CN108047090B - Aniline hydroxamic acid urease inhibitor and preparation method and application thereof - Google Patents

Aniline hydroxamic acid urease inhibitor and preparation method and application thereof Download PDF

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CN108047090B
CN108047090B CN201711356498.5A CN201711356498A CN108047090B CN 108047090 B CN108047090 B CN 108047090B CN 201711356498 A CN201711356498 A CN 201711356498A CN 108047090 B CN108047090 B CN 108047090B
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肖竹平
刘琦
倪伟伟
陈慧敏
刘佳佳
贺小素
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Jishou University
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Abstract

An aniline hydroxamic acid compound has the following structural general formula:

Description

Aniline hydroxamic acid urease inhibitor and preparation method and application thereof
Technical Field
The invention relates to a preparation method of aniline urease inhibitors and application of the aniline urease inhibitors in preparation of anti-gastritis, anti-gastric ulcer and anti-lithangiuria medicines.
Technical Field
Helicobacter pylori (Helicobacter pylori) causes various diseases such as gastritis, gastric ulcer, duodenal ulcer, gastric atrophy, intestinal metaplasia, gastric cancer, gastric lymphoma and the like. H.pyrori is listed as the first class of carcinogenic factor by the world health organization and the international center for cancer research in 1994. It is statistical that approximately half of the world population is infected with h.pyrori, with infection rates as high as 80-90% in developing countries. The infection rate of China is about 60%. The detection rate of H.pyrori of gastritis patients is 80-90%, and that of peptic ulcer patients is higher, and reaches more than 95%. More than 90% of duodenal ulcers and around 80% of gastric ulcers are caused by h. Eradication of h. pyri is a prerequisite to the treatment of the above-mentioned diseases and to the prevention of relapse. Currently, the most common method for eradicating h.pyri is the triple method: a proton pump inhibitor (omeprazole or lansoprazole) and two antibiotics (amoxicillin, ofloxacin or metronidazole). However, omeprazole has significant side effects: it can cause abdominal pain, emesis, flatulence and other side effects, and can also cause the weight of the liver to increase; it also induces gastric carcinoid and renal failure. Furthermore, H.pyri is susceptible to resistance to the antibiotics used, and therefore, the effectiveness of this approach is decreasing year by year.
It is well known that the stomach is a strongly acidic environment, and the most important reason for the survival of H.pylori in the stomach is its urease activity. The pH value of the ammonia released by the urea hydrolyzed by the urease can be improved, and the latest research shows that urea molecules in the receptor structure are the key factors for sensing the helicobacter pylori and avoiding the gastric acid environment. The action of urease creates a suitable microenvironment for h. Other pathogens, such as Proteus vulgaris (Proteus vulgaris), Proteus mirabilis (Proteus mirabilis), Ureaplasma urealyticum (Ureapalasma urealyticum), etc., when they infect the urinary tract, they cause the pH of urine to rise due to the action of urease, resulting in precipitation of magnesium ammonium phosphate, etc., and then develop into urinary calculi. The pathogenic bacteria with urease activity either hydrolyze urea by urease to generate ammonia to provide nitrogen source for own vital activities or provide a proper microenvironment for the existence of the pathogenic bacteria by using the alkalinity of the ammonia. However, the release of ammonia can cause cytotoxicity, inflammation or ulcer, and also can cause hepatic encephalopathy and the like due to hyperammonemia, and in addition, urease can stimulate the oxidation burst of human neutrophils through immune reaction to generate ammonia chloride, participate in cell damage and induce canceration, so that the urease is an important virulence factor of the pathogenic bacteria. Therefore, the urease activity is blocked, and the germs can be effectively inhibited and even killed, so that the aim of treating the diseases is fulfilled. Meanwhile, virulence factors are not essential for the survival of bacteria like DNA, proteins, etc., and therefore, compared to antibiotics, bacteria that inhibit virulence factors are less likely to develop resistance to drugs. These advantages indicate that urease inhibitors would likely be first line agents for the treatment of the above-mentioned diseases.
Urease inhibitors of various structural types have been reported, including phosphodiamides, phenols, quinones, thioureas, hydroxamates, and the like. Phosphoric acid diamides are reported to have the best activity in urease inhibitors, but are unstable in an acidic environment, which hinders clinical application of the phosphoric acid diamides. Other activity spectrumThe hydroxamic acid has good chelation effect on nickel ions of the urease active center, so that extensive research is initiated, and a clinical drug, namely, dimethachlon (acetohydroxamic acid, A) is developed, and the hydroxamic acid is the only urease inhibitor on the market at present, but has low activity and high dosage, so that side effects are caused. However, the urease inhibitor is a urease inhibitor which is worthy of being deeply researched, and the key and difficulty of research is to find a proper R group (B) so that the inhibitor can be combined with urease more strongly. Numerous studies have been carried out in the search for R groups, with some progress (C-G, CN 201210590437.6, Eur.J.Med.chem.2013,68, 212-221; CN 201210590535. X; CN 201210590630. X; CN 201210589812.5; CN 201210590652.6) to obtain some IC50Novel urease inhibitors up to 86 nM. These studies revealed that simple electronic isostere replacement as if the eye were closed for targeting did not work well, and good results could only be obtained based on complementary binding of the drug molecule to the target. However, designing appropriate R groups to act on specific regions of urease is a challenging and inventive task. Based on the thought, the invention discovers that hetero atoms are introduced between the aryl and the hydroxamic acid group, and can form hydrogen bonds with amino acid residues of active points, thereby remarkably improving the activity of the inhibitor.
