CN105399682A - Aryl connected metronidazole-amide type urease inhibitor, as well as synthesis and application thereof - Google Patents

Aryl connected metronidazole-amide type urease inhibitor, as well as synthesis and application thereof Download PDF

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CN105399682A
CN105399682A CN201510751044.2A CN201510751044A CN105399682A CN 105399682 A CN105399682 A CN 105399682A CN 201510751044 A CN201510751044 A CN 201510751044A CN 105399682 A CN105399682 A CN 105399682A
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metronidazole
eimsm
400mhz
dmso
hnmr
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肖竹平
师维康
李玲霞
吴浪舟
罗兴
祝璇
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Jishou University
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Jishou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members

Abstract

The invention provides an aryl connected metronidazole-amide derivative series compound. The compound has a structural general formula as shown in the specification, has a relatively good inhibition effect on urease, and can be used for preparing medicines for resisting gastritis, gastric ulcer, lithangiuria and the like. The invention further discloses a preparation method and application of the compound.

Description

Aryl connects metronidazole-acid amide type urease inhibitor and synthesis thereof and purposes
Technical field
The present invention relates to a class aryl and connect the method for making of metronidazole-acid amide type urease inhibitor and they are preparing the application in gastritis, Gastric Ulcer Treatment.
Technical background
Hp (Helicobacterpylori) can cause the various diseases such as gastritis, stomach ulcer, duodenal ulcer, gastratrophy, intestinal epithelial metaplasia, cancer of the stomach, gastric lymphoma.H.pylori is classified as first kind carcinogen by the World Health Organization in 1994 and IARC.According to statistics, the nearly half of world population has infected H.pylori, and in developing country, infection rate is up to 80-90%.The infection rate of China is about 60%.The H.pylori recall rate of gastritis sufferer is 80-90%, and Peptic Ulcers is higher, reaches more than 95%.Duodenal ulcer more than 90% and the stomach ulcer of about 80% are caused by H.pylori.Eradicating H.pylori is the above-mentioned disease for the treatment of and the prerequisite preventing recurrence.What current elimination H.pylori was the most frequently used is triplex process: a kind of proton pump inhibitor (omeprazole or lansoprazole) and two kinds of microbiotic (amoxycilline Trihydrate bp, Ofloxacine USP 23 or metronidazole).But omeprazole has obvious side effect: except causing the side effects such as stomachache, vomiting, flatulence, liver weight increase etc. also can be caused; Bring out carcinoid of stomach in addition, cause the danger such as renal failure.In addition H.pylori easily produces resistance to microbiotic used, and therefore, the efficient of this method declines just year by year.
As everyone knows, be a strong acid environment in stomach, the main reason that Hp can be survived in stomach is its urease activity.The ammonia that urease hydrolyze urea discharges can improve pH value, and current research display, in receptor structure, urea molecule is Hp perception and the key factor avoiding gastric acid environment.Therefore the H.pylori that act as of urease has built a suitable microenvironment.Some other germ, as proteus vulgaris (Proteusvulgaris), Proteus mirabilis (Proteusmirabilis), ureaplasma urealyticum (Ureaplasmaurealyticum) etc., after they infect urinary tract system, because the effect of urease causes the pH of urine to raise, cause the precipitation of the materials such as magnesium ammonium phosphate, and then develop into lithangiuria.There is the pathogenic bacteria of urease activity or to produce ammonia be self that vital movement provides nitrogenous source by urease hydrolyze urea, or utilize the alkalescence of ammonia to provide a suitable microenvironment for its existence.Therefore blocked urease activity, just can effectively kill this kind of germ.Therefore, urease inhibitor will become the first-line drug for the treatment of this kind of disease.But existing urease inhibitor comes with some shortcomings, such as N-acetylhydroxylamine due to activity low, consumption is large, result in some side effects, and highly active di(2-ethylhexyl)phosphate amides urease inhibitor is unstable in sour environment, hinders its application clinically.Therefore the screening of new and effective low toxicity urease inhibitor is the key developing this kind of medicine.
Utilize computer modeling technique, based on scaffold hopping principle, design and synthesize the new urea enzyme inhibitors with structure shown in I.Test shows, some compound shows excellent inhibit activities to urease.
Summary of the invention
The object of the invention is to design and synthesize a series of aryl and connect metronidazole-acid amide type urease inhibitor (I), on the basis of further investigation structure activity relationship, find the new urea enzyme inhibitors that activity is higher, toxic side effect is lower, and provide aryl to connect the method for making of metronidazole-amide type compound.
