CN109081795A - N- aroylamino thiocarbamide type urease inhibitor and its preparation method and purposes - Google Patents

N- aroylamino thiocarbamide type urease inhibitor and its preparation method and purposes Download PDF

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CN109081795A
CN109081795A CN201811135581.4A CN201811135581A CN109081795A CN 109081795 A CN109081795 A CN 109081795A CN 201811135581 A CN201811135581 A CN 201811135581A CN 109081795 A CN109081795 A CN 109081795A
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thiosemicarbazides
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肖竹平
倪伟伟
何界玲
朱文艳
李芳�
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Jishou University
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    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis

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Abstract

It is a kind ofNAroylamino thiourea compound, they have the following structure general formula:

Description

N- aroylamino thiocarbamide type urease inhibitor and its preparation method and purposes
Technical field
The present invention relates to the preparation method of a kind of N- aroylamino thiocarbamide type urease inhibitor and they preparing anti-stomach Inflammation, anti-gastric-ulcer, the application in anti-lithangiuria drug.
Technical background
Helicobacter pylori (Helicobacter pylari) can cause gastritis, gastric ulcer, duodenal ulcer, stomach and wither A variety of diseases such as contracting, intestinal metaplasia, gastric cancer, gastric lymphoma.The World Health Organization in 1994 and International Cancer Research Center will H. pylori is classified as first kind carcinogen.According to statistics, world population about half has infected H. pylori, in development Infection rate is up to 80-90% in country.The infection rate in China is 60% or so.The H. pylori recall rate of gastritis sufferer is 80- 90%, Peptic Ulcers are higher, up to 95% or more.Duodenal ulcer more than 90% and 80% or so gastric ulcer are H. caused by pylori.Eradicating H. pylori is the above-mentioned disease for the treatment of and the premise for preventing recurrence.H. pylori is eradicated at present The most commonly used is three furnace process: a kind of proton pump inhibitor (Omeprazole or Lansoprazole) and two kinds of antibiotic (Amoxicillins, oxygen Flucloxacillin or metronidazole).But Omeprazole has apparent side effect: in addition to it can cause the side effects such as abdominal pain, vomiting, flatulence, Liver weight increase etc. can also be caused；There are also induce carcinoid of stomach, cause the danger such as renal failure.Furthermore H. pylori is to antibiosis used Element is easy to produce drug resistance, and therefore, the effective percentage of this method just declines year by year.
It is well known that be a strong acid environment in stomach, can survive in stomach main of helicobacter pylori the reason is that it Urease activity.The ammonia that urea enzyme hydrolysis urea releases can improve pH value, and current research is shown, in receptor structure Urea molecule is helicobacter pylori perception and the key factor for avoiding gastric acid environment.Therefore the effect of urease is H. Pylori has built a suitable microenvironment.Some other germ, such as proteus vulgaris (Proteus vulgaris), surprise Different proteus (Proteus mirabilis), ureaplasma urealyticum (Ureaplasma urealyticum) etc., when they are infected After urinary tract system, because the effect of urease causes the pH of urine to increase, lead to the precipitating of the substances such as ammonium magnesium phosphate, and then develop into Lithangiuria.Pathogen with urease activity or ammonia is generated by urea enzyme hydrolysis urea provide for the vital movement of itself Nitrogen source or for its existence a suitable microenvironment is provided using the alkalinity of ammonia.But the release of ammonia will cause cytotoxicity, Cause inflammation or ulcer, also can because caused by excessively high initiations hepatic encephalopathy of blood ammonia etc., furthermore urease itself can by it is immune instead It answers, stimulates the oxidative burst of human neutrophil, generate chlorine ammonia, participate in cellular damage and induce canceration, therefore on urease is State the important virulence factor of pathogenic bacteria.Therefore urease activity has been blocked, it can effectively inhibit even to kill this kind of germ, reach The purpose for treating above-mentioned disease.Meanwhile virulence factor is not as DNA, protein etc., is that bacteria live is essential, Therefore compared with conventional antibiotic, virulence factor bacterium is inhibited to be not easy to develop drug resistance.These superiority show that urease presses down Preparation would be possible to become the first-line drug for treating above-mentioned disease.
It has been reported that the urease inhibitors of various structures types, including phosphoric acid diamide, phenols, quinones, thiocarbamide Class, hydroxamic acid class etc..Phosphoric acid diamide is to have reported in urease inhibitor activity preferably, but unstable in acidic environment It is fixed, hinder its application clinically.Existing thiocarbamide type urease inhibitor could not cause this field because activity is not high The attention of researcher.We are after furtheing investigate the structure of existing thiocarbamide type urease inhibitor and urease activity point, discovery Have all by substituent group on two N atoms of the thiocarbamide segment of thiocarbamide type urease inhibitor, and the active pocket of urease compares It is small, be only capable of accommodate and the much the same segment of urea, thus make existing thiocarbamide type urease inhibitor all cannot well with urine Plain enzyme combines, therefore activity is difficult to improve, and is based on this understanding, we devise in thiocarbamide segment has on only one N atom The new urea enzyme inhibitor of substituent group.