Figure BDA0001511190460000021
Disclosure of Invention
A novel urease inhibitor with a structure shown as I is designed and synthesized by a computer-aided drug design technology according to the principle of action of a specific drug and a target spot and on the basis of complementarity between a drug molecule and the target spot. Experiments show that all the compounds show excellent inhibitory activity on urease.
Figure BDA0001511190460000031
The invention aims to design and synthesize a series of aniline (I) urease inhibitors, find a novel urease inhibitor with higher activity and lower toxic and side effects, and provide a preparation method of aniline hydroxamic acid compounds.
The technical scheme of the invention is as follows:
an aniline hydroxamic acid compound has the following structural general formula:
Figure BDA0001511190460000032
when n is 1 in formula I, R1、R2、R3、R4And R5Is taken from any one of the following groups:
(1)R1＝R2＝R4＝R5＝H，R3f, Cl, Br, H, Me or OMe;
(2)R2＝R3＝R4＝R5＝H，R1OMe, Cl or Br;
(3)R1＝R3＝R4＝R5＝H，R2OMe, Cl, Br or NO2；
(4)R1＝R3＝R5＝H，R2＝R4Me, OMe, Cl or F;
(5)R3＝R4＝R5＝H，R1＝R2cl, F, Me, OMe, or Br;
(6)R2＝R4＝R5＝H，R1＝R3cl, Me, Br or NO2；
(7)R1＝R4＝R5＝H，R2＝R3＝Cl、Br、NO2Or Me;
(8)R2＝R3＝R5＝H，R1＝R4cl or Br;
(9)R2＝R3＝R4＝H，R1＝R5cl or Me;
in the formula IWhen n is 2, R1、R2、R3、R4And R5Is taken from any one of the following groups:
(10)R1＝R2＝R4＝R5＝H，R3h, F or NO2；
(11)R2＝R3＝R4＝R5＝H，R1OMe, Cl, Br or NO2；
(12)R1＝R3＝R4＝R5＝H，R2＝NO2Br, H or Me;
(13)R1＝R3＝R5＝H，R2＝R4cl, Me or F;
(14)R3＝R4＝R5＝H，R1＝R2cl, Br or Me;
(15)R2＝R4＝R5＝H，R1＝R3cl, Me or Br;
(16)R1＝R4＝R5＝H，R2＝R3＝Cl、NO2or OMe;
(17)R2＝R3＝R5＝H，R1＝R4cl or OMe;
(18)R2＝R3＝R4＝H，R1＝R5cl or Br;
a method for preparing aniline hydroxamic acid series compounds comprises the following steps:
step 1, taking 2-R1-3-R2-4-R3-5-R4-6-R5Dissolving substituted aniline (III) in anhydrous tetrahydrofuran, stirring for 10min, adding bromocarboxylic acid ethyl ester (IV) and anhydrous K2CO3The ratio of the amounts of the substances is: 2-R1-3-R2-4-R3-5-R4-6-R5Substituted anilines (III), bromocarboxylic acid ethyl esters (IV), anhydrous K2CO31, (1-3) and (2-36), controlling the reaction temperature to be 40-80 ℃,reacting for 6-48 h, cooling, evaporating tetrahydrofuran, adding water, extracting for three times by using ethyl acetate, combining organic phases, washing by using water, and carrying out anhydrous MgSO4Drying, evaporating the solvent, purifying by silica gel column chromatography, and eluting with the following solvents in volume ratio: AcOEt, petroleum ether is 1: 3-1: 10, and white solid 2-R is obtained1-3-R2-4-R3-5-R4-6-R5Substituted phenylaminocarboxylic acid ethyl ester (II);
Figure BDA0001511190460000041
step 2, 2-R1-3-R2-4-R3-5-R4-6-R5Dissolving substituted phenylamino carboxylic acid ethyl ester (II) in anhydrous methanol, adding CH3NHOH HCl and sodium methoxide, and stirring for 10-35 h, wherein the mass ratio of the substances is as follows: 2-R1-3-R2-4-R3-5-R4-6-R5Substituted phenylaminocarboxylic acid ethyl ester (II): NH2OH·HCl:CH3(1-4) to (2-8), evaporating methanol, adding deionized water, extracting with AcOEt, combining organic layers, washing with water, and MgSO4Drying, evaporating the solvent, purifying by silica gel column chromatography, and eluting with the following solvents in volume ratio: AcOEt is 4: 1-1: 6 petroleum ether, and 2-R is obtained1-3-R2-4-R3-5-R4-6-R5Substituted phenylaminocarboxylic hydroxamic acids (I) wherein R is as defined1、R2、R3、R4And R5The definition of (A) is the same as that of the above formula (I).
Figure BDA0001511190460000042
The aniline hydroxamic acid series compounds have better inhibitory activity on urease, and have better activity than positive control acetylhydroxamic acid. Can be used for preparing medicine for resisting gastritis, gastric ulcer or lithangiuria.
Detailed Description
The present invention is further illustrated in detail by the following examples, but it should be noted that the scope of the present invention is not limited by these examples at all.
