbenzoic acid again.Add water (20mL), and separate organic phase, and with saturated sodium bicarbonate aqueous solution, water and salt water washing, drying (Na then
2SO
4), filter, evaporation, remaining yellow oil.Add diethyl ether and cause that throw out forms, filter, also use methylene dichloride/isopropanol mixture recrystallization.Obtain white crystal 4-[5-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-pyridine 1-oxide compound (0.239g, 70%).
C) under argon shield, (0.232g, 0.468mmol) solution in methylene dichloride (5mL) is cooled to-78 ℃, and (0.586g 2.34mmol) drips processing with boron tribromide with above-mentioned dibenzyl ether while stirring.Be cooled to before-78 ℃ the garnet suspension that stirring at room temperature obtains 1 hour then once more.The careful methyl alcohol that adds makes mixture cures.After at room temperature stirring 1 hour, boil off volatile matter, residue is handled with ethanol/toluene, and evaporation once more.With the boiling ethanol efflorescence of yellow residue, and be incubated filtration, obtain the title product (0.102g, 69%) of yellow solid, fusing point 280-282 ℃.
Embodiment 2
3-nitro-5-[3-(1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol (compound 5, table 1)
A) at room temperature, to 3 of stirring, 4-dimethoxy-5-nitrobenzoic acid (0.232g, 1.022mmol) solution in dimethyl formamide (5mL) adds 1 part 1, the 1-N,N'-carbonyldiimidazole (0.174g, 1.073mmol).The mixture that obtains was stirred 90 minutes, add thereupon 1 part of N '-pyridone-3-carboxylic Imidamide (carboximidamide) 1-oxide compound (0.156g, 1.022mmol).The mixture that stirring at room temperature obtains two hours is then 75 ℃ of following standing over night.After being cooled to room temperature, mixture is poured in the water (100mL), and leaches throw out, wash with water, then at air drying, use the diethyl ether recrystallization.Obtain white solid 3-[5-(3,4-dimethoxy-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-pyridine 1-oxide compound (0.162g, 46%).
B) under argon shield, to the above-mentioned dme that stir down in-78 ℃ (0.153g, 0.445mmol) solution in methylene dichloride (10mL) drip boron tribromide (0.445g, 1.779mmol).Reaction mixture is incubated to room temperature, and before carefully inclining in the water (100mL), stirred 90 minutes.After stirring 20 minutes, use the ethyl acetate extraction mixture.Organic extract water and salt water washing, dry (Na
2SO
4), filter evaporation.Obtained yellow solid 2-methoxyl group-3-nitro-5-[3-(1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-phenol (0.12g, 82%).
C) under argon shield, the above-mentioned methyl ether that at room temperature will stir (0.108g, 0.327mmol) 1, suspension in the 2-ethylene dichloride (10mL) with aluminum chloride (0.087g 0.654mmol) handles, then drip pyridine (0.207g, 2.62mmol).Then mixture heating up was refluxed seven hours, further add subsequently aluminum chloride (0.087g, 0.654mmol) and pyridine (0.207g, 2.62mmol), again with mixture stirring and refluxing seven hours.Then mixture is cooled to room temperature, and in the cold 1N hydrochloric acid (30mL) of impouring.Leach the throw out that obtains, wash with water, and 50 ℃ of following vacuum-dryings.Obtained the expection product (0.075g, 72%) of orange solids, fusing point 278-280 ℃.
Embodiment 3
3-nitro-5-[3-(1-oxygen-pyridine-2-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol (compound 6, table 1)
A) at room temperature, to 3 of stirring, 4-dimethoxy-10-nitrobenzoic acid (1.0g, 4.40mmol) solution in dimethyl formamide (10mL) adds 1 part 1, the 1-N,N'-carbonyldiimidazole (0.821g, 5.06mmol).The mixture that obtains was stirred 90 minutes, add subsequently 1 part of N '-pyridone-2-carboxylic Imidamide (carboximidamide) 1-oxide compound (0.775g, 5.06mmol).The mixture that obtains at room temperature stirred spend the night, then in the impouring water (100mL).Leach the throw out that obtains, wash with water, add then in the methylene dichloride (30mL).With organic layer water and salt water washing, dry (Na
2SO
4), filter, and evaporation, remaining white solid (1.37g, 86%).
B) under argon shield, under room temperature to the above-mentioned gained solid that stirs (1.365g, 3.77mmol) solution of tetrabutylammonium in tetrahydrofuran (THF) that adds 1N of the suspension in tetrahydrofuran (THF) (14mL) (3.8ml, 3.8mmol).The limpid yellow solution that obtains was at room temperature stirred seven hours, during form new throw out.Mixture is filtered, and wash solids with several parts of cold tetrahydrofuran (THF)s.Obtain white solid 2-[5-(3,4-dimethoxy-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-pyridine 1-oxide compound (0.97g, 75%).
C) under argon shield, under-78 ℃ to the above-mentioned gained dimethyl ether that stirs (0.961g, 2.79mmol) suspension in methylene dichloride (15mL) drip boron tribromide (3.5g, 13.97mmol).Before being then to cool off in the ice/water-bath, the purple suspension that obtains was at room temperature stirred seven hours.Add methyl alcohol carefully, make mixture cures.Leach throw out and with methanol wash before, the yellow mixture that obtains was at room temperature stirred 1 hour.With boiling ethanol efflorescence solid, and insulation is filtered.After the drying, obtained the expecting compound (0.712g, 81%) of orange solids, 168 ℃ of fusing points.
Embodiment 4
5-(5-methyl-[1,2,4] oxadiazole-3-yl]-3-oil of mirbane-1,2-glycol (compound 2, table 1)
A) at room temperature to 3 of stirring, 4-two benzyloxies-N '-hydroxyl-5-oil of mirbane carbonamidine (1.0g, 2.54mmol) solution in dimethyl formamide (5mL) adds 1 part 1,1-N,N'-carbonyldiimidazole (0.494g, 3.048mmol), and mixture at room temperature stirred 90 minutes.Subsequently, (0.184g 3.067mmol), at room temperature stirred the mixture two hours, stirred three hours down at 155 ℃ then to drip acetate.Mixture is cooled to room temperature, and in the impouring ice-water-bath (100mL).Add salt solution (10mL), take out the throw out that obtains, wash with water by filtering, and at air drying.Then solid is dissolved in methylene dichloride (20mL), and adds a shovel top gac.After stirring 20 minutes, suspension is by diatomite filtration, and with the filtrate evaporation, remaining yellow oil leaves standstill curing.Behind recrystallization from methylene dichloride/sherwood oil, obtained light yellow solid 3-(3,4-two benzyloxies-5-nitrophenyl)-5-methyl-[1,2,4] oxadiazole (0.537g, 51%).
B) under argon shield, under-78 ℃ to the above-mentioned gained solid that stirs (0.128g, 0.307mmol) solution in methylene dichloride (15mL) drip boron tribromide (0.318g, 1.269mmol).At room temperature the purple suspension that obtains was stirred 1 hour, and then be cooled to-78 ℃.The careful methyl alcohol that adds makes mixture cures, and after at room temperature stirring 1 hour, boils off solvent.With the yellow residue of diethyl ether efflorescence, filter drying.Obtained the expecting compound (0.070g, 96%) of yellow solid, fusing point 169.8-172 ℃.
Embodiment 5
5-(the 5-methyl-[1,3,4] oxadiazole-2-yls)-3-oil of mirbane-1,2-glycol (compound 3, table 1)
A) at room temperature, to 3 of stirring, 4-dimethoxy-5-nitrobenzoic acid (0.438g, 1.93mmol) solution in tetrahydrofuran (THF) (10mL) adds 1 part 1, the 1-N,N'-carbonyldiimidazole (0.343g, 2.12mmol), and at room temperature mixture was stirred 1 hour, stirred two hours down at 70 ℃ then, add subsequently acetic acid hydrazides (0.157g, 2.12mmol).At room temperature the mixture that obtains was stirred 30 minutes, stirred two hours down at 70 ℃ then.After being cooled to room temperature, in mixture impouring ice-water-bath (100mL), leach throw out, wash with water.Obtained white solid 3,4-dimethoxy-5-nitrobenzoic acid N '-ethanoyl hydrazides (0.296g, 54%).
B) (0.288g, 1.017mmol) suspension in phosphoryl chloride (7mL) is two hours, is cooled to room temperature then to stir above-mentioned gained solid down at 120 ℃.With in the solution impouring ice-water-bath (200mL), form white depositions then.Use dichloromethane extraction, and organic extraction water and salt water washing, dry then, filter, stay white solid after the evaporation.Recrystallization from methylene dichloride/sherwood oil obtains white crystal 2-(3,4-dimethoxy-5-nitrophenyl)-5-methyl-[1,3,4] oxadiazoles (0.151g, 56%).
C) under argon shield, under-78 ℃ to the above-mentioned gained solid that stirs (0.145g, 0.547mmol) solution in methylene dichloride (10mL) drip boron tribromide (0.685g, 2.74mmol).At room temperature, the purple suspension stirring that obtains is spent the night, and then be cooled to-78 ℃.By adding methyl alcohol, make the reactant sclerosis, and after at room temperature stirring 1 hour, boil off volatile matter.Add toluene (20mL) in the residue, and evaporation once more.With the residue efflorescence, and insulation filters, and obtains the expection product (0.107g, 82%) of orange solids, fusing point 245-246 ℃ with boiling ethanol.
Embodiment 6
5-[3-(3,5-two chloro-1-oxygen-pyridine 4-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol (compound 7, table 1)
A) at room temperature, to 3 of stirring, 4-two benzyloxies-5-nitrobenzoic acid (0.50g, 1.32mmol) solution in dimethyl formamide (5mL) adds 1 part 1, the 1-N,N'-carbonyldiimidazole (0.246g, 1.52mmol), and mixture was stirred 90 minutes, add 1 part 3 subsequently, and 5-two chloro-N '-hydroxyl-1-oxygen isonicotine amidine (0.337g, 1.52mmol).The mixture that obtains at room temperature stirred spend the night, in the impouring ice-water-bath then (100mL).Add salt solution (10mL), leach throw out, wash with water, and be dissolved in 30% Virahol/methylene dichloride.Distillate methylene dichloride then, and the Virahol suspension that obtains was stored 1 hour down at 0 ℃.Leach solid then, with cold washed with isopropyl alcohol, drying, remaining white solid (0.756g, 98%).
B) (0.664g, 1.14mmol) and 1, (0.185g 1.14mmol) is dissolved in dimethyl formamide (10mL) to the 1-N,N'-carbonyldiimidazole, stirs nine hours down at 100 ℃, then standing over night at room temperature with 1 part of this solid.In the mixture impouring ice-water-bath (100mL) that obtains, by dripping 2N hydrochloric acid, be acidified to pH1-2 then.Leach the yellow mercury oxide of formation, wash with water, and be dissolved in 10% Virahol/methylene dichloride (50mL).With the organic phase drying, filter, and evaporate to dryness.Use ethyl acetate/petroleum ether (1: 1) mixed solvent, residue is carried out chromatographic separation by silica gel.Compile similar component and evaporation, and, obtain yellow solid 2-benzyloxy-4-[3-(3,5-two chloro-1-oxygen-pyridin-4-yls)-[1,2,4] oxadiazole-5-yl residue recrystallization from methylene dichloride/Virahol]-6-nitrophenols (0.263g, 49%).