Summary of the invention
Using computer aided drug design technology, according to the principle of specific drug and target spot effect, based on drug point It is complementary between son and target spot, design and synthesize the new urea enzyme inhibitor with structure shown in I.Experiments have shown that all Compound shows excellent inhibitory activity to urease.
It is an object of the invention to design and synthesize a series of N- aroylamino thiocarbamide (I) type urease inhibitors, hair Active higher, the lower new urea enzyme inhibitor of toxic side effect is showed, and N- aroylamino Thiourea series chemical combination is provided The preparation method of object.
Technical scheme is as follows:
A kind of N- aroylamino thiourea, they have the following structure general formula:
In Formulas I, R1、R2、R3、R4And R5Definition be derived from any group of following each group:
(1)R1=R2=R4=R5=H, R3=F, Cl, Br, H, Me, NO2、NH2, CN, OH, OEt or OMe；
(2)R2=R3=R4=R5=H, R1=OMe, F, Cl, Br, Me, Et, NO2、NH2, OEt, CN or OH；
(3)R1=R3=R4=R5=H, R2=OMe, F, Cl, Me, Br, CN, Et, OH, OEt, NH2Or NO2；
(4)R1=R3=R5=H, R2=R4=Cl, Br, Me, OMe, OH, NO2、Et、OEt、CN、NH2Or F；
(5)R3=R4=R5=H, R1=R2=Cl, F, Br, Me, OH, Et, OEt, NH2, CN, OMe or NO2；
(6)R2=R4=R5=H, R1=R3=Cl, Me, OMe, OH, Br, F, NH2, Et, OEt, CN or NO2；
(7)R1=R4=R5=H, R2=R3=F, Cl, Br, OMe, OH, CN, NO2、Et、OEt、NH2Or Me；
(8)R2=R3=R5=H, R1=R4=Cl, F, Br, Me, Et, OEt, OH, CN, OMe, NH2Or NO2；
(9)R2=R3=R4=H, R1=R5=F, Cl, Br, Et, OEt, NH2、OMe、OH、CN、NO2Or Me；It is a kind of to prepare The method of N- aroylamino thiocarbamide series compound, it includes the following steps:
Step 1. takes 2-R1-3-R2-4-R3-5-R4-6-R5Substituted benzoic acid (II) is dissolved into thionyl chloride (III), is stirred Mix heating.The ratio between amount of substance are as follows: 2-R1-3-R2-4-R3-5-R4-6-R5Substituted benzoic acid (II): thionyl chloride (III)=1: (1~10) controls reaction temperature between 80~120 DEG C, reacts 1~2h, cooling, boils off thionyl chloride, adds water, with acetic acid second Ester extracts three times, merges organic phase, washing, anhydrous MgSO4It is dry, boil off solvent, silica gel column chromatography purifying, eluant, eluent volume Than: AcOEt: petroleum ether=1:3~1:9 obtains white solid 2-R1-3-R2-4-R3-5-R4-6-R5Substituted benzoyl chloride (II)；
Step 2 is by 2-R1-3-R2-4-R3-5-R4-6-R5Substituted benzoyl chloride (II) is dissolved in toluene, after thiocarbamide is added, stirring 2~4h, the ratio between amount of substance: 2-R1-3-R2-4-R3-5-R4-6-R5Substituted benzoyl chloride (II): thiocarbamide=1:(1~4), it boils off Toluene adds deionized water, is extracted with AcOEt, merges organic layer, washing, MgSO4It is dry, solvent is boiled off, silica gel column chromatography is pure Change, eluant, eluent volume ratio: AcOEt: petroleum ether=4:1~1:6 obtains N2- (2-R1-3-R2-4-R3-5-R4-6-R5Substituted benzene formyl Base) amido thiocarbamide (I), wherein the R1、R2、R3、R4And R5Definition it is identical as the definition of above-mentioned (I) formula.
N- aroylamino Thiourea series compound of the present invention has preferable inhibitory activity to urease, than sun Property control acetohydroxamic acid activity it is more preferable.It can be used for preparing the drug of gastritis, gastric ulcer or anti-lithangiuria.
Specific embodiment
By following embodiment, present invention be described in more detail, but should be noted that the scope of the present invention is not implemented by these Any restrictions of example.
