CN102617561B - 2-benzylthio benzene heterocyclic-fused derivative, preparation method thereof and medical application thereof - Google Patents
2-benzylthio benzene heterocyclic-fused derivative, preparation method thereof and medical application thereof Download PDFInfo
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Abstract
The invention relates to the field of medicinal chemistry, in particular to a 2-benzylthio benzene heterocyclic-fused derivative (I), a preparation method thereof and medical application thereof. R1 and R2 are defined in an instruction book, and pharmacological experiments prove that the derivative has a high inhibiting effect on growth of tubercle bacillus standard strain H37Rv and clinical drug-resistant tubercle bacillus and can be used for treating clinical tuberculosis. The derivative (I) is shown in the description.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to the purposes in a class 2-benzylthio-Benzheterocyclic derivatives, their preparation method and the infectious disease medicament that causes for the treatment of infectious diseases, particularly tubercule bacillus thereof.
Background technology
Tuberculosis (Tuberculosis, TB) is to be infected and caused by mycobacterium tuberculosis (Mycobacterium tuberculosis, Mtb), is one of the widest disease of Global prevalence.In people's paratuberculosis, modal is pulmonary tuberculosis.Due to the appearance of Resistance Mycobacterium Tuberculosis and the parallel infection of AIDS disease, add the exploitation that there is no new antitubercular agent take nearly 40 years, cause the treatment that is difficult to lungy.
The existing active tuberculosis patient 4,500,000 of official website data presentation China in 2009 of the Ministry of Health, wherein 80% tuberculosis patient concentrates on Rural areas.Tuberculosis and poverty are accompanied, substantially overlapping in areal distribution with acquired immune deficiency syndrome (AIDS).Expanding economy promotes the movement of population in global range, and the medicine exposing shortage or/and its quality problems, irrational prescription, treat discontinuous not thoroughly and the factor such as resistance generation, form lungy staging a comeback.
The treatment plan using is at present first-line drug vazadrine, Rifampin, the drug combination of pyrazinoic acid amide and Tibutol and Second line Drug, treatment time reaches 6-9 month, and to Resistance Mycobacterium Tuberculosis, stay bacterium there is no good result for the treatment of with holding, to patient, bring very large puzzlement and economical load.The resistance mechanism of the line antitubercular agent using is at present all very clear and definite, and major cause is the life-time service due to medicine, causes corresponding action target spot producer sudden change, causes drug failure.Therefore,, under the starting of global antitubercular agent exploitation alliance (the Global Alliance for TB Drug Development), people start again again to pay close attention to the R&D work of antitubercular agent.Novel medicine should have following characteristics: 1. exploitation can foreshorten to treatment cycle the new drug that is no more than 2 months from present 6～9 months; 2. develop the medicable medicine to MDR-TB; 3. the new drug that latent form bacterium infects can be effectively treated in exploitation.
Vazadrine and pyrazinoic acid amide are widely used antitubercular agents clinically.But these medicines of life-time service have certain toxic side effect to hepatic and renal function and neural system, therefore people have carried out the research of a lot of structural modification and derivative to vazadrine and pyrazinoic acid amide.For the modification of vazadrine, mostly be at present Vanizide analog derivative.Studies show that, the compound of Vanizide class can increase the fat-soluble of compound, improves the character of the pharmacokinetics of compound, reduces the ability of the permeability of toxicity and enhancing cell.Meanwhile, for the modification of pyrazinoic acid amide, there is report that the derivative of pyrazine carboxylic acid and nitrogen heterocyclic ring amalgamation is shown to good tuberculosis activity, but not yet find the medicine with DEVELOPMENT PROSPECT at present.
Summary of the invention
The present invention dexterously by vazadrine with pyrazinoic acid amide together with the amalgamation of 2-benzylthio-benzheterocycle, design class 2-benzylthio-benzheterocycle acid amides and a hydrazone analog derivative.Pharmacological evaluation proves, the compounds of this invention has stronger restraining effect to the growth of tubercule bacillus type strain H37Rv and clinical drug-resistant tubercule bacillus, for treatment lungy provides new selection.