C) under argon shield, under-78 ℃ to the above-mentioned gained solid that stirs (0.24g, 0.505mmol) suspension in methylene dichloride (5mL) drip boron tribromide (0.371g, 1.5mmol).The purple suspension that obtains is at room temperature stirred 1 hour, and then be cooled to-78 ℃, and make its sclerosis by adding methyl alcohol.After at room temperature stirring 1 hour, desolvate by evaporating to remove.With the yellow foams recrystallization from methylene dichloride/Virahol that obtains, obtained the expection product (0.153g, 79%) of yellow solid, fusing point 252-253 ℃.
Embodiment 7
5-[3-(2-chloro-1-oxygen-pyridine-4)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol (compound 8, table 1)
A) at room temperature, to 3 of stirring, 4-two benzyloxies-5-nitrobenzoic acid (0.50g, 1.32mmol) solution in dimethyl formamide (5mL) adds 1 part 1, the 1-N,N'-carbonyldiimidazole (0.246g, 1.52mmol), and with mixture stirring 1 hour, add subsequently 1 part of 2-chloro-N '-hydroxyl-1-oxygen isonicotine amidine (0.284g, 1.52mmol).At room temperature the mixture that obtains was stirred 30 minutes, stirred four hours down at 140 ℃ then.After being cooled to room temperature, in mixture impouring water (100mL), and by dripping the 2N hcl acidifying to pH1-2.Use the ethyl acetate extraction mixture, and water and salt water washing organic extract, dry then, filter, and evaporation, remaining orange solids is from methylene dichloride/Virahol behind the recrystallization, obtained greenish orange look crystalline 4-[5-(3,4-two benzyloxies-5-nitre phenyl)-[1,2,4] oxadiazole-3-yl]-2-chloropyridine 1-oxide compound (0.265g, 38%).
B) under argon shield, under-78 ℃ to the above-mentioned gained solid that stirs (0.25g, 0.471mmol) solution in methylene dichloride (5mL) drip boron tribromide (0.59g, 2.36mmol).At room temperature, the intense violet color suspension that obtains was stirred 1 hour, and then be cooled to-78 ℃.By adding methyl alcohol, make the reactant sclerosis, and after at room temperature stirring 1 hour, desolvate by evaporating to remove.Add ethanol (5mL) and toluene (20mL) in the residue, and evaporation once more.With boiling ethanol residue efflorescence and insulation are filtered, obtained the expection product (0.12g, 72%) of yellow crystals, it can decompose more than 300 ℃.
Embodiment 8
2,5-two chloro-3-[5-(3,4-dihydroxyl-2-nitrophenyl)-1,2,4-oxadiazole-3-yl)-4,6-lutidine 1-oxide compound.
A) at room temperature, (0.900g is 4.22mmol) at N to the 3-hydroxyl-4-methoxyl group-2-nitrobenzoic acid that stirs, suspension in the N-N,N-DIMETHYLACETAMIDE (10.35mL) drips 1,1-N,N'-carbonyldiimidazole (1.540g, 9.506mmol) solution 7.65ml in N,N-dimethylacetamide.After stirring three hours, with 1 part of (Z)-2,5-two chloro-N '-hydroxyls-4, (1.19g 5.107mmol) is added in the N,N-dimethylacetamide of 2.7ml 6-dimethyl nicotine imide acid amides.The mixture that obtains was stirred 1 hour 45 minutes, heated 1 hour down at 135 ℃ then.In the mixture with reaction mixture impouring ice/2N HCl.Leach throw out, wash with water and vacuum-drying, obtained yellow solid.Recrystallization from methylene dichloride/Virahol, obtained yellow solid 3-[3-(2,5-two chloro-4,6-lutidine-3-yl]-1,2,4-oxadiazole-5-yl]-6-methoxyl group-2-nitrophenol (0.317g, 18%).
B) at room temperature, to the above-mentioned gained solid that stirs (0.315g, 0.766mmol) suspension in methylene dichloride (4.3mL) add urea-hydrogen peroxide addition complex (0.231g, 2.451mmol).The suspension that obtains is cooled to 0 ℃, and the dropping trifluoroacetic anhydride (TFAA) (0.483g, 2.30mmol).At room temperature, mixture is stirred twenty four hours, add entry then, and stirred 1 hour.Leach throw out, wash with water, drying.In methylene chloride (99: 1) mixture, thick product is carried out chromatographic separation.Steam pure component, obtained yellow crystals 2,5-two chloro-3-[5-(3-hydroxyl-4-methoxyl group-2-nitrophenyl)-1,2,4-oxadiazole-3-yl]-4,6-lutidine 1-oxide compound (0.195g, 59%).
C) under argon shield, under 0 ℃ to the above-mentioned gained solid that stirs (0.143g, 0.335mmol) suspension in N-Methyl pyrrolidone (2.5mL) add 1 part of aluminum chloride (0.056g, 0.42mmol), then add pyridine (0.106g, 1.34mmol).The solution that obtains was heated 25 minutes down at 60 ℃, and then be cooled to room temperature, and in the impouring ice/2N HCl mixture.After at room temperature stirring 45 minutes, leach throw out, wash with water and vacuum-drying.With thick product recrystallization from methylene dichloride/isopropanol mixture.After the drying, obtained the expecting compound (0.101g, 73%) of yellow crystals, 230 ℃ of fusing points (decomposition).
Embodiment 9-17
By adopting above-mentioned technology and the relevant step that has been well known to those skilled in the art, and use suitable N-hydroxyl-1-oxygen isonicotine amidine, prepare following compound:
3-nitro-5-[3-(1-oxygen-2-phenylpyridine-4-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 264-264.8 ℃ (compound 9, table 1)
5-[3-(2-furans-3-base-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, 304 305 ℃ of fusing points (compound 10, table 1)
5-[3-(2-morpholine-4-base-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 277-280 ℃ (compound 11, table 1)
3-nitro-5-[3-(1-oxygen-2-thiomorpholine-4-base-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 260-262 ℃ (compound 12, table)
3-nitro-5-[3-(1-oxygen-2-phenyl sulfane yl pyridines-4-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 299-301 ℃ (compound 13, table 1)
3-nitro-5-[3-(1-oxygen-2-phenoxypyridines-4-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 245-246 ℃ (compound 14, table 1)
5-[3-(2,6-dimethyl-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 280-282 ℃ (compound 15, table 1)
5-[3-(2-methane sulfane base-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 282-285 ℃ (compound 16, table 1)
5-[3-(2-methyl sulfane base-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 239-240 ℃ (compound 17, table 1)
Embodiment 18
3-nitro-5-[3-(1-oxygen-4-5-flumethiazine-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol (compound 18, table 1)
A) at room temperature, to 3 of stirring, 4-two benzyloxies-5-nitrobenzoic acid (0.291g, 0.769mmol) solution in dimethyl formamide (5mL) adds 1 part 1, the 1-N,N'-carbonyldiimidazole (0.131g, 0.808mmol).After stirring 90 minutes, add 1 part of N '-hydroxyl-1-oxygen-4-trifluoromethyl nicotine amidine (0.17g, 0.769mmol).The mixture that obtains was stirred two hours, in the impouring ice-water-bath then (100mL).Leach throw out, wash with water, and, obtained white solid (0.192g, 43%) at air drying.
B) under argon shield, under room temperature to the above-mentioned gained solid that stirs (0.192g, 0.33mmol) solution of tetrabutylammonium in tetrahydrofuran (THF) that drips 1N of the suspension in tetrahydrofuran (THF) (10mL) (1.2mL, 1.2mmol).After at room temperature stirring is spent the night, in this mixture impouring water-bath (100mL), and use dichloromethane extraction.Water and salt water washing organic extract, dry (Na
2SO
4), filter evaporation.Use methylene chloride (99: 1) mixed solvent as elutriant, residue is carried out chromatographic separation by silica gel.Compile similar component, and evaporate, then from methylene dichloride/Virahol with the residue recrystallization.Obtain white solid 3-[5-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-4-5-flumethiazine 1-oxide compound (0.092g, 49%).
C) under argon shield, under-78 ℃ to the above-mentioned gained solid that stirs (0.09g, 0.16mmol) solution in methylene dichloride (5mL) drip boron tribromide (0.16g, 0.64mmol).At room temperature, the purple suspension that obtains was stirred 1 hour, and then be cooled to-78 ℃, and make the suspension sclerosis by adding entry carefully.After at room temperature stirring 1 hour, leach throw out, wash with water, and, obtain the expecting compound (0.048g, 79%) of yellow crystals, fusing point 239-240 ℃ 50 ℃ of following vacuum-dryings.
Embodiment 19-35
By adopting above-mentioned technology and the relevant step that has been well known to those skilled in the art, and use suitable N '-hydroxyl-1-oxygen isonicotine amidine, prepare following compound:
5-[3-(5-bromo-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 258-260 ℃ (compound 19, table 1)
6-[3-(6-methyl isophthalic acid-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 325-326 ℃ (compound 20, table 1)
5-[3-(4-methyl isophthalic acid-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, 297 ℃ of fusing points (compound 21, table 1)
3-nitro-5-[3-(1-oxygen-2-phenylpyridine-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 288-289 ℃ (compound 22, table 1)
5-[3-(6-chloro-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 268-270 ℃ (compound 23, table 1)
5-[3-(2-chloro-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 265-267 ℃ (compound 24, table 1)
5-[3-(2-chloro-6-methyl isophthalic acid-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 218-220 ℃ (compound 25, table 1)
5-[3-(2-morpholine-4 bases-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 175-177 ℃ (compound 26, table 1)
5-[3-(6-methyl sulfane base-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 264-266 ℃ (compound 27, table 1)
3-nitro-5-[3-(1-oxygen-6-5-flumethiazine-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 269.5-271.3 ℃ (compound 28, table 1)
5-[3-(2-methyl isophthalic acid-oxygen-6-5-flumethiazine-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 240-242 ℃ (compound 29, table 1)
5-[3-(6-methyl isophthalic acid-oxygen-4-5-flumethiazine-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 250-252.5 ℃ (compound 30, table 1)
5-[3-(2,6-dimethyl-1-oxygen-4-5-flumethiazine-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 252-253 ℃ (compound 31, table 1)
5-[3-(2-methyl isophthalic acid-oxygen-6-phenyl-4-5-flumethiazine-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 256-256.5 ℃ (compound 32, table 1)
5-[3-(6-methyl isophthalic acid-oxygen-2-phenyl-4-5-flumethiazine-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 237-239 ℃ (compound 33, table 1)
3-nitro-5-[3-(1-oxygen quinolyl-4)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 306-307 ℃ (compound 34, table 1)
3-nitro-5-[3-(1-oxygen quinoline-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 276-277 ℃ (compound 35, table 1)
3-nitro-5-[3-(1-oxygen-2-5-flumethiazine-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 253-254 ℃ (compound 42, table 1)
Embodiment 36
5-[3-(2-bromo-6-methyl isophthalic acid-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol (compound 36, table 1)
A) at room temperature, to 3 of stirring, 4-two benzyloxies-5-nitrobenzoic acid (1.355g, 3.576mmol) solution in dimethyl formamide (10mL) adds 1 part 1, the 1-N,N'-carbonyldiimidazole (0.667g, 4.113mmol).After stirring 90 minutes, add 2-bromo-N '-hydroxyl-6-methyl nicotine amidine (0.946g, 4.113mmol) and stir and spend the night, then with in the mixture impouring water (100mL).Add salt solution (10mL), leach throw out, wash with water, and be dissolved in methylene dichloride (50mL).With organic layer water and salt water washing, dry (Na2SO4) then filters, and evaporation, remaining white foam body (1.91g, 90%).