Embodiment 1:N2- (2,6- dichloro-benzoyl base) thiosemicarbazides (90)
190mg 2 is taken, 6- dichlorobenzoic acid is dissolved into 50mL thionyl chloride, and 1h is stirred at 80 DEG C, and it is cooling, boil off chlorine Change sulfoxide, add water, be extracted with ethyl acetate three times, merges organic phase, washing, anhydrous MgSO4It is dry, boil off solvent, silicagel column Chromatographic purifying, eluant, eluent volume ratio: AcOEt: petroleum ether=1:4 obtains white solid 2,6- dichlorobenzoyl chloride 200mg, yield 97%.2,6- dichlorobenzoyl chloride 120mg is dissolved in 50mL toluene, thiocarbamide 500mg is added with stirring, 2h is stirred at room temperature, boil off After toluene plus 8mL deionized water, AcOEt extraction merge organic layer, washing, anhydrous MgSO4It is dry, boil off solvent, silica gel column layer Analysis purifying, eluant, eluent volume ratio: AcOEt: petroleum ether=1:4 obtains white solid N2- (2,6- dichloro-benzoyl base) thiosemicarbazides (90) 138mg, yield 96%.Fusing point: 159~161 DEG C；EIMS m/z:143 [M+]；1H NMR (400MHz, DMSO, δ): 7.54 (t,1H),7.35(d,2H),6.94(s,2H)。
Embodiment 2:
By the similar method of embodiment 1, the benzoic acid with different substitution forms is raw material, has synthesized table 1,2 table of table, 3 institute The N- aroylamino Thiourea series compound 1~99 of column.
Each R group of 1 general formula I N- aroylamino thiocarbamide series compound of table
Note: initial feed is purchased from aldrich company
Embodiment 3: the Inhibiting enzyme activity of compound
The molten of 25 μ LJack bean (sword bean) ureases (4U) and 25 μ L (1mM) test compounds is added into 96 orifice plates Liquid, cultivates 2h at 37 DEG C, and the 55 μ L of phosphate buffer containing 100mM urea and 100mM is then added, cultivates at 30 DEG C 15min, is added 45 μ L phenol reagents (containing phenol 1% and the mixed solution containing sodium nitroprussiate 0.005%) and 70 μ L base reagents (contain The mixed solution of NaOH0.5% and the NaOCl of 0.1% Active Chlorine), after placing 50min at room temperature, measured with microplate reader OD value under 630nm, percent inhibition are calculated as follows:
All tests all carry out the (K of 0.01M in the solution that pH is 8.22HPO4, the EDTA of 1mM, 0.01M's LiCl), active height is with rate IC half-suppressed50It indicates, IC50Smaller, the activity of this compound is higher, the results are shown in Table 2.
The result shows that: N- aroylamino thiocarbamide series compound in part of the present invention has preferable suppression to urease System activity is higher than the activity of positive control acetohydroxamic acid.
Inhibiting effect (IC of the 2 N- aroylamino Thiourea series compound of table to sword bean urease50)
The result shows that all compounds have significant inhibiting effect to sword bean urease, it is market drug acetohydroxamic acid 150-1400 times.