Technical scheme of the present invention is as follows:
One class aryl connects metronidazole-acid amide type urease inhibitor series compound, and they have following general structure:
In formula I, X, Y and Z are defined as follows:
X＝OH、NO 2、Cl、Br、F、OMe、OEt、NMe 2、NEt 2，Y＝CHOH、O、S、NH，Z＝OH、
Prepare the method that above-mentioned aryl connects metronidazole-amide type compound, it is characterized in that it comprises the following steps:
Disubstituted benzenes phenol (II), NaOH, ethyl bromoacetate are placed in round-bottomed flask by step 1., the ratio of amount of substance: II:NaOH: ethyl bromoacetate=1:(1 ~ 5): (1 ~ 8), take acetone as solvent, every gram of II adds acetone 7 ~ 20mL, after 50 ~ 80 DEG C of stirring 12 ~ 48h, pour distilled water into, AcOEt extracts, anhydrous MgSO 4drying, boils off solvent, and with purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=1:3 ~ 1:10, obtains the pendant carboxylic acid ester derivative (III) of phenol;
The pendant carboxylic acid ester derivative (III) of phenol is dissolved in anhydrous THF by step 2., every gram of III adds THF8 ~ 20mL, after adding chloro metronidazole, add appropriate Anhydrous potassium carbonate, stir 5 ~ 10h, the ratio of amount of substance is: III: chloro metronidazole: Anhydrous potassium carbonate=1:(2 ~ 7): (1 ~ 3), boil off THF, add distilled water, extract with AcOEt, merge organic layer, MgSO 4drying, boils off solvent, and with purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=1:4 ~ 2:1, obtains metronidazole-carboxylates derivatives (IV) that aryl connects;
Metronidazole-carboxylates derivatives (IV) that aryl connects by step 3. is dissolved in anhydrous methanol, every gram of IV adds anhydrous methanol 3 ~ 10mL, add HZ, stir 5 ~ 10h, the ratio of amount of substance is: IV:HZ=1:(2 ~ 7), boil off methyl alcohol, adding distil water, with AcOEt extraction, merge organic layer, MgSO 4drying, boils off solvent, and with purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=1:8 ~ 5:1, obtains aryl and connect metronidazole-amide derivatives (I);
Wherein said X, Y are identical with the definition in above-mentioned general formula with the definition of Z.
Aryl of the present invention connects metronidazole-amide derivatives series compound has good inhibit activities to urease, wherein most better than the activity of positive control N-acetylhydroxylamine.Therefore may be used for the medicine preparing gastritis, stomach ulcer or anti-lithangiuria.
Embodiment
Further describe the present invention by following examples, but scope of the present invention should be noted not by any restriction of these embodiments.
The preparation of embodiment 1:2-(5-(O-metronidazole-2'-base)-3-hydroxybenzene sulfenyl) N-acetylhydroxylamine (5)
28.5g3,5-dihydroxyl thiophenol, 10gNaOH, 15mL ethyl bromoacetate are placed in 100mL round-bottomed flask, add 50mLDMSO, at 60 DEG C, stir 16h, after pouring 20mL distilled water into, extract with AcOEt, by organic layer saturated common salt water washing 3 times, anhydrous MgSO 4drying, boils off solvent, purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=1:6, obtains yellow oily liquid 2-(3,5-dihydroxy-benzene sulfenyl) ethyl acetate 21.5g.2-(3,5-dihydroxy-benzene sulfenyl) ethyl acetate 10.5g, chloro metronidazole 10g are dissolved in 50mL dehydrated alcohol, Anhydrous potassium carbonate 8g, stirring at room temperature 0.5h, is heated to 60 DEG C of reaction 5h, adds 30mL distilled water after boiling off ethanol, AcOEt extracts, and merges organic layer, anhydrous MgSO 4drying, boils off solvent, purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=4:1, obtains yellow solid 2-(5-(O-metronidazole-2'-base)-3-hydroxybenzene sulfenyl) ethyl acetate IV5.5g.2-(5-(O-metronidazole-2'-base)-2-hydroxybenzene sulfenyl) ethyl acetate 1.5g, oxammonium hydrochloride 1.5g, sodium methylate 3g are dissolved in 25ml anhydrous methanol, and stirring at room temperature reaction 15h, boils off methyl alcohol, pH is regulated to be neutral, with AcOEt extraction, merge organic layer, anhydrous MgSO 4drying, boils off solvent, purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=7:1, obtain white solid 2-(5-(O-metronidazole-2'-base)-3-hydroxybenzene sulfenyl) N-acetylhydroxylamine (5) 0.68g, productive rate 55%, fusing point: 268 ~ 269 DEG C; EIMSm/z:197 [M +]; 1hNMR (400MHz, DMSO, δ): 7.87 ~ 8.0 ((s, 1H), 7.81 (s, 1H), 6.15 ~ 6.32 (m, 3H), 5.35 (s, 1H), 4.45 ~ 4.60 (m, 4H), 3.97 ~ 4.03 (s, 1H), (3.84 s, 2H), 2.51 (s, 3H), 1.98 ~ 2.08 (s, 1H).