B) to above-mentioned gained solid (1.91g, 3.23mmol) solution in dimethyl formamide (30mL) adds 1, (0.576g 3.55mmol), and stirs the mixture that obtains three hours down at 120 ℃ the 1-N,N'-carbonyldiimidazole, is cooled to room temperature then.In mixture impouring ice-water-bath (150mL), and, be acidified to pH1-2 by dripping 2 N hydrochloric acid.Use the dichloromethane extraction mixture, and water and salt water washing organic extract, dry then (Na
2SO
4), filter evaporation, remaining orange solids.Recrystallization from methylene dichloride/ethanol obtains orange solids 3-[5-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-2-bromo-6-picoline (0.702g, 38%).
C) at room temperature, to the above-mentioned gained solid that stirs (0.609g, 1.063mmol) solution in methylene dichloride (15mL) add urea-hydrogen peroxide addition complex (0.525g, 5.579mmol).The suspension that obtains is cooled to 0 ℃, and the dropping trifluoroacetic anhydride (TFAA) (1.12g, 5.314mmol).Mixture was at room temperature stirred five hours, leach insoluble substance then, and with the washed with dichloromethane of small volume.The filtrate that merges is stirred 15 minutes to remove excessive superoxide with 10% metabisulfite solution (10mL), separate each phase then.Water, saturated aqueous solution of sodium bicarbonate, water and salt water washing organic phase again, dry then (Na
2SO
4), filter evaporation, remaining white solid.Twice recrystallization from methylene dichloride/ethanol obtains white crystal 3-[5-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-2-bromo-6-picoline 1-oxide compound (0.344g, 55%).
D) under argon shield, under-78 ℃ to the above-mentioned gained solid that stirs (0.337g, 0.572mmol) solution in methylene dichloride (10mL) drip boron tribromide (0.717g, 2.86mmol).The purple suspension that obtains is at room temperature stirred 1 hour, and then be cooled to-78 ℃, and make the suspension sclerosis by adding methyl alcohol.After at room temperature stirring 1 hour, steam solvent.Add ethanol (5mL) and toluene (20mL) in the residue, and evaporation once more.Residue is stirred in boiling ethanol and the insulation filtration.After the drying, obtained orange crystalline expecting compound (0.187g, 80%), fusing point 246-247 ℃.
Embodiment 37-41
By adopting above-mentioned technology and the relevant step that has been well known to those skilled in the art, and use suitable N '-hydroxyl nicotine amidine, prepare following compound:
5-[3-(2-chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 234-235 ℃ (compound 37, table 1)
5-[3-(2-bromo-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 205-207 ℃ (compound 38, table 1)
3-nitro-5-[3-(1 '-oxygen-pyridine-3 ylmethyl)-[1,2,4] oxadiazole-5-yl]-Benzenediol, 232 ℃ of fusing points (compound 39, table 1)
3-nitro-5-[3-(1 '-oxygen-6-5-flumethiazine-3 ylmethyl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, 195.2 ℃ of fusing points (compound 43, table 1)
3-nitro-5-[3-(1 '-oxygen-5-5-flumethiazine-2 yloxymethyl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, 222 ℃ of fusing points (compound 44, table 1)
Embodiment 42
5-[3-(2-bromo-4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol (compound 40, table 1)
A) at room temperature, to 3 of stirring, 4-two benzyloxies-5-nitrobenzoic acid (0.945g, 2.49mmol) solution in dimethyl formamide (10mL) adds 1 part 1,1-N,N'-carbonyldiimidazole (0.465g, 2.87mmol), and the mixture that obtains was stirred two hours, add 1 part of 2-bromo-N '-hydroxyl-4,5 subsequently, 6-trimethylammonium nicotine amidine (0.74g, 2.87mmol).The mixture that obtains at room temperature stirred spend the night, then in the impouring water (150mL).Add salt solution (10mL), leach the throw out that obtains, and wash with water.Then mixture is dissolved in methylene dichloride (50mL), and water and salt water washing organic phase, dry then (Na
2SO
4), filter evaporation, remaining white solid (1.40g, 91%).
B) under argon shield, under room temperature to the above-mentioned gained solid that stirs (1.39g, 2.245mmol) solution of the tetrabutylammonium of the 1N that adds of the solution in tetrahydrofuran (THF) (20mL) in tetrahydrofuran (THF) (2.47mL, 2.47mmol).After at room temperature stirring is spent the night, this is almost in the reaction mixture impouring water (150mL) of black, and uses dichloromethane extraction.Water and salt water washing organic extract, dry then, filter evaporation, remaining brown oil.Add methylene dichloride (4mL) and ether (4mL), cause throw out formation, it is leached, and from Virahol recrystallization.Obtain beige solid 3-[5-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-2-bromo-4,5,6-trimethylpyridine (0.879g, 65%).
C) at room temperature, to the above-mentioned gained pyridines material that stirs (0.621g, 1.033mmol) solution in methylene dichloride (20mL) add 1 part of urea-hydrogen peroxide addition complex (1.018g, 10.82mmol).The suspension that obtains is cooled off in ice-water-bath, and the dropping trifluoroacetic anhydride (TFAA) (2.23g, 10.62mmol).The suspension cooling that obtains was stirred 15 minutes down, at room temperature stir then and spend the night.Leach insoluble substance then, and with the washed with dichloromethane of small volume.The filtrate that merges was stirred 15 minutes with 10% metabisulfite solution, separate each phase then.The full aqueous solution of water, sodium bicarbonate, water and salt water washing organic phase again, dry then, filter evaporation, the remaining greenish orange look solid of spumescence.Use petrol ether/ethyl acetate (1: 1) mixed solution as elutriant, this solid is carried out chromatographic separation by silica gel.Compile the component and the evaporation that contain similar product.Obtain spumescence light yellow solid 3-[5-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,4] oxadiazole-3-yl]-2-bromo-4,5,6-trimethylpyridine 1-oxide compound (0.342g, 54%).
D) under argon shield, under-78 ℃ to the above-mentioned gained solid that stirs (0.325g, 0.527mmol) solution in methylene dichloride (10mL) drip boron tribromide (0.66g, 2.633mmol).The intense violet color suspension that obtains is at room temperature stirred 1 hour, and then be cooled to-78 ℃, and make its sclerosis by careful dropping methyl alcohol.After at room temperature stirring 1 hour, desolvate by evaporating to remove.Add toluene (20mL) and ethanol (5mL) in the residue, and evaporation once more.With the yellow solid that obtains boiling ethanol (15mL) efflorescence, and insulation is filtered.Obtained the expection product (0.172g, 75%) of yellow solid, fusing point 242-243 ℃.
Embodiment 43-46
By adopting above-mentioned technology and the relevant step that has been well known to those skilled in the art, and use suitable N '-hydroxyl nicotine amidine, prepare following compound:
5-[3-(2-chloro-4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 246-247.3 ℃ (compound 41, table 1)
5-[3-(2,5-two chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 237-240 ℃ (compound 45, table 1)
3-nitro-5-[3-(4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1,2-glycol, fusing point 255-256 ℃ (compound 46, table 1)
5-[3-(2-bromo-5-chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1,2-glycol, fusing point 227-228 ℃ (compound 47, table 1)
Embodiment 47
As having center cell 2H-pyrazoles-1,5-two replaces the embodiment of the compound of general formula (I) partly, prepares 3-nitro-5-[2-(1-oxygen-2-5-flumethiazine-3-yl)-2H-pyrazole-3-yl by following step]-benzene-1, the 2-glycol:
A) to the 1-(3 that stirs, 4-dimethoxy-5-nitrophenyl)-3-dimethylamino-2-propylene-1-ketone (0.5g, 1.79mmol) and (2-5-flumethiazine-3-yl)-hydrazine (0.33g, 1.87mmol) solution in ethanol (10mL) adds 10 concentrated hydrochloric acids, and mixture heating up was refluxed two hours.Mixture is cooled to room temperature, and leaches the throw out that obtains, use washing with alcohol, drying has obtained 3-[5-(3,4-dimethoxy-5-nitrophenyl)-pyrazol-1-yl]-2-5-flumethiazine 0.58g (82%).
B) to 3-[5-(3,4-dimethoxy-5-nitrophenyl)-pyrazol-1-yl]-2-5-flumethiazine (0.50g, 1.27mmol) in methylene dichloride (10mL) with 1 part of urea-hydrogen peroxide complex thing (0.26g of ice-water-bath refrigerative solution adding, 2.76mmol), then drip trifluoroacetic anhydride (TFAA) (0.53g, 2.52mmol).The mixture that obtains at room temperature stirred spend the night, leach insoluble substance then.Water and salt solution wash filtrate are used anhydrous sodium sulfate drying then, filter evaporation, remaining pale solid.Recrystallization from ethanol obtains 3-[5-(3,4-dimethoxy-5-nitrophenyl)-pyrazol-1-yl]-2-5-flumethiazine 1-oxide compound 0.34g (65%).
C) under 140 ℃, stir 3-[5-(3,4-dimethoxy-5-nitrophenyl)-pyrazol-1-yl]-(0.3g, 0.73mmol) suspension in 48% hydrobromic acid aqueous solution (10mL) is 1 hour, is cooled to room temperature then for 2-5-flumethiazine 1-oxide compound.Then with in the mixture impouring ice-water-bath (100mL), and leach the yellow mercury oxide that obtains, wash with water and dry, obtained 3-nitro-5-[2-(1-oxygen-2-5-flumethiazine-3-yl)-2H-pyrazole-3-yl]-benzene-1,2-glycol 0.16g (57%).
Embodiment 48
As having center cell 1,3,4-oxadiazole-2,5-two replaces the compound embodiment of the general formula (I) of part, prepares 3-nitro-5-[5-(1-oxygen-2-5-flumethiazine-3-yl)-[1,3,4] oxadiazole-2-yl]-benzene-1 by following step, the 2-glycol:
A) at room temperature, with 3, (0.53g, 2.34mmol) and 1, (0.42g, mixture 2.59mmol) reflux three hours in tetrahydrofuran (THF) (10mL) is cooled to room temperature to the 1-N,N'-carbonyldiimidazole to 4-dimethoxy-5-nitrobenzoic acid then.(0.53g 2.57mmol), and should lurid mixture stirring and refluxing spend the night, and is cooled to room temperature then to add 1 part of 2-trifluoromethyl nicotinic acid hydrazide.In mixture impouring cold water (100mL), leach a large amount of precipitations, wash with water and drying, obtained 2-trifluoromethyl nicotinic acid N '-(3,4-dimethoxy-5-nitro benzoyl)-hydrazides, 0.71g (73%).
B) under 130 ℃, (0.60g, 1.44mmol) suspension in phosphoryl chloride (10mL) stirred three hours, became pale yellow solution with 2-trifluoromethyl-nicotinic acid N '-(3,4-dimethoxy-5-nitro benzoyl)-hydrazides.Mixture is cooled to room temperature, in the impouring ice-water-bath then (200mL).Leach white precipitate, wash with water, drying has obtained 3-[5-(3,4-dimethoxy-5-nitrophenyl)-[1,3,4] oxadiazole-2-yl]-2-5-flumethiazine, 0.48g (84%).