The above embodiment of the present invention shows: the present invention finds the critical sites of compound Yu urea enzyme effect, significantly mentions The high activity for inhibiting urease, and to the anxious poison experiment of rat show compound 2,5,10,12,14,16,24,25,27, 32,38,41,44,48,61,65,67,77,88,89,98 dosage reach 5g/kg (this dosage be States Pharmacopoeia specifications without toxic agent Amount) when, do not find that rat has signs of toxicity, therefore under normal dose, they are safe as medicinal application.
Fusing point, mass spectrum and the hydrogen modal data of compound 1~99:
N2- (4- fluoro benzoyl) thiosemicarbazides (1):
162~164 DEG C of Mp；EIMS m/z:213 [M+]；1H NMR (400MHz, DMSO, δ): 8.94 (s, 1H), 8.39 (s,1H),7.92–7.84(m,2H),7.31–7.23(m,2H),6.68(s,2H)。
N2- (4- chlorobenzene formacyl) thiosemicarbazides (2):
180~182 DEG C of Mp；EIMS m/z:229 [M+]；1H NMR (400MHz, DMSO, δ): 8.94 (s, 1H), 8.40 (s,1H),7.86–7.79(m,2H),7.59–7.52(m,2H),6.67(s,2H)。
N2- (4- benzoyl bromide) thiosemicarbazides (3):
185~187 DEG C of Mp；EIMS m/z:272 [M+]；1H NMR (400MHz, DMSO, δ): 8.93 (s, 1H), 8.39 (s,1H),7.82–7.75(m,2H),7.67–7.60(m,2H),6.67(s,2H)。
N2- benzoyl-amido thiocarbamide (4):
190~192 DEG C of Mp；EIMS m/z:195 [M+]；1H NMR (400MHz, DMSO, δ): 8.90 (s, 1H), 8.39 (s,1H),7.79–7.73(m,2H),7.38(t,2H),7.35–7.27(m,1H),6.67(s,2H)。
N2- (4- methyl benzoyl) thiosemicarbazides (5):
202~204 DEG C of Mp；EIMS m/z:209 [M+]；1H NMR (400MHz, DMSO, δ): 8.91 (s, 1H), 8.38 (s,1H),7.77–7.70(m,2H),7.30–7.24(m,2H),6.67(s,2H),2.30(s,2H),2.30(d,1H)。
N2- (4- nitro benzoyl) thiosemicarbazides (6):
187~189 DEG C of Mp；EIMS m/z:243 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.37- 8.31(m,2H),8.18–8.09(m,3H),6.84(s,2H)。
N2- (4- methoxybenzoyl base) thiosemicarbazides (7):
212~214 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 8.89 (s, 1H), 8.36 (s,1H),7.90–7.84(m,2H),7.00–6.94(m,2H),6.67(s,2H),3.80(s,3H)。
N2- (4- hydroxy benzoyl) thiosemicarbazides (8):
225~227 DEG C of Mp；EIMS m/z:211 [M+]；1H NMR (400MHz, DMSO, δ): 9.95 (s, 1H), 8.97 (s,1H),8.09(s,1H),7.62–7.55(m,2H),6.89–6.82(m,2H),6.18(s,2H)。
N2- (4- cyanobenzoyl) thiosemicarbazides (9):
175~177 DEG C of Mp；EIMS m/z:220 [M+]；1H NMR (400MHz, DMSO, δ): 8.90 (s, 1H), 8.38 (s,1H),8.10–8.04(m,2H),7.86–7.79(m,2H),6.56(s,2H)。
N2- (4- amido benzoyl) thiosemicarbazides (10):
175~176 DEG C of Mp；EIMS m/z:210 [M+]；1H NMR (400MHz, DMSO, δ): 8.98 (s, 1H), 8.08 (s,1H),7.63–7.56(m,2H),6.60–6.54(m,2H),6.13(s,2H),4.59(s,2H)。
N2- (4- ethoxybenzo) thiosemicarbazides (11):
200~202 DEG C of Mp；EIMS m/z:239 [M+]；1H NMR (400MHz, DMSO, δ): 8.92 (s, 1H), 8.37 (s,1H),7.75–7.69(m,2H),7.01–6.94(m,2H),6.67(s,2H),4.05(q,2H),1.34(t,3H)。
N2- (2- methoxybenzoyl base) thiosemicarbazides (12):
200~202 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.61 (s,1H),7.81(dd,1H),7.42(td,1H),7.05(td,1H),7.00(dd,1H),6.66(s,2H),3.80(s,3H)。
N2- (2- ethoxybenzo) thiosemicarbazides (13):
213~214 DEG C of Mp；EIMS m/z:239 [M+]；1H NMR (400MHz, DMSO, δ): 8.74 (s, 1H), 8.54 (s,1H),7.82(dd,1H),7.50(td,1H),7.09–6.99(m,2H),6.67(s,2H),4.35(q,2H),1.65(t, 3H)。
N2- (2- ethylamino benzonitrile acyl group) thiosemicarbazides (14):