Embodiment 2:
By the method that embodiment 1 is similar, be raw material with the phenyl aldehyde of different replacement forms, the aryl synthesized listed by table 1 connects metronidazole-amide derivatives series compound 1 ~ 72.
In table 1 general formula I, aryl connects each X, Y, Z group of metronidazole-amide derivatives series compound
Note: initial feed is all purchased from aldrich company
Embodiment 3: the Inhibiting enzyme activity of compound
The solution of 25 μ LJackbean (sword bean) ureases (4U) and 25 μ L (1mM) test compounds is added in 96 orifice plates, 2h is cultivated at 37 DEG C, then the phosphoric acid buffer 55 μ L containing 100mM urea and 100mM is added, 15min is cultivated at 30 DEG C, add 45 μ L phenol reagents (containing phenol 1% and the mixing solutions containing Sodium Nitroprusside 0.005%) and 70 μ L alkali reagents (mixing solutions containing the NaOCl of NaOH0.5% and 0.1% reactive chlorine), after at room temperature placing 50min, the OD value under 630nm is measured by microplate reader, percent inhibition is calculated as follows:
All tests are all carry out (the K of 0.01M in the solution of 7.8 at pH 2hPO 4, the LiCl of the EDTA of 1mM, 0.01M), active height is with half inhibiting rate IC 50represent, IC 50less, the activity of this compound is higher, the results are shown in Table 2.
Result shows: part aryl of the present invention connects metronidazole-amide derivatives series compound has good inhibit activities to urease, and some are higher than the activity of positive control N-acetylhydroxylamine.
Table 2 aryl connects the restraining effect (IC of metronidazole-amide derivatives series compound sword bean urease 50)
Result shows, compound 6,12,29,30,35,36,37,38,39,41,46,49,53,58,68,70,71,72 pairs of sword bean ureases have significant restraining effect, and restraining effect comparatively N-acetylhydroxylamine is higher, active best 170 times that reach N-acetylhydroxylamine.
The above embodiment of the present invention shows: connect in metronidazole-amide derivatives series compound at the aryl of synthesis, the Urease inhibitor effect of a part is higher than positive control N-acetylhydroxylamine, the anxious poison experiment of rat is shown, when the dosage of compound 6,12,29,58,41,46,53,58 reaches 5g/kg (this dosage is the non-toxic of States Pharmacopoeia specifications), do not find that rat has signs of toxicity, therefore, under normal dose, they are safe as medicinal application.
The fusing point of compound 1 ~ 72, mass spectrum and hydrogen modal data:
2-(5-(O-metronidazole-2'-base)-2-hydroxybenzyloxy) propionyl hydroxamic acid (1):
Mp214～215℃；EIMSm/z：365[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0((s，1H)，7.81(s，1H)，6.65～6.72(m，2H)，6.45～6.51(s，1H)，5.35(s，1H)，4.70～4.75(m，4H)，4.45～4.60(m，1H)，3.65(s，1H)，2.49～2.53(m，5H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-hydroxybenzyloxy) propionamido urea (2):
Mp221～223℃；EIMSm/z：407[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0((s，1H)，7.81(s，1H)，6.65～6.72(m，2H)，6.45～6.51(s，1H)，5.96～6.03(s，3H)，4.45～4.60(m，4H)，5.35(s，1H)，4.70～4.75(m，4H)，3.65(s，1H)，2.49～2.53(m，5H)。
2-(5-(O-metronidazole-2'-base)-3-hydroxybenzene phenolic group) acetyl amido thiourea (3):
Mp232～233℃；EIMSm/z：409[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0((s，1H)，7.81(s，1H)，6.10(s，2H)，5.93(s，1H)，5.35(s，1H)，4.48～4.65(m，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-hydroxybenzene phenolic group) kharophen guanidine (4):
Mp265～267℃；EIMSm/z：392[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，1H)，7.81(s，1H)，6.10(s，2H)，5.93(s，1H)，5.35(s，1H)，4.48～4.65(m，6H)，4.21～4.35(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-hydroxybenzene sulfenyl) N-acetylhydroxylamine (5):
Mp268～269℃；EIMSm/z：197[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0((s，1H)，7.81(s，1H)，6.15～6.32(m，3H)，5.35(s，1H)，4.45～4.60(m，4H)，3.97～4.03(s，1H)，3.84(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-hydroxybenzene sulfenyl) kharophen guanidine (6):
Mp224～226℃；EIMSm/z：211[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0((s，1H)，7.81(s，1H)，6.15～6.32(m，3H)，5.96～6.03(s，2H)，5.35(s，1H)，4.70～4.75(m，4H)，3.73(s，1H)，2.51(s，3H)。.