Example 1: 2- (4-Chlorobenzen-1-ylamino) acetoxyhydroxamic acid (10)
Dissolving 635mg of parachloroaniline in 15mL of anhydrous tetrahydrofuran, stirring for 10min, and adding 1.7mL of ethyl bromoacetate and anhydrous K2CO32.76g, stirring at 60 deg.C for 12h and cooling, evaporating off tetrahydrofuran, adding water, extracting with ethyl acetate three times, combining the organic phases, washing with water, anhydrous MgSO4Drying, evaporating the solvent, purifying by silica gel column chromatography, and eluting with the following solvents in volume ratio: AcOEt petroleum ether 1:6, to give 1.05g of ethyl 2- (4-chlorobenzen-1-ylamino) carboxylate as a white solid in 92% yield. 228mg of ethyl 2- (4-chlorobenzen-1-ylamino) carboxylate was dissolved in 5mL of anhydrous methanol, and NH was added thereto with stirring2OH·HCl 278mg、CH3ONa432mg, stirring at room temperature for 19h, evaporating methanol, adding 8mL deionized water, extracting with AcOEt, combining organic layers, washing with water, anhydrous MgSO4Drying, evaporating the solvent, purifying by silica gel column chromatography, and eluting with the following solvents in volume ratio: AcOEt Petroleum Ether 1:2 gave 150mg of 2- (4-chlorobenzen-1-ylamino) acetoxyhydroxamic acid (10) as a white solid in 75% yield. Melting point: 175-176 ℃; EIMS m/z: 200[ M ]+]；1H NMR(400MHz，DMSO，)： 10.09(s，1H)，8.67(s，1H)，7.28(d，2H)，6.58(d，2H)，3.75(d，2H)，4.92(t， 1H)。
3- (2-Chlorobenzen-1-ylamino) propionyloxyoxime acid (38)
Dissolving 635mg of o-chloroaniline into 15mL of anhydrous tetrahydrofuran, stirring for 10min, adding 1.96mL of ethyl 3-bromopropionate and anhydrous K2CO32.76g, stirring at 70 deg.C for 24h and cooling, spinning off tetrahydrofuran, adding water, extracting with ethyl acetate three times, combining the organic phases, washing with water, anhydrous MgSO4Drying, evaporating the solvent, purifying by silica gel column chromatography, and eluting with the following solvents in volume ratio: AcOEt petroleum ether 1:8, to give 1.1g of ethyl 3- (2-chlorobenzen-1-ylamino) propionate as a white solid in 90% yield. 275mg of ethyl 3- (2-chlorobenzen-1-ylamino) propionate was dissolved in 5mL of anhydrous methanol, and NH was added thereto with stirring2OH·HCl 278mg、CH3ONa432mg, stirring at room temperature for 28h, evaporating methanol, adding 8mL deionized water, AcOEt extracting, combining organic layers, washing with water, drying with anhydrous MgSO4, evaporating solvent, purifying by silica gel column chromatography, eluting the solventProduct ratio: AcOEt Petroleum Ether 1:3 to give 175mg of 3- (2-chlorobenzen-1-ylamino) propionyloxyhydroxamic acid (38) as a white solid in 72% yield. Melting point: 202-203 ℃; EIMS m/z: 213[ M ]+]；1H NMR(400MHz，DMSO，)： 10.16(s，1H)，8.67(s，1H)，7.46(d，1H)，7.15(t，1H)，6.95(d，1H)，6.73(t， 1H)，3.43(t，2H)，2.62(t，2H)，4.94(t，1H)。
Example 2:
aniline hydroxamic acid series compounds 1 to 61 listed in tables 1 and 2 were synthesized by a method similar to that in example 1 using anilines of different substitution forms as raw materials.
TABLE 1 respective R groups of anilines hydroxamic acid series compounds with general formula I where n ═ 1
Figure BDA0001511190460000061
Figure BDA0001511190460000071
TABLE 2 respective R groups of anilines hydroxamic acid series compounds with general formula I where n ═ 2
Figure BDA0001511190460000072
Figure BDA0001511190460000081
Note: the starting materials were all purchased from aldrich
Example 3: enzyme inhibiting activity of compound
A solution of 25. mu.L of Jack bean urease (4U) and 25. mu.L (1mM) of the compound to be detected was added to a 96-well plate, incubated at 37 ℃ for 2 hours, then 55. mu.L of a phosphate buffer containing 100mM urea and 100mM was added, incubated at 30 ℃ for 15 minutes, 45. mu.L of a phenol reagent (a mixed solution of phenol 1% and sodium nitroprusside 0.005%) and 70. mu.L of an alkali reagent (a mixed solution of NaOCl containing NaOH0.5% and active chlorine 0.1%) were added, and after standing at room temperature for 50 minutes, the OD at 630nm was measured with a microplate reader, and the percentage inhibition was calculated by the following formula:
Figure BDA0001511190460000082
all experiments were carried out in a solution of pH 8.2 (0.01M K)2HPO41mM EDTA, 0.01M LiCl), the level of activity and the half-inhibition ratio IC50To represent, IC50The smaller the activity of this compound, the higher the results are shown in Table 3.
The results show that: the partial aniline hydroxamic acid series compounds have better inhibitory activity on urease, and the activity of some of the aniline hydroxamic acid series compounds is higher than that of positive control acetylhydroxamic acid.
TABLE 3 Inhibition of Canavalise (IC) by anilines hydroxamic acid compounds50)
Figure BDA0001511190460000083
Figure BDA0001511190460000091
Figure BDA0001511190460000101
The results show that all the compounds have remarkable inhibitory effect on canavalise, and the urease inhibitory activity (IC) of the class is reported5086nM) which is 1000 times that of the commercial drug acetohydroxamic acid (600-.
The above embodiments of the invention show: the invention finds a key site of the compound acting with urease, obviously improves the activity of inhibiting the urease, and acute toxicity experiments on rats show that when the dosage of the compounds 2, 10, 16, 23, 29, 35, 38, 39, 42, 48, 51, 58 and 60 reaches 5g/kg (the dosage is a nontoxic dosage specified by pharmacopoeia), no toxic sign of rats is found, so that the compounds are safe to be applied as medicaments under normal dosage.