122~124 DEG C of Mp；EIMS m/z:223 [M+]；1H NMR (400MHz, DMSO, δ): 8.75 (s, 1H), 8.13 (s,1H),7.67(dd,1H),7.57(td,1H),7.38(td,1H),7.31(ddt,1H),6.67(s,2H),2.66(qd, 2H),1.14(t,3H)。
N2- (2- fluoro benzoyl) thiosemicarbazides (15):
198~199 DEG C of Mp；EIMS m/z:213 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.63 (s,1H),8.15(ddd,1H),7.55(tdd,2.0Hz,1H),7.28–7.17(m,2H),6.66(s,2H)。
N2- (2- chlorobenzene formacyl) thiosemicarbazides (16):
156~157 DEG C of Mp；EIMS m/z:229 [M+]；H NMR (400MHz, DMSO, δ): 9.26 (s, 1H), 8.95 (s,1H),8.04(dd,1H),7.49(dd,1H),7.43(td,1H),7.27(td,1H),6.66(s,2H)。
N2- (2- benzoyl bromide) thiosemicarbazides (17):
221~222 DEG C of Mp；EIMS m/z:273 [M+]；1H NMR (400MHz, DMSO, δ): 8.99 (s, 1H), 8.87 (s,1H),7.82(dd,1H),7.70(dd,1H),7.37(dtd,2H),6.67(s,2H)。
N2- (2- hydroxy benzoyl) thiosemicarbazides (18):
155~157 DEG C of Mp；EIMS m/z:211 [M+]；1H NMR (400MHz, DMSO, δ): 9.11 (s, 1H), 8.80 (s,1H),7.87(dd,1H),7.43(td,1H),6.98–6.90(m,2H),6.59(s,2H),5.32(s,1H)。
N2- (2- methyl benzoyl) thiosemicarbazides (19):
133~134 DEG C of Mp；EIMS m/z:209 [M+]；1H NMR (400MHz, DMSO, δ): 8.82 (s, 1H), 8.21 (s,1H),7.67(dd,1H),7.46(td,1H),7.42–7.33(m,2H),6.67(s,2H),2.35(d,3H)。
N2- (2- nitro benzoyl) thiosemicarbazides (20):
178~180 DEG C of Mp；EIMS m/z:240 [M+]；1H NMR (400MHz, DMSO, δ): 8.22 (dd, 1H), 8.02 (dd,1H),7.84(td,1H),7.72(td,1H),7.45(s,2H),7.20(s,1H),6.81(s,1H)。
N2- (2- amido benzoyl) thiosemicarbazides (21):
157~158 DEG C of Mp；EIMS m/z:210 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.43 (s,1H),7.59(dd,1H),7.08(td,1H),6.65(dd,1H),6.54(td,1H),6.26(s,2H),4.81(s,2H)。
N2- (2- cyanobenzoyl) thiosemicarbazides (22):
198~200 DEG C of Mp；EIMS m/z:220 [M+]；1H NMR (400MHz, DMSO, δ): 8.68 (s, 1H), 8.11 (s,1H),7.97(dd,1H),7.83(dd,1H),7.70(td,1H),7.60(td,1H),6.67(s,2H)。
N2- (3- methoxybenzoyl base) thiosemicarbazides (23):
156~158 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 8.70 (s, 1H), 8.19 (s,1H),7.45–7.36(m,2H),7.15–7.05(m,2H),6.72(s,2H),3.83(s,3H)。
N2- (3- ethoxybenzo) thiosemicarbazides (24):
142~143 DEG C of Mp；EIMS m/z:239 [M+]；1H NMR (400MHz, DMSO, δ): 8.93 (s, 1H), 8.37 (s,1H),7.41–7.33(m,2H),7.20(q,1H),7.12(ddd,1H),6.67(s,2H),4.11(q,2H),1.34(t, 3H)。
N2- (3- ethylamino benzonitrile acyl group) thiosemicarbazides (25):
175~176 DEG C of Mp；EIMS m/z:223 [M+]；1H NMR (400MHz, DMSO, δ): 8.73 (s, 1H), 8.16 (s,1H),7.59(dt,1H),7.51(tt,1H),7.46–7.39(m,1H),7.32(t,1H),6.68(s,2H),2.32– 2.24(m,2H),1.27(t,3H)。
N2- (3- cyanobenzoyl) thiosemicarbazides (26):
211~212 DEG C of Mp；EIMS m/z:220 [M+]；1H NMR (400MHz, DMSO, δ): 8.88 (s, 1H), 8.37 (s,1H),8.16(t,1H),8.08(dt,1H),7.89(dt,1H),7.58(t,1H),6.68(s,2H)。
N2- (3- hydroxy benzoyl) thiosemicarbazides (27):
135~136 DEG C of Mp；EIMS m/z:211 [M+]；1H NMR (400MHz, DMSO, δ): 9.03 (s, 1H), 8.17 (s,1H),7.34(dt,1H),7.32–7.23(m,2H),6.97(dt,1H),6.17(s,2H),4.87(s,1H)。
N2- (3- amido benzoyl) thiosemicarbazides (28):
213~214 DEG C of Mp；EIMS m/z:210 [M+]；1H NMR (400MHz, DMSO, δ): 8.97 (s, 1H), 8.11 (s,1H),7.21–7.11(m,2H),6.90–6.80(m,2H),6.16(s,2H),4.00(s,2H)。
N2- (3- fluoro benzoyl) thiosemicarbazides (29):