Compound general formula I of the present invention is as follows:
Wherein Ar represents phenyl ring, pyridine ring, pyrazine ring or 1～4 five yuan or hexa-atomic aromatic nucleus containing 0～2 nitrogen-atoms, sulphur atom or Sauerstoffatom that Y substituting group replaces, and wherein substituting group Y is H, halogen, NH
2, OH, NO
2or CN;
Represent-(CH of L
2) n-,-(CH=CH-CH
2)-, be connected with imino--(CH
2) n-or be connected with imino--(CH=CH-CH
2)-, be n=1-3 wherein;
X represents CH
2, O, S or NH;
R represents H, NO
2, CN, NH
2, OH, OCH
3, C
1-C
4alkyl or halogen.
Wherein imino-be NH=or-NH-.
Ar preferably represents pyridine ring or pyrazine ring.
L preferably represents CH
2or N=CH.
X preferably represents O, S or NH.
R preferably represents H.
The present invention also comprises Compound I pharmacy acceptable salt, and they have the medicinal efficacy same with Compound I.The invention provides and comprise and the medicinal compositions of the compounds of this invention of acceptable carrier combinations or combination pharmaceutically.Say in more detail, the invention provides a kind of medicinal compositions, wherein contain the compounds of this invention I or its pharmacy acceptable salt and pharmaceutically acceptable carrier.Can be prepared into the various formulations that need clinically, can be dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when structural formula I compound of the present invention is used for the treatment of, people is 0.001-100mg/kg/ days with dosage range.Also can be according to the difference of formulation and disease severity, using dosage exceeds this scope.
The present invention more preferably part of compounds is:
N-(4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) benzyl) picolinamide (I-1)
N-(4-(2-thiopurine methyltransferase benzoxazole) benzyl) picolinamide (I-2)
N-(4-(2-thiopurine methyltransferase benzothiazole) benzyl) picolinamide (I-3)
N-(4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) benzyl) niacinamide (I-4)
N-(4-(2-thiopurine methyltransferase benzoxazole) benzyl) niacinamide (I-5)
N-(4-(2-thiopurine methyltransferase benzothiazole) benzyl) niacinamide (I-6)
N-(4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) benzyl) Isonicotinamide (I-7)
N-(4-(2-thiopurine methyltransferase benzoxazole) benzyl) Isonicotinamide (I-8)
N-(4-(2-thiopurine methyltransferase benzothiazole) benzyl) Isonicotinamide (I-9)
N-(4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) benzyl) pyrazinoic acid amide (I-10)
N-(4-(2-thiopurine methyltransferase benzoxazole) benzyl) pyrazinoic acid amide (I-11)
N-(4-(2-thiopurine methyltransferase benzothiazole) benzyl) pyrazinoic acid amide (I-12)
N '-(4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) benzal) icotinoylhydrazones (I-13)
N '-(4-(2-thiopurine methyltransferase benzoxazole) benzal) icotinoylhydrazones (I-14)
N '-(4-(2-thiopurine methyltransferase benzothiazole) benzal) icotinoylhydrazones (I-15)
N '-(4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) benzal) Vanizide (I-16)
N '-(4-(2-thiopurine methyltransferase benzoxazole) benzal) Vanizide (I-17)
N '-(4-(2-thiopurine methyltransferase benzothiazole) benzal) different acylhydrazone (I-18).
After above-claimed cpd, in bracket, be the code name of this compound, below in pharmacological testing and embodiment same compound all adopt identical code name.
The preparation method of general formula compound of the present invention (I) is as follows:
(1) when L represents CH
2time, synthetic method is as follows:
(2), when L represents N=CH, synthetic method is as follows:
Wherein Ar, L, X and R define as described above.
Wherein a-g represents reaction conditions, specific as follows:
A:KBrO
3, NaHSO
3, illumination, 50-55 ℃
B:K
2cO
3, DMF (DMF), 20 ℃
C:LiAlH
4, dry tetrahydrofuran, N
2, 0 ℃
D:i) SOCl
2, reflux; Ii) CH
2cl
2, Et
3n, 47 ℃ of rt or or dicyclohexylcarbodiimide, 4-dimethylaminopyridine, DMF
e：NaOH，H
2O，CH
3OH，0-20℃；
F: urotropine, 60%C
2h
5oH;
G:CH
3cOOH, C
2h
5oH, refluxes.
Compound of the present invention is evaluated with several standard pharmacology inspection procedures, result shows that the compounds of this invention has stronger restraining effect to the growth of tubercule bacillus type strain H37Rv and clinical drug-resistant tubercule bacillus, can be for the preparation of the medicine for the treatment of tuberculosis bacillus infectious disease, infectious diseases that particularly multidrug resistance tubercule bacillus causes.