Melting point, mass spectrum and hydrogen spectrum data of compounds 1-61:
2- (4-fluorophen-1-ylamino) acetoxyhydroxamic acid (1):
Mp 162～164℃；EIMS m/z：184[M+]；1H NMR(400MHz，DMSO，)：10.42(s， 1H)，8.84(s，1H)，7.06(d，2H)，7.01(d，2H)，3.75(d，2H)，4.96(t，1H)。
2- (3, 5-dimethylbenzen-1-ylamino) acetoxy acid (2):
Mp 180～182℃；EIMS m/z：194[M+]；1H NMR(400MHz，DMSO，)：10.35(s， 1H)，8.81(s，1H)，6.68(d，1H)，6.35(d，2H)，3.79(d，2H)，2.36(s，6H)， 4.95(t，1H)。
2- (2-methoxybenzen-1-ylamino) acetoxyhydroxamic acid (3):
Mp 190～192℃；EIMS m/z：197[M+]；1H NMR(400MHz，DMSO，)：10.36(s， 1H)，8.75(s，1H)，7.02(d，1H)，6.88(d，1H)，6.80(t，1H)，6.68(t，1H)， 3.85(s，3H)，3.75(d，2H)，4.95(t，1H)。
2- (3-methoxybenzen-1-ylamino) acetoxyhydroxamic acid (4):
Mp 185～187℃；EIMS m/z：197[M+]；1H NMR(400MHz，DMSO，)：10.39(s， 1H)，8.73(s，1H)，7.12(t，1H)，6.40(d，1H)，6.34(d，1H)，6.17(s，1H)， 3.84(s，3H)，3.78(d，2H)，4.98(t，1H)。
2- (3, 5-dimethoxyphen-1-ylamino) acetoxyhydroxamic acid (5):
Mp 202～204℃；EIMS m/z：227[M+]；1H NMR(400MHz，DMSO，)：10.35(s，1H)， 8.76(s，1H)，5.63(s，1H)，5.71(d，2H)，3.85(s，6H)，3.78(d，2H)，4.94(t， 1H)。
2- (2, 3-dichlorophen-1-ylamino) acetoxyhydroxamic acid (6):
Mp 187～189℃；EIMS m/z：234[M+]；1H NMR(400MHz，DMSO，)：10.39(s，1H)， 8.64(s，1H)，7.15(d，1H)，7.07(t，1H)，6.88(d，1H)，3.78(d，2H)，4.96(t， 1H)。
2- (2, 4-dichlorobenzene-1-ylamino) acetoxyhydroxamic acid (7):
Mp 212～214℃；EIMS m/z：235[M+]；1H NMR(400MHz，DMSO，)：10.47(s，1H)， 8.85(s，1H)，7.84(s，1H)，7.17(d，1H)，6.45(d，1H)，3.79(d，2H)，4.92(t， 1H)。
2- (3, 4-dichlorobenzene-1-ylamino) acetoxyhydroxamic acid (8):
Mp 225～227℃；EIMS m/z：236[M+]；1H NMR(400MHz，DMSO，)：10.31(s， 1H)，8.70(s，1H)，7.35(d，1H)，6.95(s，1H)，6.74(d，1H)，3.74(d，2H)， 4.95(t，1H)。
2- (3-chlorobenzen-1-ylamino) acetoxyhydroxamic acid (9):
Mp 175～177℃；EIMS m/z：201[M+]；1H NMR(400MHz，DMSO，)：10.48(s， 1H)，8.76(s，1H)，7.19(t，1H)，6.84(d，1H)，6.75(s，1H)，6.72(d，1H)，3.72 (d，2H)，4.91(t，1H)。
2- (4-chlorobenzen-1-ylamino) acetoxyhydroxamic acid (10):
Mp 175～176℃；EIMS m/z：200[M+]；1H NMR(400MHz，DMSO，)：10.09(s， 1H)，8.67(s，1H)，7.28(d，2H)，6.58(d，2H)，3.75(d，2H)，4.92(t，1H)。
2- (3-bromobenzen-1-ylamino) acetohydroxamic acid (11):
Mp 200～202℃；EIMS m/z：246[M+]；1H NMR(400MHz，DMSO，)：10.45(s， 1H)，8.62(s，1H)，6.98(t，1H)，6.95(d，1H)，6.79(d，1H)，6.67(s，1H)，3.72 (d，2H)，4.91(t，1H)。
2- (4-bromobenzen-1-ylamino) acetohydroxamic acid (12):
Mp 200～202℃；EIMS m/z：245[M+]；1H NMR(400MHz，DMSO，)：10.44(s， 1H)，8.65(s，1H)，7.14(d，2H)，6.56(d，2H)，3.73(d，2H)，4.91(t，1H)。
2- (3, 5-dichlorobenzene-1-ylamino) acetoxyhydroxamic acid (13):
Mp 213～214℃；EIMS m/z：235[M+]；1H NMR(400MHz，DMSO，)：10.36(s， 1H)，8.71(s，1H)，7.04(s，1H)，6.68(s，2H)，3.78(d，2H)，4.96(t，1H)。
2- (3-Nitrobenzene-1-ylamino) acetoxyhydroxamic acid (14):
Mp 122～124℃；EIMS m/z：212[M+]；1H NMR(400MHz，DMSO，)：10.39(s， 1H)，8.78(s，1H)，7.58(d，1H)，7.52(s，1H)，7.48(t，1H)，7.24(d，1H)，3.75 (d，2H)，4.93(t，1H)。
2- (2, 5-dichlorobenzene-1-ylamino) acetoxyhydroxamic acid (15):
Mp 198～199℃；EIMS m/z：234[M+]；1H NMR(400MHz，DMSO，)：10.21(s， 1H)，8.52(s，1H)，7.31(d，1H)，7.08(d，1H)，6.75(s，1H)，3.71(d，2H)， 4.95(t，1H)。
2- (1-phen-1-ylamino) acetohydroxamic acid (16):