200~202 DEG C of Mp；EIMS m/z:213 [M+]；1H NMR (400MHz, DMSO, δ) 8.86 (s, 1H), 8.39 (s, 1H),7.73(dt,1H),7.64(dt,1H),7.54(td,1H),7.40(ddt,1H),6.67(s,2H)。
N2- (3- nitro benzoyl) thiosemicarbazides (30):
194~195 DEG C of Mp；EIMS m/z:240 [M+]；1H NMR (400MHz, DMSO, δ): 8.83 (s, 1H), 8.52- 8.43(m,2H),8.41(s,1H),8.32(dt,1H),7.65(t,1H),6.68(s,2H)。
N2- (3- methyl benzoyl) thiosemicarbazides (31):
176~178 DEG C of Mp；EIMS m/z:209 [M+]；1H NMR (400MHz, DMSO, δ): 8.88 (s, 1H), 8.38 (s,1H),7.67(dq,1H),7.61(dt,1H),7.45(dtd,1H),7.37(t,1H),6.67(s,2H),2.42(d,3H)。
N2- (3- chlorobenzene formacyl) thiosemicarbazides (32):
154~155 DEG C of Mp；EIMS m/z:229 [M+]；1H NMR (400MHz, DMSO, δ): .86 (s, 1H), 8.39 (s, 1H),7.89(t,1H),7.69(dt,1H),7.63(dt,1H),7.43(t,1H),6.67(s,2H)。
N2- (3- benzoyl bromide) thiosemicarbazides (33):
165~166 DEG C of Mp；EIMS m/z:273 [M+]；1H NMR (400MHz, DMSO, δ): 8.86 (s, 1H), 8.38 (s,1H),7.95(t,1H),7.72(ddt,2H),7.34(t,1H),6.67(s,2H)。
N2- (3,5- dimethylbenzoyl) thiosemicarbazides (34):
176~178 DEG C of Mp；EIMS m/z:223 [M+]；1H NMR (400MHz, DMSO, δ): 8.79 (s, 1H), 8.09 (s,1H),7.55(d,2H),7.44(dt,1H),6.05(s,2H),2.30(s,6H)。
N2- (3,5- diethylbenzene formoxyl) thiosemicarbazides (35):
210~211 DEG C of Mp；EIMS m/z:251 [M+]；1H NMR (400MHz, DMSO, δ): 8.87 (s, 1H), 8.37 (s,1H),7.50(d,2H),7.24(tt,1H),6.67(s,2H),2.32–2.24(m,4H),1.27(t,6H)。
N2- (3,5- diethoxy benzoyl) thiosemicarbazides (36):
145~146 DEG C of Mp；EIMS m/z:283 [M+]；1H NMR (400MHz, DMSO, δ): 8.94 (s, 1H), 8.40 (s,1H),6.93(d,2H),6.67(t,1H),6.34(s,2H),4.08(q,4H),1.34(t,6H)。
N2- (3,5- dicyanobenzenes formoxyl) thiosemicarbazides (37):
188~189 DEG C of Mp；EIMS m/z:245 [M+]；1H NMR (400MHz, DMSO, δ): 8.86 (s, 1H), 8.55 (d,2H),8.38(s,1H),8.18(t,1H),6.69(s,2H)。
N2- (3,5- difluoro benzoyl) thiosemicarbazides (38):
202~203 DEG C of Mp；EIMS m/z:231 [M+]；1H NMR (400MHz, DMSO, δ): 8.89 (s, 1H), 8.39 (s,1H),7.41–7.35(m,2H),7.06(tt,1H),6.53(s,2H)。
N2- (3,5- Dimethoxybenzoyl) thiosemicarbazides (39):
168~170 DEG C of Mp；EIMS m/z:255 [M+]；1H NMR (400MHz, DMSO, δ): 8.70 (s, 1H), 8.23 (s,1H),6.89(d,2H),6.74(s,2H),6.50(t,1H),3.82(s,6H)。
N2- (3,5- dichloro-benzoyl base) thiosemicarbazides (40):
210~212 DEG C of Mp；EIMS m/z:263 [M+]；1H NMR (400MHz, DMSO, δ): 8.87 (s, 1H), 8.39 (s,1H),7.83(d,2H),7.56(t,1H),6.53(s,2H)。
N2- (3,5- dibromo benzoyl) thiosemicarbazides (41):
182~183 DEG C of Mp；EIMS m/z:351 [M+]；1H NMR (400MHz, DMSO, δ): 8.87 (s, 1H), 8.36 (s,1H),7.97(d,2H),7.88(t,1H),6.52(s,2H)。
N2- (3,5- dinitrobenzoyl) thiosemicarbazides (42):
221~223 DEG C of Mp；EIMS m/z:285 [M+]；1H NMR (400MHz, DMSO, δ): 9.11 (d, 2H), 8.98- 8.91(m,2H),8.50(s,1H),6.57(s,2H).。
N2- (3,5- bis- amido benzoyl) thiosemicarbazides (43):
176~177 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 8.92 (s, 1H), 8.40 (s,1H),6.67(s,2H),6.32(d,2H),6.01(t,1H),4.14(s,4H)。
N2- (3,5- dihydroxybenzoyl) thiosemicarbazides (44):
183~184 DEG C of Mp；EIMS m/z:227 [M+]；1H NMR (400MHz, DMSO, δ): 8.88 (s, 1H), 8.39 (s,1H),6.90(d,2H),6.67(s,2H),6.57(s,2H),6.49(t,1H)。
N2- (2,3- dichloro-benzoyl base) thiosemicarbazides (45):
200~202 DEG C of Mp；EIMS m/z:263 [M+]；1H NMR (400MHz, DMSO, δ): 8.93 (d, 2H), 7.84 (dd,1H),7.70(dd,1H),7.29(t,1H),6.52(s,2H)。