2-(5-(O-metronidazole-2'-base)-3-hydroxybenzene amido) acetyl thio Urea,amino-(7):
Mp242～243℃；EIMSm/z：408[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.86(s，1H)，5.65～5.72(m，2H)，5.35(s，1H)，4.45～4.60(m，4H)，4.21～4.35(s，1H)，3.97～4.03(s，1H)，3.77(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-4-hydroxybenzene amido) kharophen guanidine (8):
Mp185～187℃；EIMSm/z：196[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.86(s，1H)，5.65～5.72(m，2H)，5.35(s，1H)，4.45～4.60(m，4H)，4.21～4.35(m，1H)，3.97～4.03(s，1H)，3.77(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-2-nitro benzyloxy) propionyl hydroxamic acid (9):
Mp267～268℃；EIMSm/z：394[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.59(s，1H)，7.53(s，1H)，4.69～4.75(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，2.75～2.80(m，2H)，2.50～2.55(m，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-nitro benzyloxy) propionamido urea (10):
Mp253～255℃；EIMSm/z：436[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.59(s，1H)，7.53(s，1H)，5.96～6.03(s，3H)，4.69～4.75(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，2.75～2.80(m，2H)，2.50～2.55(m，3H)。
2-(5-(O-metronidazole-2'-base)-3-oil of mirbane phenolic group) kharophen thiocarbamide (11):
Mp213～215℃；EIMSm/z：438[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，7.22(s，2H)，6.76(s，1H)，4.48～4.65(m，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-oil of mirbane phenolic group) kharophen guanidine ((12):
Mp218～220℃；EIMSm/z：421[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，7.22(s，2H)，6.76(s，1H)，4.48～4.65(m，6H)，4.21～4.35(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-nitrophenylsulfenyl) (13):
Mp221～222℃；EIMSm/z：396[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.67(s，1H)，7.42(s，1H)，7.06(s，1H)，4.45～4.60(m，4H)，3.84(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-nitrophenylsulfenyl) kharophen urea (14):
Mp227～228℃；EIMSm/z：438[M +]； 1HNMR(400MHz，DMSO，δ)7.87～8.0(m，2H)，7.81(s，1H)，7.67(s，1H)，7.42(s，1H)，7.06(s，1H)，5.96～6.03(s，3H)，4.45～4.60(m，4H)，3.73(s，1H)，2.51(s，3H)。
2-(5-(O-metronidazole-2'-base)-3-oil of mirbane amido) kharophen thiocarbamide (15):
Mp263～265℃；EIMSm/z：437[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，7.09(s，1H)，6.89(s，1H)，6.54(s，1H)，4.45～4.60(m，4H)，4.21～4.35(m，H)，3.97～4.03(s，1H)，3.77(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-4-oil of mirbane amido) kharophen guanidine (16):
Mp277～279℃；EIMSm/z：420[M +]；HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，7.09(s，1H)，6.89(s，1H)，6.54(s，1H)，4.45～4.60(m，4H)，4.21～4.35(m，1H)，3.97～4.03(s，1H)，3.77(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-2-chlorine benzyloxy) propionyl hydroxamic acid (17):
Mp161～163℃；EIMSm/z：226[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.12(s，2H)，7.02(s，1H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，2.51～2.79(m，5H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-chlorine benzyloxy) propionamido urea (18):
Mp274～275℃；EIMSm/z：425[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.12(s，2H)，7.02(s，1H)，5.96～6.03(s，3H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，2.51～2.79(m，5H)。
2-(5-(O-metronidazole-2'-base)-3-chlorobenzene phenolic group) kharophen thiocarbamide (19):
Mp237～238℃；EIMSm/z：427[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.75(s，2H)，6.25(s，1H)，6.45～6.65(m，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-chlorobenzene phenolic group) kharophen guanidine ((20):
Mp262～263℃；EIMSm/z：410[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.75(s，2H)，6.25(s，1H)，6.45～6.65(m，6H)，4.21～4.35(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-chlorophenylsulfanyl) N-acetylhydroxylamine (21):
Mp281～283℃；EIMSm/z：385[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.13(s，1H)，6.95(s，1H)，6.55(s，1H)，4.45～4.60(m，4H)，3.84(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-chlorophenylsulfanyl) kharophen urea (22):
Mp255～257℃；EIMSm/z：427[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.13(s，1H)，6.95(s，1H)，6.55(s，1H)，5.96～6.03(s，3H)，4.45～4.60(m，4H)，3.73(s，2H)，2.51(s，3H)。