C) to the 3-[5-(3 that stirs, 4-dimethoxy-5-nitrophenyl)-[1,3,4] oxadiazole-2-yl]-2-5-flumethiazine (0.45g, 1.13mmol) in methylene dichloride (10mL), add 1 part of urea-hydrogen peroxide complex thing (0.23g with ice-water-bath refrigerative solution, 2.45mmol), then drip trifluoroacetic anhydride (TFAA) (0.47g, 2.24mmol).The mixture that obtains at room temperature stirred spend the night, leach insoluble substance then.Water and salt solution wash filtrate are used anhydrous sodium sulfate drying then, filter evaporation, remaining white solid.Recrystallization from ethanol obtains 3-[5-(3,4-dimethoxy-5-nitrophenyl)-[1,3,4] oxadiazole-2]-2-5-flumethiazine 1-oxide compound, 0.39g (83%).
D) with 3-[5-(3,4-dimethoxy-5-nitrophenyl)-[1,3,4] oxadiazole-2-yl]-2-5-flumethiazine 1-oxide compound (0.30g, 0.73mmol) add in the mixture of 48% Hydrogen bromide (5mL) and the acetic acid solution of 30% hydrogen bromide and form suspension, under 140 ℃,, be cooled to room temperature then with the suspension heated overnight.After the evaporated under reduced pressure, toluene (10mL) is added residue, and reduction vaporization once more.The solid that obtains recrystallization from Virahol has obtained yellow solid 3-nitro-5[5-(1-oxygen-2-5-flumethiazine-3-yl)-[1,3,4] oxadiazole-2-yl]-benzene-1,2-glycol, 0.19g (68%).
Embodiment 49
As having center cell pyrimidine-2,4-two replaces the compound embodiment of the general formula (I) of part, prepares 3-nitro-5-[2-(1-oxygen-2-5-flumethiazine-3-yl)-pyrimidine-4-yl by following step]-benzene-1, the 2-glycol:
A) with 1-(3,4-dimethoxy-5-nitrophenyl)-3-dimethylamino-2-propylene-1-ketone (0.28g, 1.0mmol), 1-oxygen-2-trifluoromethyl nicotine amidine (0.31g, 1.5mmol) and potassium tert.-butoxide (0.17g, 1.5mmol) the middle suspension that forms of adding absolute ethanol (5mL), the suspension that stirs is heated to 80 ℃ of insulations 1 hour in the sealing test tube, is cooled to room temperature then.In mixture impouring cold water (100mL), leach the precipitation that obtains, wash with water and drying, obtained 4-(3,4-dimethoxy-5-nitrophenyl)-2-(1-oxygen-2-5-flumethiazine-3-yl)-pyrimidine, 0.31g (73%).
B) under 140 ℃, 4-(3,4-dimethoxy-5-nitrophenyl)-(0.25g, 0.59mmol) suspension in 48% Hydrogen bromide (5mL) is four hours, is cooled to room temperature then for 2-(1-oxygen-2-5-flumethiazine-3-yl)-pyrimidine in stirring.Then with in the mixture impouring ice-water-bath (100mL), and leach the filtrate that obtains, wash with water and dry, obtained 3-nitro-5-[2-(1-oxygen-2-5-flumethiazine-3-yl)-pyrimidine-4-yl]-benzene-1,2-glycol, 0.21g (90%).
Embodiment 50
As having center cell benzene-1,3-two replaces the compound embodiment of the general formula (I) of part, by following step prepare 5-nitro-3 '-(1-oxygen-6-5-flumethiazine-2-yl)-biphenyl-3, the 4-glycol:
A) with 4-benzene methoxy-3-methoxyphenyl boric acid (1.0g; 3.87mmol) and 2-(3-bromophenyl)-6-5-flumethiazine 1-oxide compound (1.12g; 3.52mmol) adding toluene (10mL) and the middle solution that forms of ethanol (1mL); under argon shield; under room temperature, add 2 N aqueous sodium carbonate (5.41mL to the solution that stirs; 10.82mmol), then add tetrakis triphenylphosphine palladium (0.22g, 0.19mmol).The mixture that obtains was stirred two hours down at 90 ℃, be cooled to room temperature then.Separate each phase, and with toluene (5mL) aqueous phase extracted.With organic phase water and the salt water washing that merges, use anhydrous sodium sulfate drying then, filter.Boil off solvent, remaining brown oil is carried out chromatographic separation (petrol ether/ethyl acetate, 9: 1) by silica gel, obtained clear oily matter 2-(4 '-benzyloxy-3 '-methoxy phenylbenzene-3-yl)-6-5-flumethiazine 1-oxide compound, 1.11g (70%).
B) ice-water-bath refrigerative 2-(4 '-benzyloxy-3 '-methoxy phenylbenzene-3-yl)-6-5-flumethiazine 1-oxide compound (1.10g, 2.44mmol) solution in methylene dichloride (20mL) drips 30% hydrogen bromide at acetate (4mL, 20mmol) solution in.The solution that obtains was at room temperature stirred six hours, in the impouring ice-water-bath then (100mL).Separate each phase, and with methylene dichloride (10mL) aqueous phase extracted.With organic layer water and the salt water washing that merges, use anhydrous sodium sulfate drying then, filter.Boil off solvent, remaining brown oil is carried out chromatographic separation (petrol ether/ethyl acetate, 4: 1) by silica gel, obtained clear oily matter 3-methoxyl group-3 '-(1-oxygen-6-5-flumethiazine-2-yl)-biphenyl 4-alcohol, 0.57g (65%).
C) at room temperature, 3-methoxyl group-3 '-(1-oxygen-6-5-flumethiazine-2-yl)-biphenyl 4-alcohol (0.50g, 1.38mmol) solution in acetate (10mL) drip 60% nitric acid (0.12mL, 1.52mmol).The mixture that obtains was stirred 30 minutes, then in the impouring ice-water bath (100mL), and leach the precipitation that obtains, wash with water and dry.Carry out chromatographic separation (petrol ether/ethyl acetate, 2: 1) by silica gel after, obtained yellow solid 5-methoxyl group-3-nitro-3 '-(1-oxygen-6-5-flumethiazine-2-yl)-biphenyl 4-alcohol, 0.34g (60%).
D) to stir, in ice-water-bath refrigerative 5-methoxyl group-3-nitro-3 '-(1-oxygen-6-5-flumethiazine-2-yl)-biphenyl 4-alcohol (0.30g, 0.738mmol) 1, solution in the 2-ethylene dichloride (10mL) adds 1 part of aluminum chloride (0.123g, 0.922mmol), then drip pyridine (0.233g, 2.95mmol).The red suspension that obtains was stirred two hours down at 80 ℃, be cooled to room temperature then, in the cold 2N aqueous hydrochloric acid (100mL) of impouring.Leach precipitation, wash with water, drying, obtained 5-nitro-3 '-(1-oxygen-6-5-flumethiazine-2-yl)-biphenyl-3,4-glycol, 0.17g, (59%).
Embodiment 51
As the compound embodiment of the general formula with center cell carbonyl moiety (I), prepare (3,4-dihydroxyl-5-nitrophenyl)-(1-oxygen-2-5-flumethiazine-3-yl)-ketone by following step:
A) under argon shield, (2.0g, 6.82mmol) solution in tetrahydrofuran (THF) (50mL) drips the 2N butyllithium at normal hexane (3.75mL, 7.5mmol) solution in to 4-benzyloxy-3-methoxy bromobenzene under-78 ℃.The mixture that obtains was stirred 1 hour, drip the solution of N-methoxyl group-N-Methyl-2-trifluoromethyl niacinamide (1.76g, 7.5 mmol) in tetrahydrofuran (THF) (20mL) subsequently.Mixture is risen to room temperature, be incubated two hours, then in the cold 2N aqueous hydrochloric acid (150mL) of impouring.Extract mixture with diethyl ether, and the organic layer of water and salt water washing merging, use anhydrous sodium sulfate drying, filter.Boil off solvent, remaining brown oil is carried out chromatographic separation (petrol ether/ethyl acetate, 2: 1) by silica gel, has obtained (4-benzyloxy-3-methoxyphenyl)-(2-5-flumethiazine-3-yl)-ketone 1.72g (65%).
B) to stir, in ice-water-bath refrigerative (4-benzyloxy-3-methoxyphenyl)-(2-5-flumethiazine-3-yl)-ketone (1.60g, 4.13mmol) solution in methylene dichloride (20mL) adds 1 part of urea-hydrogen peroxide complex thing (0.85g, 9.08mmol), then drip trifluoroacetic anhydride (TFAA) (1.73g, 8.26mmol).Then the mixture that obtains is at room temperature stirred and spend the night, leach insoluble substance subsequently, and wash with methylene dichloride (5mL).With filtrate water and the salt water washing that merges, use anhydrous sodium sulfate drying then, filter.Boil off solvent, remaining orange solids, recrystallization from ethanol has obtained (4-benzyloxy-3-methoxyphenyl)-(1-oxygen-2-5-flumethiazine-3-yl)-ketone 1.0g (60%).
C) to stir, in ice-water-bath refrigerative (4-benzyloxy-3-methoxyphenyl)-(1-oxygen-2-5-flumethiazine-3-yl)-ketone (0.95g, 2.36mmol) solution in methylene dichloride drips 30% hydrogen bromide at acetate (3.54mL, 17.7mmol) solution in.The solution that obtains at room temperature stirred spend the night, in the impouring ice-water-bath then (100mL).Separate each phase, and with methylene dichloride (10mL) aqueous phase extracted.With organic layer water and the salt water washing that merges, use anhydrous sodium sulfate drying then, filter.Boil off solvent, remaining brown oil is carried out chromatographic separation (petrol ether/ethyl acetate, 1: 1) by silica gel, has obtained colorless solid (4-hydroxyl-3-methoxyphenyl)-(1-oxygen-2-5-flumethiazine-3-yl)-ketone, 0.59g (80%).
D) at room temperature, to (4-hydroxyl-3-methoxyphenyl)-(1-oxygen-2-5-flumethiazine-3-yl)-ketone (0.50g, 1.59mmol) solution in acetate (10mL) drip 60% nitric acid (0.14mL, 1.75mmol).The mixture that obtains was stirred 30 minutes, in the impouring ice-water-bath then (100mL), and leach the precipitation that obtains, wash with water and drying.Recrystallization from ethanol obtains yellow solid (4-hydroxyl-3-methoxyl group-5-nitrophenyl)-(1-oxygen-2-5-flumethiazine-3-yl)-ketone, 0.33g (58%).
E) to stir, in ice-water-bath refrigerative (4-hydroxyl-3-methoxyl group-5-nitrophenyl)-(1-oxygen-2-5-flumethiazine-3-yl)-ketone (0.30g, 0.84mmol) 1, solution in the 2-ethylene dichloride (10mL) adds 1 part of aluminum chloride (0.14g, 1.05mmol), then drip pyridine (0.26g, 3.35mmol).The red suspension that obtains was stirred two hours down at 80 ℃, be cooled to room temperature then, in the cold 2N aqueous hydrochloric acid (100mL) of impouring.Leach precipitation, wash with water and drying, obtained (3,4-dihydroxyl-5-nitrophenyl)-(1-oxygen-2-5-flumethiazine-3-yl)-ketone 0.19g, (66%).