Pharmacological testing and the result of part of compounds of the present invention below.
One: adopt quick colour-developing method-MABA (Microplate Alamar blue Assay) method [Antimicrob Agents Chemother 2005,49,1447-54] the minimum bacteriostatic activity of mensuration compound to Mycobacterium tuberculosis H37Rv type strain.
Experiment material:
Mycobacterium tuberculosis strain: Mycobacterium tuberculosis H37Rv (ATCC27294)
Substratum: Middlebrook 7H9 substratum (U.S. Difico company), containing 0.1%w/v junket peptone, 5.6 μ g/mL palmitinic acids, 5mg/mL bovine serum albumin(BSA), 4mg/mL catalase.
Positive drug: vazadrine (INH), Rifampin (RMP), Moxifloxacin (Mox), Streptomycin sulphate (SM), PA-824 (University of lllinois provides).
Test method:
200 μ l aqua sterilisas are added to aseptic 96 orifice plates (BD Optilux
tM, 96-well Microplates, black/clear flat bottom) and in each hole of surrounding.Precision takes each sample 3.2mg, with DMSO, dissolves, and obtains sample stoste.Become required each two times of concentration with 7H9 substratum doubling dilution, add aseptic 96 orifice plate 100 μ L.
Mycobacterium tuberculosis H37Rv is cultivated to the culture of 2～3 weeks and make bacteria suspension, be inoculated in the 7H9 substratum containing 0.05% tween 80,10%ADC, 37 ℃ of static cultivations 1～2 week, growing to turbidity is that McFarland 1 (is equivalent to 10
7cFU/mL).Then by the dilution in 1: 20 of bacterium liquid, add each hole 100 μ l, the final concentration of bacterium liquid is 10
6cFU/mL.Every plate is all established 2 not growth control holes of pastille, and 96 orifice plates are hatched in 37 ℃.After 7 days, in growth control hole, add 20 μ L 10 × Alamar blue (Invitrogen BioSource
tM) and the mixed solution of 5%Tween8050 μ L, hatch 24h for 37 ℃, if color becomes pink colour from blueness, in the hole of each Experimental agents, add Alamar blue and the Tween80 mixed solution of above-mentioned amount, hatch 24h for 37 ℃ and record the color in each hole, blue Kong Weiwu growth, pink hole is for there being growth, red-purple hole is continued 37 ℃ again and is cultivated 24h, do not become pink, its blue hole being connected is still blue, has been recorded as growth.MICs is defined as the lowest concentration of drug (stoping color to become pink from blueness) that suppresses tubercule bacillus growth.
Experimental result: in Table 1.
Table 1 representation compound Tuberculosis in vitro of the present invention pyrenomycetes H37Rv activity
| The compounds of this invention | MIC(μM) |
| I-8 | 0.9 |
| I-16 | 0.23 |
| I-17 | 0.24 |
| I-18 | 0.24 |
| INH | 0.81 |
| RMP | 0.08 |
| Mox | 0.50 |
| SM | 0.48 |
| PA824 | 0.44 |
As shown in Table 1, the compounds of this invention shows good Tuberculosis in vitro pyrenomycetes activity to tubercule bacillus type strain H37Rv.Part of compounds of the present invention has than the stronger tubercle bacillus resistant activity of positive control drug (INH, Mox, SM and PA824), can be used as the better antitubercular agent of result for the treatment of.
Two: the minimum bacteriostatic activity that adopts the mycobacterium trace clinical separation sensitive strain of quick medicine-sensitive test method determination compound directly perceived, MDR-TB and XDR-TB.
Experiment material
Bacterial strain: clinical sensitive strain S (numbering 960);
Clinical MDR bacterial strain (numbering 330);
Clinical X DR bacterial strain (numbering 431).
Above 3 kinds of bacterial strains are disclosed in < < Clinical Laboratory magazine > > the 25th volume the 5th phase 351-353 in 2007.
Be all that Nanjing chest hospital clinical samples is determined through improved method drug sensitive test multiple authentication.
Substratum: improvement Michaelis Middlebrook7H9 liquid nutrient medium (containing 10% nutritional additive) Nanjing chest hospital tuberculosis Basic Laboratory self-control [Clinical Laboratory magazine 2007,25,430-431].