2-(5-(O-metronidazole-2'-base)-3-chloroanilino) kharophen thiocarbamide (23):
Mp269～271℃；EIMSm/z：426[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.51(s，2H)，6.34(s，1H)，6.03(s，1H)，4.45～4.60(m，4H)，3.97～4.03(s，1H)，3.77(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-4-chloroanilino) kharophen guanidine (24):
Mp214～215℃；EIMSm/z：409[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.51(s，2H)，6.34(s，1H)，6.03(s，1H)，4.45～4.60(m，4H)，4.21～4.35(s，1H)，3.97～4.03(s，1H)，3.77(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-2-bromo-benzyloxy-) propionyl hydroxamic acid (25):
Mp236～237℃；EIMSm/z：427[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.17(s，2H)，7.07～7.08(s，2H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，2.51～2.79(m，5H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-bromo-benzyloxy-) propionamido urea (26):
Mp259～261℃；EIMSm/z：469[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.17(s，2H)，7.07～7.08(s，2H)，5.96～6.03(s，3H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，2.51～2.79(m，5H)。
2-(5-(O-metronidazole-2'-base)-3-bromobenzene phenolic group) kharophen thiocarbamide (27):
Mp222～223℃；EIMSm/z：471[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.8(s，2H)，6.31(s，1H)，6.45～6.65(m，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-bromobenzene phenolic group) kharophen guanidine (28):
Mp266～268℃；EIMSm/z：454[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.8(s，2H)，6.31(s，1H)，6.45～6.65(m，6H)，4.21～4.35(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-bromophenylthio) N-acetylhydroxylamine (29):
Mp272～273℃；EIMSm/z：428[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.13(s，1H)，7.0(s，1H)，6.91(s，1H)，6.61(s，1H)，4.45～4.60(m，4H)，3.84(s，2H)，2.51(s，3H)，1.98～2.008(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-bromophenylthio) kharophen urea (30):
Mp273～275℃；EIMSm/z：472[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.13(s，1H)，7.00(s，1H)，6.91(s，1H)，6.61(s，1H)，5.96～6.03(s，3H)，4.45～4.60(m，4H)，3.73(s，2H)，2.51(s，3H)。
2-(5-(O-metronidazole-2'-base)-3-bromobenzene amido) kharophen thiocarbamide (31):
Mp275～277℃；EIMSm/z：470[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.56(s，1H)，6.22(s，1H)，6.09(s，1H)，4.45～4.60(m，4H)，3.97～4.03(s，1H)，3.77(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-4-bromobenzene amido) kharophen guanidine (32):
Mp249～251℃；EIMSm/z：453[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.56(s，1H)，6.22(s，1H)，6.09(s，1H)，4.45～4.60(m，4H)，4.21～4.35(s，1H)，3.97～4.03(s，1H)，3.77(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-2-fluorine benzyloxy) propionyl hydroxamic acid (33):
Mp264～266℃；EIMSm/z：367[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.07(s，2H)，6.91(s，1H)，6.46(m，1H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，2.51～2.79(m，5H)，1.98～2.08(s，1H)。2-(5-(O-metronidazole-2'-base)-3-fluorine benzyloxy) propionamido urea (34):
Mp264～266℃；EIMSm/z：409[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，7.07(s，2H)，6.91(s，1H)，6.46(m，1H)，5.96～6.03(s，3H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，2.51～2.79(m，5H)。
2-(5-(O-metronidazole-2'-base)-3-fluorobenzene phenolic group) kharophen thiocarbamide (35):
Mp237～238℃；EIMSm/z：411[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.7(m，2H)，6.14(s，1H)，6.45～6.65(m，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-fluorobenzene phenolic group) kharophen guanidine (36):
Mp251～253℃；EIMSm/z：394[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.7(m，2H)，6.14(s，1H)，6.45～6.65(m，6H)，4.21～4.35(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-chlorophenylthio) N-acetylhydroxylamine (37):
Mp261～263℃；EIMSm/z：369[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.90(s，1H)，6.44～6.45(d，2H)，4.45～4.60(m，4H)，3.84(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-chlorophenylthio) kharophen urea (38):
Mp271～273℃；EIMSm/z：411[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.90(s，1H)，6.44～6.45(d，2H)，5.96～6.03(s，3H)，4.45～4.60(m，4H)，3.73(s，2H)，2.51(s，3H)。