Embodiment 52
As having center cell (Z)-1-cyano group ethylene-1,2-two replaces the compound embodiment of the general formula (I) of part, prepares 3-(3,4-dihydroxyl-5-nitrophenyl)-2-(1-oxygen-6-5-flumethiazine-3-yl)-vinyl cyanide by following step:
A) with Vanillin (1.0g, 6.57mmol), (1-oxygen-6-5-flumethiazine-3-yl)-vinyl cyanide (1.33g, 6.57mmol) and piperidines (0.71mL, 7.23mmol) the suspension stirring and refluxing in dehydrated alcohol (10mL) is 48 hours, is cooled to room temperature then.Leach the throw out that obtains, wash with water, drying.Recrystallization from Virahol obtains white crystal 3-(4-hydroxyl-3-methoxyphenyl)-2-(1-oxygen-6-5-flumethiazine-3-yl)-vinyl cyanide, 0.95g (43%).
B) at room temperature, 3-(4-hydroxyl-3-methoxyphenyl)-2-(1-oxygen-6-5-flumethiazine-3-yl)-vinyl cyanide (0.90g, 2.68mmol) solution in acetate (20mL) drip 60% nitric acid (0.23mL, 2.95mmol).To stir 30 minutes under the mixture room temperature that obtain, in the impouring ice-water-bath then (100mL).Leach yellow mercury oxide, wash with water, drying.Recrystallization from Virahol obtains yellow solid 3-(4-hydroxyl-3-methoxyl group-5-nitrophenyl)-2-(1-oxygen-6-5-flumethiazine-3-yl)-vinyl cyanide, 0.63g (62%).
C) to stir, in ice-water-bath refrigerative 3-(4-hydroxyl-3-methoxyl group-5-nitrophenyl)-2-(1-oxygen-6 5-flumethiazines-3-yl)-vinyl cyanide (0.55g, 1.44mmol) 1, solution in the 2-ethylene dichloride (10mL) adds 1 part of aluminum chloride (0.24g, 1.80mmol), then drip pyridine (0.46g, 5.77mmol).The red suspension that obtains was stirred two hours down at 80 ℃, be cooled to room temperature then, in the cold 2N aqueous hydrochloric acid (100mL) of impouring.Leach precipitation, wash with water, drying has obtained 3-(3,4-dihydroxyl-5-nitrophenyl)-2-(1-oxygen-6-5-flumethiazine-3-yl)-vinyl cyanide, 0.32g, (60%).
Embodiment 53
As having center cell 1H-imidazoles-1,5-two replaces the compound embodiment of the general formula (I) of part, by following step preparation (2-(5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl)-5-(trifluoromethyl) pyridine 1-oxide compound:
A) with 2-amino-5-(trifluoromethyl) pyridine 1-oxide compound (0.445g, 2.5mmol) add in the mixture of ethanol (12.5mL) and acetate (0.25mL) and become solution, at room temperature in this solution that stirs, add 3, and 4-dimethoxy-5-nitrobenzaldehyde (0.53g, 2.5mmol).Reactant was heated two hours under reflux temperature, boil off ethanol.The oily residue is dissolved in methyl alcohol (17mL) and 1, the mixture of 2-glycol dimethyl ether (7.5mL), add subsequently 1 part of 1-(isocyano-methyl sulphonyl)-4-toluene (TOSMIC) (0.73g, 3.75mmol) and salt of wormwood (0.69g, 5mmol).The mixture that obtains was stirred 3 hours under reflux temperature.The evaporate to dryness reactant adds in the methylene dichloride (50mL) then.Water (50mL) washing organic phase is used anhydrous magnesium sulfate drying then, filters evaporation, remaining brown oil.Carry out chromatographic separation (petroleum ether-ethyl acetate 9: 1) by silica gel, obtained 2-(5-(3,4-dimethoxy-5-nitrophenyl)-1H-imidazoles-1-yl)-5-(trifluoromethyl) pyridine 1-oxide compound, 0.56g (55%).
B) in 48% hydrobromic acid aqueous solution (6mL), heat 2-(5-(3,4-dimethoxy-5-nitrophenyl)-1H-imidazoles-1-yl)-5-(trifluoromethyl) pyridine 1-oxide compound (0.41g, 1mmol) 2.5 hours down in 140 ℃.The homogeneous solution of dark color is cooled to room temperature, and removes volatile matter, remaining filbert crystal, vacuum-drying above P2O5 by evaporation.With the solid that the ether efflorescence obtains, obtained yellow crystals 2-(5-(3,4-dihydroxyl-5-nitrophenyl)-1H-imidazoles-1-yl)-5-(trifluoromethyl) pyridine 1-oxide compound, 0.27g (71%).
Embodiment 54
As having center cell isoxazole-3,5-two replaces the compound embodiment of the general formula (I) of part, by following step prepare 3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-2-(trifluoromethyl) pyridine 1-oxide compound:
A) (3-(3 to (the E)-3-that stirs, 4-dimethoxy-5-nitrophenyl) acryloyl)-2-(trifluoromethyl) pyridine 1-oxide compound (1.19g, 3mmol) suspension in ethanol (15mL) add 50% aqueous hydroxylamine (0.74mL, 4.5mmol), and with mixture heating up to 80 ℃.After stirring 1 hour, the particulate precipitation is begun to separate from reaction mixture.After being cooled to room temperature, leach yellow mercury oxide, with washing with alcohol and vacuum-drying, obtained 3-[3-(3,4-dimethoxy-5-nitrophenyl)-5-hydroxyl-4,5-dihydro-isoxazole-5-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 0.94g (73%).
B) with 3-[3-(3,4-dimethoxy-5-nitrophenyl)-5-hydroxyl-4,5-dihydro-isoxazole-5-yl]-(2.14g 5mmol) heats down in 70 ℃ in the 20mL ethyl acetate 2-(trifluoromethyl) pyridine 1-oxide compound.In the slurry that obtains, drip trifluoroacetic acid (0.74g, 6.5mmol).After 10 minutes, with the reactant evaporate to dryness, and with residue recrystallization from Virahol, obtained 3-[3-(3,4-dimethoxy-5-nitrophenyl) isoxazole-5-base]-2-(trifluoromethyl) pyridine 1-oxide compound, 1.27g (62%).
C) under argon shield; with 3-[3-(3; 4-dimethoxy-5-nitrophenyl) isoxazole-5-base]-2-(trifluoromethyl) pyridine 1-oxide compound (0.81g; 2mmol) add methylene dichloride (15mL); and light yellow suspension is cooled to-78 ℃; drip subsequently boron tribromide (4.5g, 18mmol).Little red reaction mixture is incubated to room temperature, and stirred 18 hours, then in the impouring ice-water-bath carefully (100mL), and stirred 1 hour.Leach yellow mercury oxide, wash with water, vacuum-drying above P2O5.With boiling ethanol efflorescence, obtained yellow solid 3-[3-(3,4-dihydroxyl-5-nitrophenyl) isoxazole-5-base]-2-(trifluoromethyl) pyridine 1-oxide compound, 0.49g (64%).
Embodiment 55
As having center cell furans-2,4-two replaces the compound embodiment of the general formula (I) of part, prepares 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl by following step]-2-(trifluoromethyl) pyridine-1-oxide compound:
A) to 3-(3-oxyethyl group-3-oxo propionyl)-2-(trifluoromethyl) pyridine-1-oxide compound that stirs (1.39g, 5mmol) solution in pyridine (25mL) add 2-bromo-1-(3,4-dimethoxy-5-nitrophenyl) ethyl ketone (1.67g, 5.5mmol).Reaction mixture is heated to 70 ℃ and stirred 5 hours, is cooled to room temperature then, in the moisture HCl aqueous solution of its impouring 6N (100mL).Leach precipitation, wash with water, at P
2O
5Top vacuum-drying.This solid recrystallization from methylene dichloride/Virahol has obtained thick 3-[4-(3,4-dimethoxy-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 1.05g (43%).
B) with 3-[4-(3,4-dimethoxy-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-(482mg 1mmol) adds in the methylene dichloride (8mL) 2-(trifluoromethyl) pyridine-1-oxide compound.Under argon shield, light yellow suspension is cooled to-78 ℃, and the dropping boron tribromide (0.85mL, 9mmol).Little red reaction mixture is incubated to room temperature, and stirred 18 hours, in the impouring ice-water-bath carefully (100mL), stirred 1 hour then.Leach yellow mercury oxide, wash with water, at P
2O
5Top vacuum-drying.Solid is recrystallization from ethanol, has obtained yellow solid 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-3-(ethoxycarbonyl) furans-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 0.31g (68%).
Embodiment 56
As having Zhong heart Dan Yuan oxazole-2,4-two replaces the compound embodiment of the general formula (I) of part, by following step prepare 3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound:
A) to 2-(3; 4-dimethoxy-5-nitrophenyl)-2-acetate oxo ethyl ester (4.24g; 15mmol) solution in dimethylbenzene (30mL) add 3-carbamyl 2-(trifluoromethyl) pyridine 1-oxide compound (3.40g, 16.5mmol) and boron-trifluoride etherate (0.18mL, 15mmol).With the yellow solution reflux that obtains 18 hours, be cooled to room temperature then.After boiling off solvent, residue distributes between ethyl acetate and saturated sodium bicarbonate aqueous solution.Separate organic phase, use the salt water washing, use anhydrous magnesium sulfate drying, filter, evaporation.By silica gel column chromatography (petrol ether/ethyl acetate 2: 1), obtained pure light yellow solid 3-[4-(3,4-dimethoxy-5-nitrophenyl) oxazole-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 2.58g (42%).
B) with 3-[4-(3,4-dimethoxy-5-nitrophenyl) oxazole-2-yl]-(1.23g 3mmol) adds in the methylene dichloride (25mL) 2-(trifluoromethyl) pyridine 1-oxide compound.Under argon shield, light yellow suspension is cooled to-78 ℃, and the dropping boron tribromide (2.55mL, 27mmol).Red reaction mixture is incubated to room temperature, and stirred 18 hours.In the careful then impouring ice-water-bath (100mL), and stirred 1 hour.Leach the yellow mercury oxide that obtains, wash with water, vacuum-drying above P2O5.Solid is recrystallization from ethanol, obtained yellow solid 3-[4-(3,4-dihydroxyl-5-nitrophenyl) oxazole-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 0.65g (57%).
Embodiment 57
As having center cell 1,2,4-triazine-3,5-two replaces the compound embodiment of the general formula (I) of part, prepares 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl by following step]-2-(trifluoromethyl) pyridine 1-oxide compound:
A) to inferior hydrazine acyl group-2-(trifluoromethyl) pyridine of (the Z)-3-formamyl that stirs 1-oxide compound (1.10g, 5mmol) solution in ethanol (30mL) add 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxo acetaldehyde (1.19g, 5mmol).With reaction mixture reflux 5 hours, be cooled to room temperature then, and remove by evaporation and to desolvate.Residue is dissolved in methylene dichloride (30mL), washes organic phase with water, use anhydrous magnesium sulfate drying then, filter, evaporation.Thick product recrystallization from Virahol has obtained 3-[5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazine-3-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 1.69g (80%).