Positive drug: vazadrine (INH)
Rifampin (RMP)
Vanizide (YYZ)
Experimental technique:
Aseptic 48 orifice plates (self-control tubercule bacillus quick medicine-sensitive is tested special microtest plate), by drug sensitive test design requirements, each hole adds respectively the medicine with 2 times of concentration substratum dilutions.Medicine to be detected is made to the first solution of proper concn, be diluted to two times of concentration of each compound used therefor with substratum (2 ×), every kind of each 10 gradients of test compounds, add 48 orifice plates, every hole 100 μ L.100 μ L are inoculated in the every hole of mycobacterium tuberculosis bacterial strain, and every pore fungi amount is 4 × 10
-3mg.Every plate is all established 2 not containing growth positive control hole and two growth positive control holes with distilled water substitutive medium of antibacterials, after 48 orifice plates are added a cover, around with scotch tape sealing, is placed in 37 ℃, wet box and hatches.Within the 3rd day, start the positive growth control hole of first observed and negative growth control hole, when observing both and having clear and definite difference, quantity and form to each experimental port bacterial growth are observed, judge inhibition or resistance and record result, within the 7th day, observe again and determine result, as not good in sun control growth, can be after the 10th day and 14 days again observed and recorded confirm.
Experimental result: in Table 2.
The external activity of table 2 part of compounds of the present invention to clinical sensitive strain and Resistant strain
As shown in Table 2, part of compounds of the present invention is to clinical sensitive strain S (960), and clinical MDR bacterial strain (330) and face XDR bacterial strain and show good tubercle bacillus resistant activity is better than positive control drug YYZ, INH and RMP.Therefore, can be used as the medicine of the infectious diseases that multidrug resistance tubercule bacillus causes.
Three, adopt 7 strains of Resazurin MIC assay test method determination to there is the minimum bacteriostatic activity of the ATCC mycobacterium tuberculosis strain (table 3) of single antibiotic resistant.Also measure the minimum fungicidal activity (MBC) of tubercule bacillus type strain H37Rv simultaneously.Experimental result is in Table 3 and table 4.
The external activity of the ATCC mycobacterium tuberculosis strain of table 3 part of compounds of the present invention to the single antibiotic resistant of 7 strain
The minimum fungicidal activity of table 4 part of compounds of the present invention to tubercule bacillus type strain H37Rv
From table 3 and table 4, I-16,7 strains are had to the ATCC mycobacterium tuberculosis strain of single antibiotic resistant for I-17 and I-18 and the inhibition of tubercule bacillus H37Rv type strain is active suitable with Vanizide (YYZ).Wherein, to ATCC 35822 Isoniazid bacterial strains suppress activity a little less than, infer that the active component of this compounds may be for vazadrine group.This experiment further confirms that the compounds of this invention has good anti-tubercle bacillus activity, is worth further investigation.
Four, adopt Cell Titer-Glo Luminescent Cell viability Assay (Promega) laboratory method to measure compound the viability (survival rate %) of African green monkey kidney passage cell (VERO cell) is carried out to Cytotoxic evaluation.
The toxicity research of table 5 representation compound of the present invention to African green monkey kidney passage cell
As shown in Table 5, the compounds of this invention I-16, I-17 and I-18 do not have cytotoxicity.
Five, adopt people's hepatomicrosome to measure the metabolic stability of compound, with vazadrine and the positive contrast of Midazolam.
The vitro stability research of table 6 part of compounds of the present invention to people's hepatomicrosome
atime detecting point is 0 o'clock, and metabolism residual content is 100%.
bnA=does not detect, to heat---and nonactive people's hepatomicrosome only detects the metabolism residual content in 60 minute moment.
As shown in Table 6, compound had metabolic reaction in various degree after 60 minutes by hepatomicrosome, be better than positive drug Midazolam, its metabolism successively order is Midazolam > I-18 > I-17 > I-16 > YYZ.