2-(5-(O-metronidazole-2'-base)-3-fluoroanilino) kharophen thiocarbamide (39):
Mp256～258℃；EIMSm/z：410[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.46(m，1H)，6.10(m，1H)，5.92(s，1H)，4.45～4.60(m，4H)，3.97～4.03(s，1H)，3.77(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-4-fluoroanilino) kharophen guanidine (40):
Mp283～284℃；EIMSm/z：393[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，6.46(m，1H)，6.10(m，1H)，5.92(s，1H)，4.45～4.60(m，4H)，4.21～4.35(s，1H)，3.97～4.03(s，1H)，3.77(s，1H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-2-methoxyl group benzyloxy) propionyl hydroxamic acid (41):
Mp295～297℃；EIMSm/z：379[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.70(s，2H)，6.30(s，1H)，4.73(m，1H)，4.45～4.60(m，4H)，3.83(s，3H)，3.65(s，1H)，2.51～2.79(m，5H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-methoxyl group benzyloxy) propionamido urea (42):
Mp269～271℃；EIMSm/z：421[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.70(s，2H)，6.30(s，1H)，5.96～6.03(s，3H)，4.73(m，1H)，4.45～4.60(m，4H)，3.83(s，3H)，3.65(s，1H)，2.51～2.79(m，5H)。2-(5-(O-metronidazole-2'-base)-3-anisole phenolic group) kharophen thiocarbamide (43):
Mp282～284℃；EIMSm/z：423[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.93(s，3H)，4.45～4.65(m，6H)，3.83(s，3H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-anisole phenolic group) kharophen guanidine (44):
Mp296～298℃；EIMSm/z：406[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.93(s，3H)，4.45～4.65(m，6H)，4.21～4.35(s，1H)，3.83(s，3H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-Methoxv-phenylsulfanvl) N-acetylhydroxylamine (45):
Mp241～243℃；EIMSm/z：381[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.23(s，2H)，6.13(s，1H)，4.45～4.60(m，4H)，3.83～3.84(d，5H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-Methoxv-phenylsulfanvl) kharophen urea (46):
Mp249～250℃；EIMSm/z：423[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.23(s，2H)，6.13(s，1H)，5.96～6.03(s，3H)，4.45～4.60(m，4H)，3.83(s，3H)，3.73(s，2H)，2.51(s，3H)。
2-(5-(O-metronidazole-2'-base)-3-anisole amido) kharophen thiocarbamide (47):
Mp284～286℃；EIMSm/z：422[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.69～5.71(m，3H)，4.45～4.60(m，4H)，3.97～4.03(s，1H)，3.83(s，3H)，3.77(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)。2-(5-(O-metronidazole-2'-base)-4-anisole amido) kharophen guanidine (48):
Mp257～259℃；EIMSm/z：405[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.69～5.71(m，3H)，4.45～4.60(m，4H)，4.21～4.35(s，1H)，3.97～4.03(s，1H)，3.83(s，3H)，3.77(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-2-oxyethyl group benzyloxy) propionyl hydroxamic acid (49):
Mp262～263℃；EIMSm/z：393[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.70(s，2H)，6.3(s，1H)，4.73(s，1H)，4.45～4.60(m，4H)，4.09(m，2H)，3.65(s，1H)，2.51～2.79(m，5H)，1.98～2.08(s，1H)，1.32(t，3H)。
2-(5-(O-metronidazole-2'-base)-3-oxyethyl group benzyloxy) propionamido urea (50):
Mp245～247℃；EIMSm/z：435[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.70(s，2H)，6.3(s，1H)，5.96～6.03(s，3H)，4.73(s，1H)，4.45～4.60(m，4H)，4.09(m，2H)，3.65(s，1H)，2.51～2.79(m，5H)，1.32(t，3H)。
2-(5-(O-metronidazole-2'-base)-3-phenetole phenolic group) kharophen thiocarbamide (51):
Mp258～260℃；EIMSm/z：437[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.93(s，1H)，4.45～4.65(m，6H)，4.09(m，2H)，2.51(s，3H)，1.98～2.08(s，1H)，1.32(t，3H)。
2-(5-(O-metronidazole-2'-base)-3-phenetole phenolic group) kharophen guanidine (52):
Mp231～232℃；EIMSm/z：420[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.93(s，1H)，4.45～4.65(m，6H)，4.21～4.35(s，1H)，4.09(m，2H)，2.51(s，3H)，1.98～2.08(s，1H)，1.32(t，3H)。
2-(5-(O-metronidazole-2'-base)-3-phenetole sulfenyl) N-acetylhydroxylamine (53):
Mp254～256℃；EIMSm/z：395[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.23(s，2H)，6.13(s，1H)，4.45～4.60(m，4H)，4.09(m，2H)，3.84(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)，1.32(t，3H)。
2-(5-(O-metronidazole-2'-base)-3-phenetole sulfenyl) kharophen urea (54):