B) with 3-[5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazine-3-yl]-(1.27g 3mmol) adds in the methylene dichloride (25mL) 2-(trifluoromethyl) pyridine 1-oxide compound.Under argon shield, pale yellow solution is cooled to-78 ℃, and the dropping boron tribromide (2.55mL, 27mmol).Red reaction mixture is incubated to room temperature, and stirred 18 hours.In the careful then impouring ice-water-bath (100mL), and stirred 1 hour.Leach yellow mercury oxide, wash with water, at P
2O
5Top vacuum-drying.Solid has obtained yellow solid 3-[5-(3,4-dihydroxyl-5-nitrophenyl)-1,2,4-triazine-3-yl with recrystallization in the dichloromethane-ethanol]-2-(trifluoromethyl) pyridine 1-oxide compound, 0.84g (71%).
Embodiment 58
As having center cell 1,3,5-triazines-2,4-two replaces the compound embodiment of the general formula (I) of part, prepares 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazines-2-yl by following step]-2-(trifluoromethyl) pyridine 1-oxide compound:
A) to (E)-N-((dimethylamino) methylene radical)-N-3,4-dimethoxy-5-nitrobenzamide (1.12g, 4mmol) solution in ethanol (30mL) add 3-ammonia auxotox radical-2-(trifluoromethyl) pyridine 1-oxide compound (0.82g, 4mmol).With reaction mixture reflux 5 hours.Be cooled to room temperature, and desolvate by evaporating to remove.Then residue is dissolved in methylene dichloride/isopropanol mixture (50mL, 70: 30), washes organic phase with water, anhydrous magnesium sulfate drying filters, evaporation.Thick product recrystallization from ethanol has obtained 3-[4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazines-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 1.27g (75%).
B) with a 3-[4-(3,4-dimethoxy-5-nitrophenyl)-1,3,5-triazines-2-yl]-(1.269g 3mmol) adds in the methylene dichloride (25mL) 2-(trifluoromethyl) pyridine 1-oxide compound.Under argon shield, pale yellow solution is cooled to-78 ℃, and the dropping boron tribromide (2.55mL, 27mmol).Red reaction mixture is incubated to room temperature, and stirred 18 hours, in the impouring ice-water-bath carefully (100mL), stirred 1 hour then.Leach yellow mercury oxide, wash with water, vacuum-drying above P2O5.Recrystallization from the dichloromethane-ethanol mixed solution has obtained yellow solid 3-[4-(3,4-dihydroxyl-5-nitrophenyl)-1,3,5-triazines-2-yl]-2-(trifluoromethyl) pyridine 1-oxide compound, 1.07g (90%).
Embodiment 59
As having center cell pyrroles-2,5-two replaces the compound embodiment of the general formula (I) of part, prepare 5-(3,4-dihydroxyl-5-nitrophenyl)-1-methyl-2-(2-Trifluoromethyl-1-hydroxyl pyridin-3-yl)-1H-pyrroles-3-carboxylic acid, ethyl ester by following step:
A) at room temperature, to the methylamine that stirs (0.63mL, 33% ethanolic soln, 5mmol) adding of the solution in ethanol (25mL) and acetate (0.5mL) mixed solution 3-oxygen-3-(1-oxygen-2-5-flumethiazine-3-yl)-ethyl propionate (1.39g, 5mmol).With reaction mixture reflux two hours, under vacuum, remove subsequently and desolvate by evaporation.(2.07g 15mmol), adds then that 1-(3,4-two benzyloxies-5-nitrophenyl)-(2.51g's 2-bromine ethyl ketone then 5.50mmol), stirs the mixture under 100 ℃ to add 1 part of salt of wormwood to the solution of thick product in dimethyl formamide (25mL).In case can not detect starting raw material by tlc, reaction mixture is cooled to room temperature, and in the ice-cold 1N aqueous hydrochloric acid (100mL) of impouring.Leach the throw out that obtains, wash with water, drying.Residue is carried out silica gel column chromatography to be separated.Compile similar component, obtain 5-(3,4-two benzyloxies-5-nitrophenyl)-1-methyl-2-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-1H-pyrroles-3-carboxylic acid, ethyl ester after the evaporation, 2.41g (79%).
B) with 5-(3; 4-two benzyloxies-5-nitrophenyl)-1-methyl-2-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-1H-pyrroles-3-carboxylic acid, ethyl ester (0.2g; 0.30mmol) solution stirring in methylene dichloride (10mL) is cooled to-78 ℃; under argon shield; (0.30g 1.21mmol) handles with boron tribromide.Be cooled to once more before 78 ℃ then, under room temperature, the intense violet color suspension that obtains stirred 1 hour.The careful methyl alcohol that adds makes mixture cures.After at room temperature stirring 30 minutes, boil off volatile matter, and residue was stirred 30 minutes in 2N hydrochloric acid (5mL).Leach the solid that obtains, water (25mL) washing, and then, obtain yellow solid 5-(3 with cold Virahol (5mL) washing, 4-dihydroxyl-5-nitrophenyl)-and 1-methyl-2-(1-oxygen-2-5-flumethiazine-3)-1H-pyrroles-3-carboxylic acid, ethyl ester, 0.13g (93%).
Embodiment 60
As having center cell 2H-tetrazolium-2,5-two replaces the compound embodiment of the general formula (I) of part, prepares 5-[2-(5-Trifluoromethyl-1-oxygen-pyridine-2-yl)-2H-tetrazolium-5-yl by following step]-3-oil of mirbane-1, the 2-glycol:
A) under 85 ℃, with 3,4-two benzyloxies-5-cyanide-nitrophenyl (0.54 g, 1.50mmol), sodiumazide (0.15g, 2.25mmol) and ammonium chloride (0.12g, 2.25mmol) mixture in dimethyl formamide (3mL) stirred 20 hours.After being cooled to room temperature, in reaction mixture impouring water (30mL), and use the dilute hydrochloric acid acidifying.The precipitation that collection obtains washes with water, and drying obtains 5-(3,4-two benzyloxies-5-nitrophenyl)-2H-tetrazolium, 0.53g (87%).
A) with 2-chloro-5-Trifluoromethyl-1-oxygen-pyridine (0.20g, 1.00mmol) 5-(3,4-two benzyloxies-5-the nitrophenyl)-2H-tetrazolium that add to stir (0.4g, 1.00mmol) and salt of wormwood (0.14g is 1mmol) in the suspension in acetonitrile (10mL).At room temperature stirred reaction mixture till reaction is finished, with the methylene dichloride dilution, washes with water then.Separate organic phase, anhydrous magnesium sulfate drying filters, evaporate to dryness, remaining thick residue.Recrystallization from methylene dichloride/Virahol mixed solution obtains 2-[5-(3,4-two benzyloxies-5-nitrophenyl)-tetrazolium-2-yl]-5-Trifluoromethyl-1-oxygen-pyridine, 0.40g (71%).
C) under argon shield; with 2-[5-(3,4-two benzyloxies-5-nitrophenyl)-tetrazolium-2-yl]-5-Trifluoromethyl-1-oxygen-pyridine (0.282g, 0.5mmol) solution stirring in methylene dichloride (15mL) is cooled to-78 ℃; (1.00g 4.00mmol) drips processing with boron tribromide.Be cooled to once more then before-78 ℃, under room temperature, will obtaining the intense violet color suspension and stir 1 hour.The careful methyl alcohol that adds makes mixture cures.After at room temperature stirring 30 minutes, boil off volatile matter, and residue was stirred 30 minutes in 2N hydrochloric acid (5mL).Leach the solid that obtains, cold Virahol (5mL) washing is used in water (25mL) washing then, has obtained yellow solid 5-[2-(5-Trifluoromethyl-1-oxygen-pyridine-2-yl)-2H-tetrazolium-5-yl)-3-oil of mirbane-1,2-glycol, 0.17g, (90%).
Embodiment 61
As having center cell 1,3-thiazoles-2,4-two replaces the compound embodiment of the general formula (I) of part, prepares 5-{2-[2-(trifluoromethyl)-1-oxygen-pyridin-3-yl by following step]-[1,3]-thiazole-4-yl }-3-oil of mirbane-1, the 2-glycol:
A) in dehydrated alcohol (5mL), with 2-(trifluoromethyl)-1-oxygen-pyridine-3-carbonyl thioamides (0.24g, 1.10mmol) and 1-[3,4-two benzyloxies-5-nitrophenyl]-(0.50g, mixture 1.10mmol) reflux and spend the night 2-bromine ethyl ketone.After being cooled to room temperature, in reaction mixture impouring water (50mL).Leach the throw out that obtains, water (25ml) washing, drying.Recrystallization from methylene dichloride/Virahol obtains 3-[4-(3,4-two benzyloxies-5-nitrophenyl)-[1,3]-thiazol-2-yl]-2-Trifluoromethyl-1-oxygen-pyridine, 0.55g (87%).
B) with 3-[4-(3,4-two benzyloxies-5-nitrophenyl)-[1,3]-thiazol-2-yl]-2-Trifluoromethyl-1-oxygen-pyridine (0.15g; 0.26mmol) solution in methylene dichloride (10mL) is cooled to-78 ℃; and under argon shield, (0.26g 1.03mmol) handles with boron tribromide.Be cooled to before-78 ℃ the intense violet color suspension that stirring at room obtains a hour then once more.The careful methyl alcohol that adds makes mixture cures.After at room temperature stirring 30 minutes, boil off volatile matter, and residue was stirred 30 minutes in 2N hydrochloric acid (5mL).Leach the solid that obtains, cold Virahol (5mL) washing is used in water (5mL) washing then, has obtained yellow solid 5-{2-[2-(trifluoromethyl)-1-oxygen-pyridin-3-yl]-[1,3]-thiazole-4-yl }-3-oil of mirbane-1,2-glycol, 0.09g, (87%).
Embodiment 62
As having center cell 1,2,4-triazole-3,5-two replaces the compound embodiment of the general formula (I) of part, prepares 5-[4-methyl-5-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-4H-[1,2 by following step, 4]-triazole-3-yl]-3-oil of mirbane-1, the 2-glycol:
A) under 0 ℃, to 3 of stirring, (0.50g, 2.04mmol) solution in methylene dichloride (10mL) drips methylamine (1.02mL, 2.04mmol, the 2M solution in tetrahydrofuran (THF)) to 4-dimethoxy-5-nitrobenzoyl chloride.At room temperature stirred reaction mixture till all starting raw materials disappear, with the methylene dichloride dilution, washes with water then.The organic phase anhydrous magnesium sulfate drying filters, evaporate to dryness, remaining thick residue.Recrystallization from methylene dichloride/Virahol mixed solution obtains 3,4-dimethoxy-N-methyl-5-nitro benzamide, 0.44g (89%).
B) to stir 3,4-dimethoxy-N-methyl-5-nitro benzamide (0.40g, 1.66mmol) suspension in toluene (10mL) by part add a phosphorus pentachloride (0.38g, 1.83mmol).After finishing addition step, the reaction mixture insulation is refluxed, up to the starting raw material completely dissolve.Evaporate to dryness obtains thick solid, with the ether washing, obtains 3,4-dimethoxy-N-methyl-5-nitro benzene auxotox radical muriate, 0.37g (85%).
C) under 85 ℃, with 2-Trifluoromethyl-1-oxygen-3-pyrimidine nitrile (0.47g, 2.50mmol), sodiumazide (0.24g, 3.75mmol) and ammonium chloride (0.20g, 3.75mmol) mixture in dimethyl formamide (2.5mL) stirred 20 hours.After being cooled to room temperature, in reaction mixture impouring water (20mL), and use the dilute hydrochloric acid acidifying.The precipitation that collection obtains washes with water, and drying obtains 3-(2H-tetrazolium-5-yl)-2-Trifluoromethyl-1-oxygen-pyridine, 0.52g (90%).