Six, adopt Double Sink PAMPA method to measure compound membrane permeability under different pH condition in three.With Vanizide (YYZ) and the positive contrast of verapamil (Verapamil), with the negative contrast of Ranitidine HCL (Ranitidine)
The external membrane permeability of table 7 representation compound of the present invention research
As shown in Table 7, P
ethe permeability of cell membrane that is worth higher expression compound is better.From experimental result, the membrane permeability order of three compounds is I-18 > I-17 > I-16, and wherein the permeability of cell membrane of Compound I-18 and I-17 is obviously better than positive drug YYZ
Embodiment
Embodiment 1
4-brooethyl cyanophenyl (II)
In the 250mL three-necked bottle that reflux condensing tube, dropping funnel and thermometer are housed, add successively the aqueous solution of alkylbenzene 3.5lg (0.03mol), ethyl acetate 50mL and potassium bromate 15.03g (0.09mol), under stirring, slowly splash into sodium bisulfite 9.36g (0.09mol) saturated solution of new system, in about 20min, drip off, with incandescence, irradiate simultaneously.After dripping, at 50-55 ℃, continue reaction 4h.Separate organic layer, anhydrous diethyl ether for water layer (30mL × 3) extraction, merges organic phase, uses Na
2s
2o
3saturated solution washing, finally uses anhydrous MgSO
4dry.Remove under reduced pressure after solvent, a large amount of solids are separated out, and suction filtration obtains white granular solid 3.53g, yield 60%, m.p.115-117 ℃ after being dried.(literature value: m.p.116.4-116.8 ℃ [applied chemistry, 2001,18,501-503.]).
MS(EI)m/z 195(M)
+。
Embodiment 2
4-(2-thiopurine methyltransferase benzoxazole) cyanophenyl (IV-2)
In the mono-neck bottle of 100ml, add salt of wormwood 8.28g (0.06mol), DMF 60Ml, 2-mercaptobenzoxazole (III-2) 3.02g (0.02mol), stir after 3min, add 4-brooethyl cyanophenyl 3.9g (0.02mol), room temperature reaction, TLC detects, and reacts about 2h.After reaction finishes, filter, filtrate is poured in trash ice, places the solid to be separated out that spends the night, suction filtration, and vacuum-drying obtains 5.17g solid, productive rate 97%, m.p.103-105 ℃.
MS(EI)m/z 266(M)
+。
Embodiment 3
4-(2-thiopurine methyltransferase benzoxazole) benzylamine (V-2)
Under ice bath is cooling, in the three-necked bottle of 50mL, add anhydrous THF 20mL, N
2gas protection, adds LiAlH
40.35g (0.009mol), reaction solution is chilled to 0 ℃ of left and right, the anhydrous THF solution that drips 4-(2-thiopurine methyltransferase benzoxazole) cyanophenyl 0.8g (0.003mol), reaction solution is slowly become orange by yellow, and the time, longer color was darker.After dropwising, reaction 3h, TLC detection reaction is complete.Reaction solution is cooling with ice bath, slowly drips the frozen water of 4mL, reaction solution yellowing jelly.Cooling, use diatomite drainage, filtrate is used anhydrous Na SO
4dry, silica gel column chromatography (ethyl acetate: methyl alcohol=5: 1) obtain yellow oil product 0.3lg, productive rate 39%.
MS(EI)m/z 270(M)
+。
Embodiment 4
N-(4-(2-thiopurine methyltransferase benzoxazole) benzyl) Isonicotinamide (I-8)
By adding thionyl chloride 5mL in γ-picolinic acid 0.37g (0.003mol), be slowly warming up to backflow, reaction 4h.Stopped reaction, cooling, boil off excessive thionyl chloride and obtain white solid, with anhydrous methylene chloride, dissolve and treat the next step.
4-(2-thiopurine methyltransferase benzoxazole) benzylamine 0.27g (0.001mol) is joined in 50mL three-necked bottle, be dissolved in dry CH
2cl
220mL, then adds anhydrous triethylamine 2mL, and ice bath is cooled to 0 ℃, drips the solution of acid chloride of above-mentioned preparation, and under room temperature, stirring reaction spends the night.Reaction solution is moved in separating funnel, separate organic layer, water layer CH
2cl
2(10mL × 1) extraction, organic layer is used Na after merging
2sO
4dry.Filter, filtrate decompression boils off solvent, and silica gel column chromatography obtains off-white color solid 0.25g, productive rate 67%, m.p.139-141 ℃.