N2- (2,3- diethylbenzene formoxyl) thiosemicarbazides (46):
210~212 DEG C of Mp；EIMS m/z:378 [M+]；1H NMR (400MHz, DMSO, δ): 8.69 (s, 1H), 7.98 (s,1H),7.52(dd,1H),7.21(ddt,1H),7.11(t,1H),6.67(s,2H),2.66(q,2H),2.45(qd,2H), 1.16(t,3H),0.99(t,3H)。
N2- (2,3- diethoxy benzoyl) thiosemicarbazides (47):
186~187 DEG C of Mp；EIMS m/z:283 [M+]；1H NMR (400MHz, DMSO, δ): 8.92 (s, 1H), 8.84 (s,1H),7.63(dd,1H),7.32(dd,1H),7.25(t,1H),6.66(s,2H),4.34(q,2H),4.08(q,2H), 1.61(t,3H),1.46(t,3H)。
N2- (2,3- bis- amido benzoyl) thiosemicarbazides (48):
203~204 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 8.72 (s, 1H), 8.65 (s,1H),7.36(dd,1H),6.67(s,2H),6.60–6.51(m,2H),4.35(s,4H)。
N2- (2,3- dimethylbenzoyl) thiosemicarbazides (49):
198~200 DEG C of Mp；EIMS m/z:223 [M+]；1H NMR (400MHz, DMSO, δ): 8.83 (s, 1H), 8.13 (s,1H),7.58(dd,1H),7.30(ddd,1H),7.06(t,1H),6.47(s,2H),2.36–2.28(m,6H)。
N2- (2,3- dicyanobenzenes formoxyl) thiosemicarbazides (50):
190~192 DEG C of Mp；EIMS m/z:245 [M+]；1H NMR (400MHz, DMSO, δ): 8.73 (s, 1H), 8.17 (s,1H),8.06(ddd,2H),7.81(t,1H),6.70(s,2H)。
N2- (2,3- Dimethoxybenzoyl) thiosemicarbazides (51):
188~189 DEG C of Mp；EIMS m/z:255 [M+]；1H NMR (400MHz, DMSO, δ): 8.88 (s, 1H), 8.78 (s,1H),7.60(dd,1H),7.32–7.22(m,2H),6.67(s,2H),3.90(s,3H),3.86(s,3H)。
N2- (2,3- dihydroxybenzoyl) thiosemicarbazides (52):
159~161 DEG C of Mp；EIMS m/z:227 [M+]；1H NMR (400MHz, DMSO, δ): 9.29 (s, 1H), 8.86 (s,1H),7.26(dd,1H),6.91–6.82(m,2H),6.40(s,2H),5.23(s,1H)。
N2- (2,3- dinitrobenzoyl) thiosemicarbazides (53):
169~170 DEG C of Mp；EIMS m/z:285 [M+]；1H NMR (400MHz, DMSO, δ): 8.64 (dd, 1H), 8.54 (d,2H),8.30(dd,1H),7.88(t,1H),6.56(s,2H)。
N2- (2,3- dibromo benzoyl) thiosemicarbazides (54):
185~186 DEG C of Mp；EIMS m/z:351 [M+]；1H NMR (400MHz, DMSO, δ): 8.91 (s, 1H), 8.64 (s,1H),7.72(ddd,2H),7.26(t,1H),6.54(s,2H)。
N2- (2,3- difluoro benzoyl) thiosemicarbazides (55):
175~177 DEG C of Mp；EIMS m/z:231 [M+]；1H NMR (400MHz, DMSO, δ): 8.79 (s, 1H), 8.64 (s,1H),7.91(ddd,1H),7.25(dddd,1H),7.16(td,1H),6.67(s,2H)。
N2- (2,4- dichloro-benzoyl base) thiosemicarbazides (56):
158~160 DEG C of Mp；EIMS m/z:263 [M+]；1H NMR (400MHz, DMSO, δ): 9.09 (s, 1H), 8.84 (s,1H),7.78(d,1H),7.65(d,1H),7.45(dd,1H),6.66(s,2H)。
N2- (2,4- difluoro benzoyl) thiosemicarbazides (57):
203~204 DEG C of Mp；EIMS m/z:231 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.61 (s,1H),8.13(dt,1H),7.11(td,1H),7.05(ddd,1H),6.67(s,2H)。
N2- (2,4- diethoxy benzoyl) thiosemicarbazides (58):
190~192 DEG C of Mp；EIMS m/z:283 [M+]；1H NMR (400MHz, DMSO, δ): 8.85 (s, 1H), 8.53 (s,1H),8.07(d,1H),6.72(s,2H),6.75–6.69(m,1H),6.62(d,1H),4.39(q,2H),4.05(q, 2H),1.65(t,3H),1.34(t,3H)。
N2- (2,4- diethylbenzene formoxyl) thiosemicarbazides (59):
157~158 DEG C of Mp；EIMS m/z:251 [M+]；1H NMR (400MHz, DMSO, δ): 8.76 (s, 1H), 8.05 (s,1H),7.62(d,1H),7.22(ddt,1H),7.16(dt,1H),6.67(s,2H),2.66(qd,2H),2.32–2.24 (m,2H),1.27(t,3H),1.07(t,3H)。
N2- (2,4- dicyanobenzenes formoxyl) thiosemicarbazides (60):
232~234 DEG C of Mp；EIMS m/z:245 [M+]；1H NMR (400MHz, DMSO, δ): 8.72 (s, 1H), 8.17 (s,1H),8.12–8.05(m,2H),8.02(dd,1H),6.69(s,2H).。