D) with 3,4-dimethoxy-N-methyl-5-nitro benzene auxotox radical muriate (0.26g, 1.08mmol) (0.23g, the 1mmol) solution in anhydrous pyridine (3mL) is preheated to 50 ℃ to add 3-(2H-tetrazolium-5-the yl)-2-Trifluoromethyl-1-oxygen-pyridine that stirs.The mixture that obtains is heated to 75-90 ℃ carefully, and under this temperature, is incubated, stop until nitrogen release.Extract then with in the reaction mixture impouring water (30mL), and with methylene dichloride (25mL).Separate organic phase, use anhydrous sodium sulfate drying, filter evaporate to dryness.By the residue that the chromatography purifying obtains, obtain 3-[5-(3,4-dimethoxy-5-nitrophenyl)-4-methyl-4H-[1,2,4]-triazole-3-yl]-2-Trifluoromethyl-1-oxygen-pyridine, 0.25g (59%).
E) under argon shield; under-78 ℃ to the 3-[5-(3 that stirs; 4-dimethoxy-5-nitrophenyl)-4-methyl-4H-[1; 2; 4]-triazole-3-yl]-2-Trifluoromethyl-1-oxygen-pyridine (0.20g; 0.47mmol) suspension in methylene dichloride (20mL) drip boron tribromide (0.47g, 1.88mmol).Before ice-water-bath cooling, the purple suspension that obtains was at room temperature stirred seven hours then.Add methyl alcohol carefully, make mixture cures.After at room temperature stirring 30 minutes, boil off volatile matter, and residue was stirred 30 minutes in 2N hydrochloric acid (5mL).Leach the solid that obtains, cold Virahol (5mL) washing is used in water (25mL) washing then, obtain orange solids 5-[4-methyl-5-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-4H-[1 after the drying, 2,4]-triazole-3-yl]-3-oil of mirbane-1, the 2-glycol, 0.16g (86%).
Embodiment 63
As having center cell 1,2,3-thiadiazoles-4,5-two replaces the compound embodiment of the general formula (I) of part, prepares 5-[5-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-[1,2,3] thiadiazoles-4-yl by following step]-3-oil of mirbane-1, the 2-glycol:
A) with 1-(3,4-two benzyloxies-5-nitrophenyl)-2-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-ethyl ketone (0.50g, 0.93mmol), carbazic acid ethyl ester (0.11g, 1.06mmol) and the mixture backflow of tosic acid (4mg) in toluene (10mL), stop until component distillation with water.Reaction mixture is cooled to room temperature, solvent evaporated, and with the thick solid of ether (15mL) efflorescence, filter, drying obtains that N '-[1-(3,4-two benzyloxies-5-nitrophenyl)-2-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-ethylidene]-hydrazine carboxylic acid's ethyl ester, 0.49g (84%).
B) with N '-[1-(3,4-two benzyloxies-5-nitrophenyl)-2-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-ethylidene]-hydrazine carboxylic acid's ethyl ester (0.40g, 0.64mmol) mixture in thionyl chloride (2mL) refluxes, until can not detecting starting raw material by TLC.Remove excessive solvent, and use methylene dichloride/alcoholic acid mixture as elutriant, by silica gel chromatography separation and purification residue.Compile similar component, obtain 3-[4-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,3] thiadiazoles-5-yl after the evaporation]-2-Trifluoromethyl-1-oxygen-pyridine, 0.19g (51%).
C) with 3-[4-(3; 4-two benzyloxies-5-nitrophenyl)-[1; 2; 3] thiadiazoles-5-yl]-2-Trifluoromethyl-1-oxygen-pyridine (0.15g; 0.26mmol) solution stirring in methylene dichloride (10mL) is cooled to-78 ℃; under argon shield, (0.26g 1.03mmol) handles with boron tribromide.Be cooled to once more before-40 ℃, the intense violet color suspension that obtains was at room temperature being stirred 1 hour.The careful methyl alcohol that adds makes mixture cures.After at room temperature stirring 30 minutes, boil off volatile matter, and residue was stirred 30 minutes in 2N hydrochloric acid (5mL).Leach the solid that obtains, cold Virahol (5mL) washing is used in water (5mL) washing then, has obtained yellow solid 5-[5-(2-Trifluoromethyl-1-oxygen-pyridin-3-yl)-[1,2,3] thiadiazoles-4-yl]-3-oil of mirbane-1,2-glycol, 0.09g (89%).
Embodiment 64
As having center cell 1,2,4-oxadiazole-3,5-two replaces the compound embodiment of the general formula (I) of part, prepares 5-[5-(2-Trifluoromethyl-1-hydroxyl pyridin-3-yl)-[1,2,4]-oxadiazoles-3-yl by following step]-3-oil of mirbane-1, the 2-glycol:
A) at room temperature, to the 2-trifluoromethyl nicotinic acid that stirs (0.38g, 2mmol) solution in dimethyl formamide (10mL) adds 1 part 1, the 1-N,N'-carbonyldiimidazole (0.34g, 2.10mmol).The yellow mixture that obtains was stirred 90 minutes, add 1 part 3 subsequently, and 4-two benzyloxies-N '-hydroxyl-oil of mirbane carbonamidine (0.79g, 2mmol).The mixture that obtains was at room temperature stirred two hours, then in the impouring water (100mL).Leach the throw out that obtains, wash with water, drying.Behind recrystallization from methylene dichloride/Virahol, obtained faint yellow solid 3,4-two benzyloxies-5-nitro-N '-[2-(trifluoromethyl) nicotinoyl oxygen] benzene first Imidamide (benzimidamide), 0.88g (78%).
B) under argon shield, (0.26g, 0.46mmol) solution in tetrahydrofuran (THF) (15mL) adds the tetrabutylammonium of 1N at tetrahydrofuran (THF) (0.7mL, 0.7mmol) solution in to the above-mentioned gained solid that stirs under room temperature.The yellow solution clearly that obtains was at room temperature stirred four hours.Add extra tetrabutylammonium (0.7mmol), and at room temperature reaction mixture is stirred 15 hours, stirred ten hours down at 55 ℃ then.After being cooled to room temperature, in reaction mixture impouring water (150mL).Leach the throw out that obtains, wash with water, drying.Use methylene dichloride as elutriant, thick product is carried out silica gel column chromatography separate.Compile similar component, obtain beige solid 3-[3-(3,4-two benzyloxies-5-nitrophenyl)-[1,2,4]-oxadiazole-5-yl after the evaporation]-2-(trifluoromethyl) pyridine, 0.21g (82%).
C) under 0 ℃, to the 3-[3-(3 that stirs, 4-two benzyloxies-5-nitrophenyl)-[1,2,4]-oxadiazoles-5-yl]-2-(trifluoromethyl) pyridine (0.33g, 0.60mmol) solution in methylene dichloride (6mL) add urea-hydrogen peroxide complex thing (0.28g, 3mmol) and trifluoroacetic anhydride (TFAA) (0.43mL, 3.00mmol).After at room temperature reaction mixture being stirred 60 hours, leach solid residue.Use Na then successively
2S
2O
5The aqueous solution (0.6g, 3.45mmol are dissolved in the 20mL water), 0.4N hydrochloric acid (20mL), saturated NaHCO
3Solution (20mL), water (20mL) and salt solution (20mL) are handled organic phase.The organic phase anhydrous magnesium sulfate drying filters evaporate to dryness.Use methylene dichloride/ethanol as elutriant, residue is carried out silica gel column chromatography separate.Compile similar component and evaporation, and, obtain yellow solid 3-[3-(3 residue recrystallization from methylene dichloride/Virahol, 4-two benzyloxies-5-nitrophenyl)-[1,2,4]-oxadiazoles-5-yl]-2-(trifluoromethyl)-1-oxygen-pyridine, 0.23g (68%).
D) under argon shield; with 3-[3-(3; 4-two benzyloxies-5-nitrophenyl)-[1; 2; 4]-oxadiazoles-5-yl]-2-(trifluoromethyl)-1-oxygen-pyridine (0.10g; 0.18mmol) solution stirring in methylene dichloride (5mL) is cooled to-78 ℃, and (0.18g 0.74mmol) drips and handles with boron tribromide.Be cooled to once more before-78 ℃, the intense violet color suspension that obtains was at room temperature being stirred 1 hour.The careful methyl alcohol that adds makes mixture cures.After at room temperature stirring 30 minutes, boil off volatile matter, and residue was stirred 30 minutes in 2N hydrochloric acid (5mL).Leach the solid that obtains, cold Virahol (5mL) washing is used in water (25mL) washing then, has obtained yellow solid 5-[5-(2-Trifluoromethyl-1-hydroxyl pyridin-3-yl)-[1,2,4]-oxadiazoles-3-yl]-3-oil of mirbane-1,2-glycol, 0.06g (88%).
Claims (24)
1. compound with chemical formula (I):
R wherein
1And R
2Be to be hydrogen or low-grade alkane acidyl or aroyl group hydrolyzable under physiological condition, that randomly replace independently of one another; X represents methylene radical; Y represents oxygen, nitrogen or sulphur atom; N represents numeral 0,1,2 or 3, and m represents numeral 0 or 1; R
3Represent the pyridine N-oxides group of chemical formula A, B or C, its by shown in unlabelled key be connected:
R wherein
4, R
5, R
6And R
7Represent hydrogen, C independently of one another
1-C
6Alkyl, C
1-C
6Alkylthio, C
1-C
6Alkoxyl group, C
6-C
12Aryloxy or C
6-C
12Thioaryl group, C
1-C
6Alkyloyl or C
7-C
13Aroyl group, amino, C
1-C
6Alkylamino, C
1-C
6Dialkyl amido, C
3-C
12Cycloalkyl amino or C
3-C
12Heterocyclylalkyl amino, C
1-C
6Alkyl sulphonyl or C
6-C
12Aryl sulfonyl, halogen, C
1-C
6Haloalkyl, trifluoromethyl, cyano group, nitro or heteroaryl groups; Perhaps, the wherein two or more residue R that lump together
4, R
5, R
6And R
7Represent aliphatics or assorted aliphatics ring or aromatic series or heteroaromatic ring, and wherein P represents center cell, this center cell is preferably selected from following regional isomer: 1,3, and 4-oxadiazole-2,5-two replaces; 1,2,4-oxadiazole-3,5-two replaces; 4-methyl-4H-1,2,4-triazole-3,5-two replaces; 1,3,5-triazines-2,4-two replaces; 1,2,4-triazine-3,5-two replaces; 2H-tetrazolium-2,5-two replaces; 1,2,3-thiadiazoles-4,5-two replaces; 1-alkyl-3-(carbalkoxy)-1H-pyrroles-2,5-two replaces, and wherein the representative of alkyl has methyl, ethyl, n-propyl and normal-butyl, and the representative of alkoxyl group has methoxyl group, oxyethyl group, positive propoxy and isopropoxy; 1-alkyl-1H-pyrroles-2,5-two replaces, and wherein the representative of alkyl has methyl, ethyl, n-propyl and normal-butyl; Thiazole-2,4-two replaces; 1H-pyrazoles-1,5-two replaces; Pyrimidine-2,4-two replaces; Oxazole-2,4-two replaces; Carbonyl; 1H-imidazoles-1,5-two replaces; Isoxazole-3,5-two replaces; Furans-2,4-two replaces; 3-carbalkoxy furans-2,4-two replaces, and wherein the representative of alkoxyl group has methoxyl group, oxyethyl group, positive propoxy and isopropoxy; Benzene-1,3-two replaces; And (Z)-1-cyanogen ethylidene-1,2-two replaces, and the regional isomer of wherein said center cell both comprised and can partly exchange the regional isomer of realizing by Nitrocatechol, and comprising again can be by-(X) n-(Y) m-R
3Part exchanges and the regional isomer of realization.