IR(KBr)v
max(cm
-1)3280，1643，1540，1494，1450，1127，758，589；
1H NMR(DMSO-d
6)4.46(2H，d)，4.60(2H，s)，7.28-7.31(2H，d，AA’BB’，J＝8.1Hz)，7.31-7.36(2H，m，overlapped)，7.46-7.49(2H，d，AA’BB’，J＝8.1Hz)，7.63-7.67(2H，m)，7.76-7.78(2H，q)，8.71-8.73(2H，q)，9.28-9.32(1H，t)ppm；
MS(EI)m/e：375(M)
+；
Anal.Calc.(％)for C
21H
17N
3O
2S·0.5H
2O：C，65.61；H，4.72；N，10.93.Found C，65.97；H，4.50；N，10.77.
Embodiment 5
N-(4-(2-thiopurine methyltransferase benzoxazole) benzyl) pyrazinoic acid amide (I-11)
By pyrazine carboxylic acid 0.37g (0.003mol), DCC 0.72g (0.0035mol), HOBT 0.47g (0.0035mol), DMAP0.012g (0.0001mol) is dissolved in DMF10mL, be cooled to 0 ℃ with ice bath, (activating carboxy acid) spends the night, in reaction solution, there is a large amount of solids, suction filtration, in filtrate, add the DMF liquid 5mL that dissolves 4-(2-thiopurine methyltransferase benzoxazole) benzylamine 0.27g (0.001mol), react about 5h, TLC monitoring.Stopped reaction, suction filtration, filtrate is dissolved with ethyl acetate 20mL, washing, then with saturated common salt washing, organic layer Na
2sO
4dry.Filter, filtrate decompression boils off solvent, and silica gel column chromatography obtains off-white color solid 0.16g, productive rate 44%, m.p.145-147 ℃.
IR(KBr)v
max(cm
-1)3352，2926，2844，1670，1627，1501，1452，1126，1023，744，656；
1H NMR(DMSO-d
6)4.47(2H，d)，4.59(2H，s)，7.28-7.33(2H，overlapped)，7.32(2H，AA’BB’，J＝7.5Hz)，7.45(2H，AA’BB’，J＝7.5Hz)，7.64(2H，d)，8.72(1H，s)，8.86(1H，s)，9.18(1H，s)，9.47(1H，t)；
MS(EI)m/e：376(M)
+；
Anal.Calc.(％)for C
20H
16N
4O
2S：C，63.81；H，4.28；N，14.88.Found C，64.11；H，4.12；N，14.57.
Embodiment 6
2-(4-chloromethyl benzylthio-)-1H-benzoglyoxaline (VI-1)
In the three-necked bottle of 100ml, add benzyl dichloride 3.85g (0.022mol) and methyl alcohol 60mL, be heated to dissolve, drip with sodium hydroxide 0.8g (0.02mol), water 20mL, the solution of methyl alcohol 40mL and 2-mercaptobenzimidazole 3.0g (0.02mol) preparation, approximately needs 20min.After dropwising, reaction 30min.Cooling, pumping rate, filtrate concentrates to obtain 5.33g crude product.By recrystallizing methanol, obtain white solid 3.6g again, productive rate 67%, m.p.91-93 ℃.
MS(EI)m/e 288(M)+。
Embodiment 7
4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) phenyl aldehyde (VII-1)
In 100ml two neck bottles, add 2-(4-chloromethyl benzylthio-)-1H-benzoglyoxaline 1.44g (0.005mol), urotropine 0.9lg (0.0065mol), 60% ethanol (ethanol 36mL and water 24mL), is heated to reflux, reaction 2h.Stopped reaction, with ether (20mL × 3) extraction, merges organic layer, uses anhydrous Na SO
4dry.Suction filtration, column chromatography (sherwood oil: ethyl acetate=10: 1), obtain colorless oil 0.44g, productive rate 33% after filtrate is concentrated.
MS(EI)m/e：268(M)
+。
Embodiment 8
N '-(4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) benzal) Vanizide (I-16)
In single neck bottle of 50ml, add vazadrine 0.17g (0.0012mol), 4-(2-thiopurine methyltransferase-1H-benzoglyoxaline) phenyl aldehyde 0.27g (0.001mol), ethanol 15mL and acetic acid 5Ml.Be heated to reflux, reaction 2h.After stopped reaction, cooling, filtrate is dissolved with ethyl acetate 20mL, washing, then use saturated NaCO
3solution is washed, organic layer Na
2sO
4dry.Filter, filtrate decompression boils off solvent, and silica gel column chromatography obtains white solid 0.27g, productive rate 69%, m.p.238-240 ℃.