Mp272～274℃；EIMSm/z：437[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.23(s，2H)，6.13(s，1H)，5.96～6.03(s，3H)，4.45～4.60(m，4H)，4.09(m，2H)，3.84(s，2H)，2.51(s，3H)，1.32(t，3H)。
2-(5-(O-metronidazole-2'-base)-3-phenetole amido) kharophen thiocarbamide (55):
Mp264～266℃；EIMSm/z：436[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.69～5.71(m，3H)，4.45～4.60(m，4H)，3.96～4.09(m，3H)，3.77(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)，1.32(t，3H)。
2-(5-(O-metronidazole-2'-base)-4-phenetole amido) kharophen guanidine (56):
Mp247～248℃；EIMSm/z：419[M+]；1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.69～5.71(m，3H)，4.45～4.60(m，4H)，4.21～4.35(s，1H)，3.96～4.09(m，3H)，3.77(s，2H)，2.51(s，3H)，1.98～2.08(s，1H)，1.32(t，3H)。
2-(5-(O-metronidazole-2'-base)-2-dimethylamino benzyloxy) propionyl hydroxamic acid (57):
Mp244～245℃；EIMSm/z：392[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.48(m，1H)，6.37(m，1H)，6.24(s，1H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，3.06(s，6H)，2.51～2.79(m，5H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-dimethylamino benzyloxy) propionamido urea (58):
Mp256～257℃；EIMSm/z：434[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.48(m，1H)，6.37(m，1H)，6.24(s，1H)，5.96～6.03(s，3H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，3.06(s，6H)，2.51～2.79(m，5H)。
2-(5-(O-metronidazole-2'-base)-3-Dimethylaminobenzene phenolic group) kharophen thiocarbamide (59):
Mp288～290℃；EIMSm/z：436[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.87(s，2H)，5.71(s，1H)，4.45～4.65(m，6H)，3.06(s，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-Dimethylaminobenzene phenolic group) kharophen guanidine (60):
Mp272～274℃；EIMSm/z：419[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.87(s，2H)，5.71(d，1H)，4.45～4.65(m，6H)，4.21～4.35(s，1H)，3.06(s，6H)，2.51(s，3H)，1.98～2.08(s，1H)。2-(5-(O-metronidazole-2'-base)-3-dimethylamino thiophenyl) N-acetylhydroxylamine (61):
Mp275～277℃；EIMSm/z：394[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.94(m，1H)，6.07(s，1H)，6.01(s，1H)，4.45～4.60(m，4H)，3.84(s，2H)，3.06(s，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-dimethylamino thiophenyl) kharophen urea (62):
Mp247～249℃；EIMSm/z：436[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，2H)，7.81(s，1H)，6.94(m，1H)，5.97～6.07(m，5H)，3.73(s，2H)，3.06(s，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-3-Dimethylaminobenzene amido) kharophen thiocarbamide (63):
Mp257～258℃；EIMSm/z：435[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.63(m，1H)，5.43～5.49(m，2H)，4.45～4.60(m，4H)，3.96～4.09(s，1H)，3.77(s，2H)，3.06(s，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-4-Dimethylaminobenzene amido) kharophen guanidine (64):
Mp249～250℃；EIMSm/z：215[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，2H)，7.81(s，1H)，5.63(m，1H)，5.43～5.49(m，2H)，4.45～4.60(m，4H)，4.21～4.35(s，1H)，3.96～4.09(s，1H)，3.77(s，2H)，3.06(s，6H)，2.51(s，3H)，1.98～2.08(s，1H)。
2-(5-(O-metronidazole-2'-base)-2-diethylin benzyloxy) propionyl hydroxamic acid (65):
Mp263～265℃；EIMSm/z：420[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，1H)，7.81(s，1H)，6.48(m，1H)，6.37(m，1H)，6.24(m，1H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，3.41(m，4H)，2.51～2.79(m，5H)，1.98～2.08(s，1H)，1.15(m，6H)。
2-(5-(O-metronidazole-2'-base)-3-diethylin benzyloxy) propionamido urea (66):
Mp272～274℃；EIMSm/z：462[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，1H)，7.81(s，1H)，6.48(m，1H)，6.37(m，1H)，6.24(m，1H)，5.96～6.03(s，3H)，4.73(m，1H)，4.45～4.60(m，4H)，3.65(s，1H)，3.41(m，4H)，2.51～2.79(m，5H)，1.15(m，6H)。
2-(5-(O-metronidazole-2'-base)-3-diethylaniline phenolic group) kharophen thiocarbamide (67):
Mp276～277℃；EIMSm/z：464[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，1H)，7.81(s，1H)，5.87。(s，2H)，5.71(s，1H)，4.45～4.65(m，6H)，3.41(m，4H)，2.51(s，3H)，1.98～2.08(s，1H)，1.15(m，6H)。
2-(5-(O-metronidazole-2'-base)-3-diethylaniline phenolic group) kharophen guanidine (68):
Mp273～275℃；EIMSm/z：447[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，1H)，7.81(s，1H)，5.87(s，2H)，5.71(s，1H)，4.45～4.65(m，6H)，4.21～4.35(s，1H)，3.41(m，4H)，2.51(s，3H)，1.98～2.08(s，1H)，1.15(m，6H)。