Mp 156～157℃；EIMS m/z：166[M+]；H NMR(400MHz，DMSO，)：10.41(s，1H)， 8.75(s，1H)，7.25(t，2H)，6.85(d，2H)，6.78(t，1H)，3.73(d，2H)，4.96(t， 1H)。
2- (2, 6-dichlorobenzene-1-ylamino) acetoxyhydroxamic acid (17):
Mp 221～222℃；EIMS m/z：235[M+]；1H NMR(400MHz，DMSO，)：10.43(s，1H)， 8.75(s，1H)，7.33(d，2H)，6.99(t，1H)，3.71(d，2H)，4.96(t，1H)。
2- (3, 5-difluorophen-1-ylamino) acetohydroxamic acid (18):
Mp 155～157℃；EIMS m/z：201[M+]；1H NMR(400MHz，DMSO，)：10.32(s， 1H)，8.74(s，1H)，6.35(s，2H)，6.02(s，1H)，3.78(d，2H)，4.92(t，1H)。
2- (4-methylbenz-1-ylamino) acetoxyhydroxamic acid (19):
Mp 133～134℃；EIMS m/z：181[M+]；1H NMR(400MHz，DMSO，)：10.37(s，1H)， 8.73(s，1H)，7.05(d，2H)，6.45(d，2H)，3.74(d，2H)，2.35(s，3H)，4.95(t， 1H)。
2- (4-methoxybenz-1-ylamino) acetoxy-hydroxamic acid (20):
Mp 178～180℃；EIMS m/z：195[M+]；1H NMR(400MHz，DMSO，)：10.33(s，1H)，8.75(s，1H)，6.78(d，4H)，3.85(s，3H)，3.75(d，2H)，4.93(t，1H)。
2- (2-chlorobenzen-1-ylamino) acetoxyhydroxamic acid (21):
Mp 157～158℃；EIMS m/z：199[M+]；1H NMR(400MHz，DMSO，)：10.23(s， 1H)，8.66(s，1H)，7.46(d，1H)，7.13(t，1H)，6.93(d，1H)，6.75(t，1H)，3.73 (d，2H)，4.91(t，1H)。
2- (2-bromobenz-1-ylamino) acetohydroxamic acid (22):
Mp 198～200℃；EIMS m/z：244[M+]；1H NMR(400MHz，DMSO，)：10.34(s， 1H)，8.78(s，1H)，7.55(d，1H)，7.19(t，1H)，6.68(t，1H)，6.47(d，1H)，3.72 (d，2H)，4.99(t，1H)。
2- (2, 3-difluorophen-1-ylamino) acetohydroxamic acid (23):
Mp 156～158℃；EIMS m/z：203[M+]；1H NMR(400MHz，DMSO，)：10.32(s， 1H)，8.72(s，1H)，6.95(t，1H)，6.55(t，1H)，6.37(d，1H)，3.73(d，2H)，4.93 (t，1H)。
2- (2, 3-dimethylbenzen-1-ylamino) acetoxy hydroxamic acid (24):
Mp 142～143℃；EIMS m/z：194[M+]；1H NMR(400MHz，DMSO，)：10.29(s， 1H)，8.68(s，1H)，6.95(t，1H)，6.70(d，1H)，6.45(d，1H)，2.35(s，3H)，2.10 (s，3H)，3.77(d，2H)，4.96(t，1H)。
2- (2, 3-dimethoxyphen-1-ylamino) acetoxyhydroxamic acid (25):
Mp 175～176℃；EIMS m/z：226[M+]；1H NMR(400MHz，DMSO，)：10.30(s， 1H)，8.59(s，1H)，6.69(t，1H)，6.56(d，1H)，6.19(d，1H)，3.83(s，3H)，3.81 (s，3H)，3.75(d，2H)，4.96(t，1H)。
2- (2, 3-dibromophen-1-ylamino) acetohydroxamic acid (26):
Mp 211～212℃；EIMS m/z：324[M+]；1H NMR(400MHz，DMSO，)：10.31(s， 1H)，8.62(s，1H)，6.95(t，1H)，6.84(d，1H)，6.44(d，1H)，3.71(d，2H)，4.99 (t，1H)。
2- (2, 4-dimethylbenzen-1-ylamino) acetoxy hydroxamic acid (27):
Mp 135～136℃；EIMS m/z：195[M+]；1H NMR(400MHz，DMSO，)：10.40(s， 1H)，8.53(s，1H)，6.89(d，1H)，6.85(s，1H)，6.33(d，1H)，2.32(s，3H)，2.12 (s，3H)，3.65(d，2H)，4.91(t，1H)。
2- (2, 4-dibromophen-1-ylamino) acetohydroxamic acid (28):
Mp 213～214℃；EIMS m/z：324[M+]；1H NMR(400MHz，DMSO，)：10.45(s， 1H)，8.67(s，1H)，7.78(s，1H)，7.34(d，1H)，6.35(d，1H)，3.71(d，2H)， 4.93(t，1H)。
2- (2, 4-dinitrophen-1-ylamino) acetoxyhydroxamic acid (29):
Mp 200～202℃；EIMS m/z：256[M+]；1H NMR(400MHz，DMSO，)：10.48(s， 1H)，8.55(s，1H)，8.89(s，1H)，8.45(d，1H)，7.29(d，1H)，3.73(d，2H)， 4.98(t，1H)。
2- (3, 4-dibromophen-1-ylamino) acetohydroxamic acid (30):
Mp 194～195℃；EIMS m/z：323[M+]；1H NMR(400MHz，DMSO，)：10.45(s， 1H)，8.39(s，1H)，7.28(d，1H)，6.55(d，1H)，6.49(d，1H)，3.69(d，2H)， 4.88(t，1H)。
2- (3, 4-dinitrophen-1-ylamino) acetohydroxamic acid (31):
Mp 176～178℃；EIMS m/z：257[M+]；1H NMR(400MHz，DMSO，)：10.43(s， 1H)，8.45(s，1H)，8.35(d，1H)，7.76(S，1H)，7.15(d，1H)，3.79(d，2H)， 4.89(t，1H)。
2- (3, 4-dimethylbenzen-1-ylamino) acetoxy hydroxamic acid (32):