IR(KBr)v
max(cm
-1)3153，3046，2963，1665，1550，1409，1298，1225，1066，738，686；
1H NMR(DMSO-d
6)4.61(2H，s)，7.11-7.14(2H，q)，7.45(2H，s)，7.54(2H，d，AA’BB’，J＝8.1Hz)，7.69(2H，d，AA’BB’，J＝8.1Hz)，7.81(2H，d)，8.42(1H，s)，8.78(2H，d)，12.04(1H，s)，12.59(1H，s)ppm；
MS(EI)m/e：387(M)
+；
Anal.Calcd.(％)for C
21H
17N
5OS：C，65.10；H，4.42；N，18.08.Found C，64.78；H，4.49；N，17.92.
Embodiment 9
N '-(4-(2-thiopurine methyltransferase benzoxazole) benzal) Vanizide (I-17)
Synthetic according to 6 to 8 methods of enforcement, it is starting raw material that the 2-mercaptobenzimidazole in enforcement 6 is replaced to 2-mercaptobenzoxazole, and other preparation methods are identical, obtain white solid 0.28g, productive rate 72%, m.p.229-231 ℃.
IR(KBr)v
max(cm
-1)3256，3039，1658，1555，1501，1454，1293，1132，1067，746，682；
1H NMR(DMSO-d
6)4.64(2H，s)，7.29-7.37(2H，m)，7.47-7.67(2H，m)，7.61(2H，d，AA’BB’，J＝8.1Hz，overlapped)，7.72(2H，d，AA’BB’，J＝8.1Hz)，7.85-7.80(2H，t)，8.44(1H，s)，8.73-8.79(2H，t)，12.06(1H，s)ppm；
MS(EI)m/e：388(M)
+；
Anal.Calc.(％)for C
21H
16N
4O
2S：C，64.93；H，4.15；N，14.42.Found C，64.72；H，4.06；N，14.55.
Embodiment 10
N '-(4-(2-thiopurine methyltransferase benzothiazole) benzal) different acylhydrazone (I-18)
Synthetic according to 6 to 8 methods of enforcement, it is starting raw material that the 2-mercaptobenzimidazole in enforcement 6 is replaced to 2-mercaptobenzothiazole, and other preparation methods are identical, obtain white solid 0.29g, productive rate 72%, m.p.215-217 ℃.
IR(KBr)v
max(cm
-1)3425，3282，3044，1662，1543，1454，1423，1280，1008，840，749，682；
1H NMR(DMSO-d
6)4.71(2H，s)，7.34-7.40(1H，t)，7.46-7.50(1H，t)，7.61(2H，d，AA’BB’，J＝8.1Hz)，7.73(2H，d，AA’BB’，J＝8.1Hz)，7.82(2H，d)，7.90(1H，d，J＝7.8Hz)，8.02(1H，d，J＝7.8Hz)，8.45(1H，s)，8.78(2H，d)，12.05(1H，s)ppm；
MS(EI)m/e：404(M)
+；
Anal.Calcd.(％)for C
21H
16N
4OS
2：C，62.35；H，3.99；N，13.85.Found C，62.10；H，4.04；N，14.01.
Embodiment 11
By gained compound 0.5g in embodiment 8, starch 2g, dextrin 1g mixes, and with appropriate 30% ethanol, makes wetting agent, granulate, compressing tablet.
Claims (8)
1. the compound of general formula (I) or its pharmacy acceptable salt:
Wherein Ar represents pyridine ring;
Represent-(CH of L
2) n-or-N=CH-, wherein n=1-3;
X represents CH
2, O, S or NH;
R represents H, NO
2, CN, NH
2, OH, OCH
3, C
1-C
4alkyl or halogen.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein L represents CH
2or-N=CH-.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein X represents O, S or NH.
4. the compound of claim 1 or its pharmacy acceptable salt, wherein R represents H.
5. a pharmaceutical composition, wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
6. the compound of claim 1 is for the preparation of the purposes of the medicine for the treatment of infectious diseases.
7. the purposes of claim 6, wherein infectious diseases is the infectious diseases that tubercule bacillus causes.
8. the purposes of claim 6, wherein infectious diseases is the infectious diseases that resistance tubercule bacillus causes.
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