2-(5-(O-metronidazole-2'-base)-3-diethylin thiophenyl) N-acetylhydroxylamine (69):
Mp279～281℃；EIMSm/z：422[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，H)，7.81(s，1H)，6.94(m，H)，6.07(s，1H)，6.01(s，1H)，4.45～4.60(m，4H)，3.84(s，2H)，3.41(m，4H)，2.51(s，3H)，1.98～2.08(s，1H)，1.15(m，6H)。
2-(5-(O-metronidazole-2'-base)-3-diethylin thiophenyl) kharophen urea (70):
Mp233～234℃；EIMSm/z：464[M +]； 1HNMR(400MHz，DMSO，δ)：7.87～8.0(m，H)，7.81(s，1H)，6.94(m，1H)，5.97～6.07(m，5H)，4.45～4.60(m，4H)，3.73(s，1H)，3.41(m，4H)，2.51(s，3H)，1.15(m，6H)。
2-(5-(O-metronidazole-2'-base)-3-diethylin anilino) kharophen thiocarbamide (71):
Mp214～216℃；EIMSm/z：463[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，1H)，7.81(s，1H)，5.63(m，1H)，5.49(m，1H)，5.43(m，1H)，4.45～4.60(m，4H)，3.97～4.03(s，1H)，3.77(s，1H)，3.41(m，4H)，2.51(s，3H)，1.98～2.08(s，1H)，1.15(m，6H)。
2-(5-(O-metronidazole-2'-base)-4-diethylin anilino) kharophen guanidine (72):
Mp284～286℃；EIMSm/z：446[M +]； 1HNMR(400MHz，DMSO，δ)：8.56(s，1H)，7.87～8.0(m，1H)，7.81(s，1H)，5.63(m，1H)，5.49(m，1H)，5.43(m，1H)，4.45～4.60(m，4H)，4.21～4.35(s，1H)，3.97～4.03(s，1H)，3.77(s，1H)，3.41(m，4H)，2.51(s，3H)，1.98～2.08(s，1H)，1.15(m，6H)。

Claims (3)

1. a class aryl connects metronidazole-amide derivatives series compound, it is characterized in that they have following general structure:
Formula imiddle X, Y and Z are defined as:
X=OH、NO 2、Cl、Br、F、OMe、OEt、NMe 2、NEt 2，Y=CHOH、O、S、NH，Z=OH、 、 、 。
2. prepare the method that aryl described in claim 1 connects metronidazole-amide derivatives series compound, it is characterized in that it comprises the following steps:
Step 1. by disubstituted benzenes phenol ( iI), NaOH, ethyl bromoacetate be placed in round-bottomed flask, the ratio of amount of substance: iI: NaOH: ethyl bromoacetate=1:(1 ~ 5): (1 ~ 8) take acetone as solvent, every gram iIadd acetone 7 ~ 20mL, after 50 ~ 80 DEG C of stirring 12 ~ 48h, pour distilled water into, AcOEt extracts, anhydrous MgSO 4drying, boils off solvent, with purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=1:3 ~ 1:10, obtain phenol pendant carboxylic acid ester derivative ( iII);
Step 2. by the pendant carboxylic acid ester derivative of phenol ( iII) be dissolved in anhydrous THF, every gram iIIadd THF8 ~ 20mL, after adding chloro metronidazole, add appropriate Anhydrous potassium carbonate, stir 5 ~ 10h, the ratio of amount of substance is: iII: chloro metronidazole: Anhydrous potassium carbonate=1:(2 ~ 7): (1 ~ 3), boils off THF, adds distilled water, with AcOEt extraction, merges organic layer, MgSO 4drying, boils off solvent, with purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=1:4 ~ 2:1, obtain aryl connect metronidazole-carboxylates derivatives ( iv);
Metronidazole-carboxylates derivatives that aryl connects by step 3. ( iV) be dissolved in anhydrous methanol, every gram iVadd anhydrous methanol 3 ~ 10mL, add HZ, stir 5 ~ 10h, the ratio of amount of substance is: iV: HZ=1:(2 ~ 7), boil off methyl alcohol, adding distil water, with AcOEt extraction, merge organic layer, MgSO 4drying, boils off solvent, with purification by silica gel column chromatography, eluent volume ratio: AcOEt: sherwood oil=1:8 ~ 5:1, obtain aryl connect metronidazole-amide derivatives ( i);
Disubstituted benzenes phenol ( iI), the pendant carboxylic acid ester derivative of phenol ( iII) be connected with aryl metronidazole-carboxylates derivatives ( iv) structure is as follows:
Wherein said X, Y are identical with definition according to claim 1 with the definition of Z.
3. a class aryl according to claim 1 connects metronidazole-amide derivatives series compound and is preparing the application in gastritis, stomach ulcer or anti-lithangiuria medicine.
CN201510751044.2A 2015-11-06 2015-11-06 Aryl connected metronidazole-amide type urease inhibitor, as well as synthesis and application thereof Pending CN105399682A (en)

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