Mp 154～155℃；EIMS m/z：195[M+]；1H NMR(400MHz，DMSO，)：10.39(s， 1H)，8.55(s，1H)，6.88(d，1H)，6.43(S，1H)，6.30(d，1H)，2.33(s，3H)， 2.31(s，3H)，3.65(d，2H)，4.93(t，1H)。
2- (2, 5-dibromophen-1-ylamino) acetohydroxamic acid (33):
Mp 165～166℃；EIMS m/z：324[M+]；1H NMR(400MHz，DMSO，)：10.33(s， 1H)，8.47(s，1H)，7.28(d，1H)，6.83(d，1H)，6.57(s，1H)，3.75(d，2H)， 4.97(t，1H)。
2- (2, 5-dimethylbenzen-1-ylamino) acetoxy acid (34):
Mp 176～178℃；EIMS m/z：195[M+]；1H NMR(400MHz，DMSO，)：10.39(s， 1H)，8.55(s，1H)，6.90(d，1H)，6.72(s，1H)，6.45(d，1H)，2.35(s，3H)，2.10 (s，3H)，3.75(d，2H)，4.97(t，1H)。
2- (3, 5-dichlorobenzene-1-ylamino) propionyloxyoxime acid (35):
Mp 210～211℃；EIMS m/z：249[M+]；1H NMR(400MHz，DMSO，)：10.26(s， 1H)，8.58(s，1H)，7.03(s，1H)，6.58(s，2H)，3.48(t，2H)，2.67(t，2H)，4.90 (t，1H)。
3- (1-phen-1-ylamino) propionyloxyoxime acid (36):
Mp 145～146℃；EIMS m/z：182[M+]；1H NMR(400MHz，DMSO，)：10.19(s， 1H)，8.87(s，1H)，7.25(t，2H)，6.72(t，1H)，6.55(d，2H)，3.43(t，2H)，2.65 (t，2H)，4.93(t，1H)。
3- (2-methoxybenz-1-ylamino) propionyloxyoxime acid (37):
Mp 188～189℃；EIMS m/z：211[M+]；1H NMR(400MHz，DMSO，)：10.24(s，1H)， 8.56(s，1H)，7.08(d，1H)，6.88(d，1H)，6.75(t，1H)，6.65(t，4H)，3.48(t， 2H)，2.59(t，2H)，4.90(t，1H)。
3- (2-Chlorobenzen-1-ylamino) propionyloxyoxime acid (38):
Mp 202～203℃；EIMS m/z：213[M+]；1H NMR(400MHz，DMSO，)：10.16(s，1H)， 8.67(s，1H)，7.46(d，1H)，7.15(t，1H)，6.95(d，1H)，6.73(t，1H)，3.43(t， 2H)，2.62(t，2H)，4.94(t，1H)。
3- (4-fluorophen-1-ylamino) propionyloxyoxime acid (39):
Mp 168～170℃；EIMS m/z：198[M+]；1H NMR(400MHz，DMSO，)：10.37(s， 1H)，8.73(s，1H)，7.06(d，2H)，7.01(d，2H)，3.47(t，2H)，2.64(t，2H)，4.92 (t，1H)。
3- (2-bromobenz-1-ylamino) propionyloxyoxime acid (40):
Mp 210～212℃；EIMS m/z：258[M+]；1H NMR(400MHz，DMSO，)：10.46(s， 1H)，8.72(s，1H)，7.55(d，1H)，7.20(t，1H)，6.68(t，1H)，6.45(d，1H)，3.44 (t，2H)，2.61(t，2H)，4.98(t，1H)。
3- (3, 5-dimethylbenzen-1-ylamino) propionyloxyoxime acid (41):
Mp 182～183℃；EIMS m/z：208[M+]；1H NMR(400MHz，DMSO，)：10.05(s， 1H)，8.56(s，1H)，6.70(s，1H)，6.35(s，2H)，3.46(t，2H)，2.60(t，2H)，2.35 (s，6H)，4.92(t，1H)。
3- (2, 5-dichlorobenzene-1-ylamino) propionyloxyoxime acid (42):
Mp 221～223℃；EIMS m/z：248[M+]；1H NMR(400MHz，DMSO，)：10.26(s，1H)，8.92(s，1H)，7.37(d，1H)，7.08(d，1H)，6.75(s，1H)，3.42(t，2H)，2.63 (t，2H)，4.95(t，1H)。
3- (3, 4-dichlorobenzene-1-ylamino) propionyloxyoxime acid (43):
Mp 155～156℃；EIMS m/z：248[M+]；1H NMR(400MHz，DMSO，)：10.20(s， 1H)，8.85(s，1H)，7.35(d，1H)，6.94(s，1H)，6.45(d，1H)，3.45(t，2H)，2.60 (t，2H)，4.90(t，1H)。
3- (2, 6-dichlorobenzene-1-ylamino) propionyloxyoxime acid (44):
Mp 176～177℃；EIMS m/z：250[M+]；1H NMR(400MHz，DMSO，)：10.21(s，1H)， 8.70(s，1H)，7.35(d，2H)，6.95(t，1H)，3.41(t，2H)，2.64(t，2H)，4.95(t， 1H)。
3- (4-Nitrobenzene-1-ylamino) propionyloxyoxime acid (45):
Mp 183～184℃；EIMS m/z：225[M+]；1H NMR(400MHz，DMSO，)：10.55(s， 1H)，8.67(s，1H)，8.08(d，2H)，6.75(d，2H)，3.45(t，2H)，2.59(t，2H)，4.90 (t，1H)。
3- (3-nitrophenyl-1-ylamino) propionyloxyoxime acid (46):
Mp 200～202℃；EIMS m/z：225[M+]；1H NMR(400MHz，DMSO，)：10.34(s， 1H)，8.57(s，1H)，7.55(d，1H)，7.50(s，1H)，7.43(t，1H)，7.20(d，1H)，3.42 (t，2H)，2.54(t，2H)，4.93(t，1H)。
3- (2-Nitrobenzene-1-ylamino) propionyloxyoxime acid (47):