2. compound as claimed in claim 1, it is characterized in that, it comprises: 5-[3-(3,5-two chloro-1-oxygen-pyridin-4-yls)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(2-chloro-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(2-morpholine-4-base-1-oxygen-pyridin-4-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 3-nitro-5-[3-(1-oxygen-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1, the 2-glycol, 5-[3-(4-bromo-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-chloro-6-methyl isophthalic acid-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-morpholine-4-base-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 3-nitro-5-[3-(1-oxygen-6-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1, the 2-glycol, 5-[3-(2-methyl isophthalic acid-oxygen-6-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(6-methyl isophthalic acid-oxygen-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2,6-dimethyl-1-oxygen-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(2-methyl isophthalic acid-oxygen-6-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(6-methyl isophthalic acid-oxygen-2-phenyl-4-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(2-bromo-6-methyl isophthalic acid-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(2-chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(2-bromo-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-nitro-benzene-1, the 2-glycol, 5-[3-(2-bromo-4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-chloro-4,5,6-trimethylammonium-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2,5-two chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, 5-[3-(2-bromo-5-chloro-4,6-dimethyl-1-oxygen-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-3-oil of mirbane-1, the 2-glycol, and 3-nitro-5-[3-(1-oxygen-2-trifluoromethyl-pyridin-3-yl)-[1,2,4] oxadiazole-5-yl]-benzene-1, the 2-glycol.
3. a treatment suffers the subject's of nervus centralis and peripheral nervous system dysfunction misery method, wherein, minimizing catecholamine oxygen position methylates may be to treatment such as Parkinson's disease and useful like parkinsonian dysfunction, gastrointestinal dysfunction, edema formation situation and hypertension, and described method comprises: impose a certain amount of to treating the effective compound as claimed in claim 1 or 2 of described subject's disease to the subject.
4. pharmaceutical composition, its comprise combine with pharmaceutically acceptable carrier, effective therapeutic dose, compound as claimed in claim 1 or 2.
5. compound as claimed in claim 1 or 2 is used for the treatment of application in the subject's who suffers central nervous system or peripheral nervous system dysfunction misery the medicine in manufacturing.
6. compound as claimed in claim 1 or 2 is used for the treatment of application in the medicine of following disease in manufacturing: mood disorder, Parkinson's disease and form situation and hypertension like parkinsonian dysfunction, restless leg syndrome, gastrointestinal dysfunction, edema.
7. the application of compound as claimed in claim 1 or 2 in treatment.
8. compound as claimed in claim 1 or 2 is in the application that is used for making as the medicament of COMT inhibitor.
9. the method for preparing the compound shown in Formula I; it comprises the steps: to make the compound shown in compound shown in Formulae II A, IIB or the IIC and the Formulae II I under the condition that is suitable for producing the derivative of De oxadiazole shown in Formula I VA, IVB or the IVC; carry out annulation, then remove protecting group R alternatively
8/ or R
9,
Wherein, R
4, R
5, R
6And R
7In the general formula I as claimed in claim 1 define R
8And R
9Represent hydrogen independently of one another or be used for the suitable blocking group of aromatic hydroxyl group.
10. the method for preparing the compound shown in Formula I; it comprises the steps: to make the compound shown in compound shown in chemical formula VA, VB or the VC and the Formulae II I under the condition that is suitable for producing the derivative of De oxadiazole shown in chemical formula VIA, VIB or the VIC; carry out annulation; then make pyridyl nitrogen-atoms generation oxidation; obtain the compound shown in Formula I VA, IVB or the IVC, then remove protecting group R alternatively
8And/or R
9,
R wherein
4, R
5, R
6And R
7Define in the general formula I as claimed in claim 1.
11. as claim 9 or 10 described methods, it is characterized in that, the compound shown in the Formulae II I by with thionyl chloride or 1, the 1-N,N'-carbonyldiimidazole reacts and is activated.
12., it is characterized in that described annulation step is included in the one kettle way reaction carries out condensation and dehydration in regular turn as each described method in the claim 9～11.
13., it is characterized in that described annulation step is to carry out as each described method in the claim 9～12 when having suitable organic bases.
14. method as claimed in claim 13 is characterized in that, described annulation step is to carry out when pyridine exists.
15., it is characterized in that described radicals R as each described method in the claim 9～14
8And R
9Be removed independently of one another or jointly, and by hydrogen or under physiological condition hydrolyzable group replace.
16., it is characterized in that the R shown in the Formulae II I in the compound as each described method in the claim 9～15
8And R
9Represent methylidene or hydrogen independently of one another.
17. method as claimed in claim 16 is characterized in that, described methyl is removed by reacting with aluminum chloride and pyridine in N-Methyl pyrrolidone.
18., it is characterized in that described condensation and dehydration are carried out as each described method in the claim 9～17 in dipolar aprotic solvent.
19. method as claimed in claim 18 is characterized in that, described condensation and dehydration are carried out in N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone or methyl-sulphoxide.
20. as each described method in the claim 10～19, it is characterized in that the pyridyl nitrogen-atoms in chemical formula VIA, VIB or the VIC Suo Shi oxadiazole based compound is by hydrogen peroxide, peracetic acid, trifluoroperacetic acid or urea-hydrogen peroxide complex thing and the oxidation of trifluoroacetic anhydride (TFAA) institute.
21. as each described method in claim 9 and 11～19, it is characterized in that, by make compound VI IA, VIIB or VIIC respectively with azanol, exist and be fit to produce under the condition of amidoxim derivative at sequestrant and react, obtain the compound shown in Formulae II A, IIB or the IIC
R wherein
4, R
5, R
6And R
7Defined in the general formula I as claimed in claim 1.
22. as each described method in the claim 10～19, it is characterized in that, by compound VIII A, VIIIB or VIIIC respectively with azanol, exist and be fit to produce under the condition of amidoxim derivative at sequestrant and react, obtain the compound shown in chemical formula VA, VB or the VC
R wherein
4, R
5, R
6And R
7Defined in the general formula I as claimed in claim 1.
23., it is characterized in that described sequestrant is selected from by oxine, o-phenanthroline and their group that hydrate or derivative constituted as claim 19 or 20 described methods.
24. prepare the method for compound shown in the Formula I, it comprises each pyridine compounds and their is oxidized to pyridine N-oxides.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210142381.8A CN102816157B (en) | 2005-07-26 | 2006-07-26 | As the Nitrocatechol derivatives of COMT inhibitor |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0515327.5 | 2005-07-26 | ||
| GB0515327A GB0515327D0 (en) | 2005-07-26 | 2005-07-26 | Comt inhibitors |
| EP06008203.9 | 2006-04-20 | ||
| EP06008203 | 2006-04-20 | ||
| EP06011073.1 | 2006-05-30 | ||
| EP06011073 | 2006-05-30 | ||
| PCT/PT2006/000020 WO2007013830A1 (en) | 2005-07-26 | 2006-07-26 | Nitrocatechol derivatives as comt inhibitors |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210142381.8A Division CN102816157B (en) | 2005-07-26 | 2006-07-26 | As the Nitrocatechol derivatives of COMT inhibitor |
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|---|---|
| CN101248064A true CN101248064A (en) | 2008-08-20 |
| CN101248064B CN101248064B (en) | 2012-07-04 |
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| CN2006800266140A Active CN101248064B (en) | 2005-07-26 | 2006-07-26 | Nitrocatechol derivatives as COMT inhibitors |
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| Country | Link |
|---|---|
| CN (1) | CN101248064B (en) |
| GB (1) | GB0515327D0 (en) |
| UA (1) | UA94054C2 (en) |
| ZA (1) | ZA200800672B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102858177A (en) * | 2010-03-04 | 2013-01-02 | 默沙东公司 | Inhibitors of catechol o-methyl transferase and their use in the treatment of psychotic disorders |
| CN101631548B (en) * | 2007-01-31 | 2014-08-27 | 比艾尔-坡特拉有限公司 | Dosage regimen for COMT inhibitors |
| CN107935953A (en) * | 2017-12-31 | 2018-04-20 | 佛山市赛维斯医药科技有限公司 | COMT inhibitor, preparation method and its usage containing terminal olefinic link and hydrazide structure |
| CN108148004A (en) * | 2017-12-31 | 2018-06-12 | 佛山市赛维斯医药科技有限公司 | The compound of a kind of hydrazine containing propionyl and pyrimidine structure, preparation method and its usage |
| CN108191775A (en) * | 2017-12-31 | 2018-06-22 | 佛山市赛维斯医药科技有限公司 | A kind of terminal allylic propionyl hydrazine structural compounds and application thereof |
| CN108218796A (en) * | 2017-12-31 | 2018-06-29 | 佛山市赛维斯医药科技有限公司 | Compound, preparation method and its usage containing hydrazide structure |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2363792A (en) * | 2000-06-21 | 2002-01-09 | Portela & Ca Sa | Nitrocatechols |
| GB0015228D0 (en) * | 2000-06-21 | 2000-08-16 | Portela & Ca Sa | Substituted nitrated catechols, their use in the treatment of some central and peripheral nervous system disorders |
-
2005
- 2005-07-26 GB GB0515327A patent/GB0515327D0/en not_active Ceased
-
2006
- 2006-07-26 UA UAA200802153A patent/UA94054C2/en unknown
- 2006-07-26 CN CN2006800266140A patent/CN101248064B/en active Active
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101631548B (en) * | 2007-01-31 | 2014-08-27 | 比艾尔-坡特拉有限公司 | Dosage regimen for COMT inhibitors |
| CN102858177A (en) * | 2010-03-04 | 2013-01-02 | 默沙东公司 | Inhibitors of catechol o-methyl transferase and their use in the treatment of psychotic disorders |
| CN102858177B (en) * | 2010-03-04 | 2016-02-03 | 默沙东公司 | Catechol-O-methyltransferase inhibitor and the purposes in treatment mental disorder thereof |
| CN107935953A (en) * | 2017-12-31 | 2018-04-20 | 佛山市赛维斯医药科技有限公司 | COMT inhibitor, preparation method and its usage containing terminal olefinic link and hydrazide structure |
| CN108148004A (en) * | 2017-12-31 | 2018-06-12 | 佛山市赛维斯医药科技有限公司 | The compound of a kind of hydrazine containing propionyl and pyrimidine structure, preparation method and its usage |
| CN108191775A (en) * | 2017-12-31 | 2018-06-22 | 佛山市赛维斯医药科技有限公司 | A kind of terminal allylic propionyl hydrazine structural compounds and application thereof |
| CN108218796A (en) * | 2017-12-31 | 2018-06-29 | 佛山市赛维斯医药科技有限公司 | Compound, preparation method and its usage containing hydrazide structure |
Also Published As
| Publication number | Publication date |
|---|---|
| UA94054C2 (en) | 2011-04-11 |
| ZA200800672B (en) | 2009-01-28 |
| GB0515327D0 (en) | 2005-08-31 |
| CN101248064B (en) | 2012-07-04 |
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