Mp 186～187℃；EIMS m/z：224[M+]；1H NMR(400MHz，DMSO，)：10.32(s，1H)， 8.65(s，1H)，8.07(d，1H)，7.65(t，1H)，7.38(d，1H)，7.34(t，1H)，3.45(t， 2H)，2.51(t，2H)，4.98(t，1H)。
3- (2, 4-dichlorobenzene-1-ylamino) propionyloxyoxime acid (48):
Mp 203～204℃；EIMS m/z：250[M+]；1H NMR(400MHz，DMSO，)：10.43(s，1H)， 8.62(s，1H)，7.85(s，1H)，7.13(d，1H)，6.50(d，1H)，3.41(t，2H)，2.50(t， 2H)，4.93(t，1H)。
3- (2, 3-dichlorophen-1-ylamino) propionyloxyoxime acid (49):
Mp 198～200℃；EIMS m/z：249[M+]；1H NMR(400MHz，DMSO，)：10.23(s，1H)， 8.68(s，1H)，7.14(d，1H)，7.02(t，1H)，6.85(d，1H)，3.42(t，2H)，2.57(t， 2H)，4.94(t，1H)。
3- (3, 5-difluorophen-1-ylamino) propionyloxyoxime acid (50):
Mp 190～192℃；EIMS m/z：216[M+]；1H NMR(400MHz，DMSO，)：10.34(s，1H)， 8.77(s，1H)，6.36(S，2H)，6.02(S，1H)，3.41(t，2H)，2.54(t，2H)，4.90(t， 1H)。
3- (3, 5-difluorophen-1-ylamino) propionyloxyoxime acid (51):
Mp 188～189℃；EIMS m/z：259[M+]；1H NMR(400MHz，DMSO，)：10.40(s，1H)， 8.65(s，1H)，6.98(t，1H)，6.93(d，1H)，6.75(d，1H)，6.63(s，1H)，3.50(t， 2H)，2.64(t，2H)，4.90(t，1H)。
3- (1-phen-1-ylamino) propionyloxyoxime acid (52):
Mp 159～161℃；EIMS m/z：181[M+]；1H NMR(400MHz，DMSO，)：10.45(s，1H)， 8.85(s，1H)，7.24(t，2H)，6.59(d，2H)，6.78(t，1H)，3.47(t，2H)，2.66(t， 2H)，4.91(t，1H)。
3- (3-methylbenzen-1-ylamino) propionyloxyoxime acid (53):
Mp 169～170℃；EIMS m/z：195[M+]；1H NMR(400MHz，DMSO，)：10.48(s，1H)， 8.81(s，1H)，7.15(t，1H)，6.59(d，1H)，6.54(s，1H)，6.34(d，1H)，3.47(t， 2H)，2.66(t，2H)，2.35(s，3H)，4.91(t，1H)。
3- (2, 3-dibromophen-1-ylamino) propionyloxyoxime acid (54):
Mp 185～186℃；EIMS m/z：338[M+]；1H NMR(400MHz，DMSO，)：10.42(s，1H)， 8.85(s，1H)，6.93(t，1H)，6.80(d，1H)，6.45(d，1H)，3.45(t，2H)，2.59(t， 2H)，4.94(t，1H)。
3- (2, 3-dimethylbenzen-1-ylamino) propionyloxyoxime acid (55):
Mp 175～177℃；EIMS m/z：208[M+]；1H NMR(400MHz，DMSO，)：10.43(s，1H)， 8.79(s，1H)，6.95(t，1H)，6.70(d，1H)，6.41(d，1H)，3.45(t，2H)，2.59(t， 2H)，2.32(s，3H)，2.11(s，3H)，4.97(t，1H)。
3- (2, 4-dimethylbenzen-1-ylamino) propionyloxyoxime acid (56):
Mp 158～160℃；EIMS m/z：207[M+]；1H NMR(400MHz，DMSO，)：10.46(s，1H)， 8.81(s，1H)，6.88(s，1H)，6.83(d，1H)，6.35(d，1H)，3.45(t，2H)，2.59(t， 2H)，2.32(s，3H)，2.12(s，3H)，4.92(t，1H)。
3- (2, 4-dibromophen-1-ylamino) propionyloxyoxime acid (57):
Mp 203～204℃；EIMS m/z：338[M+]；1H NMR(400MHz，DMSO，)：10.41(s，1H)， 8.80(s，1H)，7.75(s，1H)，7.35(d，1H)，6.40(d，1H)，3.41(t，2H)，2.60(t， 2H)，4.97(t，1H)。
3- (3, 4-dinitrophen-1-ylamino) propionyloxyoxime acid (58):
Mp 190～192℃；EIMS m/z：271[M+]；1H NMR(400MHz，DMSO，)：10.45(s，1H)， 8.84(s，1H)，7.80(s，1H)，8.32(d，1H)，7.12(d，1H)，3.43(t，2H)，2.66(t， 2H)，4.93(t，1H)。
3- (3, 4-dimethoxyphen-1-ylamino) propionyloxyoxime acid (59):
Mp 157～158℃；EIMS m/z：240[M+]；1H NMR(400MHz，DMSO，)：10.41(s，1H)， 8.76(s，1H)，6.65(d，1H)，6.35(d，1H)，6.01(s，1H)，3.47(t，2H)，3.83(s， 3H)，3.82(s，3H)，2.63(t，2H)，4.95(t，1H)。
3- (2, 5-dimethoxyphen-1-ylamino) propionyloxyoxime acid (60):
Mp 187～189℃；EIMS m/z：240[M+]；1H NMR(400MHz，DMSO，)：10.44(s，1H)， 8.81(s，1H)，6.85(d，1H)，6.24(d，1H)，6.03(s，1H)，3.48(t，2H)，3.83(s， 3H)，3.81(s，3H)，2.67(t，2H)，4.93(t，1H)。
3- (2, 6-dibromophen-1-ylamino) propionyloxyoxime acid (61):
Mp 215～216℃；EIMS m/z：337[M+]；1H NMR(400MHz，DMSO，)：10.45(s，1H)， 8.88(s，1H)，7.56(d，2H)，6.25(t，1H)，3.44(t，2H)，2.65(t，2H)，4.93(t， 1H)。

Claims (3)

1. the aniline hydroxamic acid compounds are characterized by having the following structural general formula:
Figure FDA0002539490860000011
when n is 1 in formula I, R1、R2、R3、R4And R5Is taken from any one of the following groups:
(1)R2＝R3＝R4＝R5＝H，R1OMe or Br;
(2)R1＝R3＝R4＝R5＝H，R2OMe, Br or NO2；
(3)R1＝R3＝R5＝H，R2＝R4Me, OMe, Cl or F;
(4)R3＝R4＝R5＝H，R1＝R2cl, F, OMe or Br;
(5)R2＝R4＝R5＝H，R1＝R3br or NO2；
(6)R1＝R4＝R5＝H，R2＝R3＝Br、NO2Or Me;
(7)R2＝R3＝R5＝H，R1＝R4＝Br；
(8)R2＝R3＝R4＝H，R1＝R5＝Cl；
when n is 2 in formula I, R1、R2、R3、R4And R5Is taken from any one of the following groups:
(9)R1＝R2＝R4＝R5＝H，R3h, F or NO2；
(10)R2＝R3＝R4＝R5＝H，R1Cl or Br;
(11)R1＝R3＝R4＝R5＝H，R2＝NO2br, H or Me;
(12)R1＝R3＝R5＝H，R2＝R4cl or F;
(13)R3＝R4＝R5＝H，R1＝R2cl, Br or Me;
(14)R2＝R4＝R5＝H，R1＝R3cl, Me or Br;
(15)R1＝R4＝R5＝H，R2＝R3＝Cl、NO2or OMe;
(16)R2＝R3＝R5＝H，R1＝R4cl or OMe;
(17)R2＝R3＝R4＝H，R1＝R5either Cl or Br.
2. A process for preparing the anilinic hydroxamic acid compounds of claim 1, characterized in that: it comprises the following steps:
step 1, taking 2-R1-3-R2-4-R3-5-R4-6-R5Dissolving substituted aniline (III) in anhydrous tetrahydrofuran, stirring for 10min, adding bromocarboxylic acid ethyl ester (IV) and anhydrous K2CO3The ratio of the amounts of the substances is: 2-R1-3-R2-4-R3-5-R4-6-R5Substituted anilines (III), bromocarboxylic acid ethyl esters (IV), anhydrous K2CO3(1-3) and (2-36), reacting for 6-48 h at the reaction temperature of 40-80 ℃, cooling, evaporating tetrahydrofuran, adding water, extracting with ethyl acetate for three times, combining organic phases, washing with water, and anhydrous MgSO4Drying, evaporating the solvent, purifying by silica gel column chromatography, and eluting with the following solvents in volume ratio: AcOEt, petroleum ether is 1: 3-1: 10, and white solid 2-R is obtained1-3-R2-4-R3-5-R4-6-R5Substituted phenylaminocarboxylic acid ethyl ester (II);
step 2, 2-R1-3-R2-4-R3-5-R4-6-R5Dissolving substituted phenylamino carboxylic acid ethyl ester (II) in absolute methanol, adding NH2OH, HCl and sodium methoxide are stirred for 10 to 35 hours, and the substancesThe ratio of the amounts of: 2-R1-3-R2-4-R3-5-R4-6-R5Substituted phenylaminocarboxylic acid ethyl ester (II): NH2OH·HCl:CH3(1-4) to (2-8), evaporating methanol, adding deionized water, extracting with AcOEt, combining organic layers, washing with water, and MgSO4Drying, evaporating the solvent, purifying by silica gel column chromatography, and eluting with the following solvents in volume ratio: AcOEt is 4: 1-1: 6 petroleum ether, and 2-R is obtained1-3-R2-4-R3-5-R4-6-R5Substituted phenylaminocarboxylic hydroxamic acids (I) wherein R is as defined1、R2、R3、R4And R5The definition of (A) is the same as that of the above formula (I);
the structural general formulas of the formula (II), the formula (III) and the formula (IV) are as follows:
Figure FDA0002539490860000021
3. the use of the aniline hydroxamic acid series compounds according to claim 1 in the preparation of anti-gastritis, gastric ulcer or anti-lithangiuria medicaments.
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