N2- (2,4- bis- amido benzoyl) thiosemicarbazides (61):
223~224 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 9.01 (s, 1H), 8.55 (s,1H),7.72(d,1H),6.67(s,2H),6.21(dd,1H),6.04(d,1H),4.24(s,2H),3.91(s,2H)。
N2- (2,4- dihydroxybenzoyl) thiosemicarbazides (62):
204~205 DEG C of Mp；EIMS m/z:227 [M+]；1H NMR (400MHz, DMSO, δ): 8.85 (s, 1H), 8.34 (s,1H),7.36(d,1H),7.00(s,1H),6.67(s,2H),6.48(dd,1H),6.38(d,1H)。
N2- (2,4- dinitrobenzoyl) thiosemicarbazides (63):
215~216 DEG C of Mp；EIMS m/z:285 [M+]；1H NMR (400MHz, DMSO, δ): 8.70-8.66 (m, 2H), 8.57(dd,1H),8.31(s,1H),8.23(d,1H),6.46(s,2H)。
N2- (2,4- dimethylbenzoyl) thiosemicarbazides (64):
205~206 DEG C of Mp；EIMS m/z:223 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 7.88 (s,1H),7.65(d,1H),7.11–7.03(m,2H),6.09(s,2H),2.38–2.32(m,6H)。
N2- (2,4- dibromo benzoyl) thiosemicarbazides (65):
187~189 DEG C of Mp；EIMS m/z:351 [M+]；1H NMR (400MHz, DMSO, δ): 9.05 (s, 1H), 8.95 (s,1H),7.84(d,1H),7.70(d,1H),7.54(dd,1H),6.66(s,2H)。。
N2- (2,4- Dimethoxybenzoyl) thiosemicarbazides (66):
236~237 DEG C of Mp；EIMS m/z:255 [M+]；1H NMR (400MHz, DMSO, δ): 8.83 (s, 1H), 8.63 (s,1H),8.09–8.04(m,1H),6.66–6.60(m,1H),6.62(s,1H),6.50(s,2H),3.92(s,3H),3.78 (s,3H)。
N2- (3,4- dichloro-benzoyl base) thiosemicarbazides (67):
198~199 DEG C of Mp；EIMS m/z:263 [M+]；1H NMR (400MHz, DMSO, δ): 8.90 (s, 1H), 8.38 (s,1H),8.16(d,1H),7.92(dd,1H),7.69(d,1H),6.54(s,2H)。
N2- (3,4- diethoxy benzoyl) thiosemicarbazides (68):
Mp178~179 DEG C；EIMS m/z:283 [M+]；1H NMR (400MHz, DMSO, δ): 8.82 (s, 1H), 8.16 (s, 1H),7.67(d,1H),7.40(dd,1H),7.21(d,1H),6.08(s,2H),4.06(dq,4H),1.46(t,6H)。
N2- (3,4- diethylbenzene formoxyl) thiosemicarbazides (69):
201~202 DEG C of Mp；EIMS m/z:251 [M+]；1H NMR (400MHz, DMSO, δ): 8.92 (s, 1H), 8.38 (s,1H),7.68(dd,1H),7.53(dd,1H),7.29(dd,1H),6.61(s,2H),2.45(qd,4H),1.18(q,6H)。
N2- (3,4- dibromo benzoyl) thiosemicarbazides (70):
175~176 DEG C of Mp；EIMS m/z:351 [M+]；1H NMR (400MHz, DMSO, δ): 8.94 (s, 1H), 8.39 (s,1H),8.06(d,1H),7.73(dd,1H),7.58(d,1H),6.52(s,2H)。
N2- (3,4- dinitrobenzoyl) thiosemicarbazides (71):
186~188 DEG C of Mp；EIMS m/z:285 [M+]；1H NMR (400MHz, DMSO, δ): 8.88 (s, 1H), 8.79 (d,1H),8.38(s,1H),8.40–8.34(m,1H),8.24(d,1H),6.45(s,2H)。
N2- (3,4- dimethylbenzoyl) thiosemicarbazides (72):
187~189 DEG C of Mp；EIMS m/z:223 [M+]；1H NMR (400MHz, DMSO, δ): 8.91 (s, 1H), 8.37 (s,1H),7.65(dd,1H),7.47(dd,1H),7.15(dd,1H),6.52(s,2H),2.33(dd,6H)。
N2- (3,4- difluoro benzoyl) thiosemicarbazides (73):
196~197 DEG C of Mp；EIMS m/z:231 [M+]；1H NMR (400MHz, DMSO, δ): 8.90 (s, 1H), 8.37 (s,1H),7.68–7.56(m,2H),7.16(ddd,1H),6.56(s,2H)。
N2- (3,4- dihydroxybenzoyl) thiosemicarbazides (74):
168~170 DEG C of Mp；EIMS m/z:227 [M+]；1H NMR (400MHz, DMSO, δ): 8.83 (s, 1H), 8.30 (s,1H),7.26–7.18(m,2H),6.75(d,1H),6.67(s,2H),5.94(s,1H),5.32(s,1H)。
N2- (3,4- Dimethoxybenzoyl) thiosemicarbazides (75):
223~224 DEG C of Mp；EIMS m/z:255 [M+]；1H NMR (400MHz, DMSO, δ): 8.90 (s, 1H), 8.34 (s,1H),7.57(dd,1H),7.51(d,1H),6.99(d,1H),6.67(s,2H),3.89(d,6H)。
N2- (3,4- bis- amido benzoyl) thiosemicarbazides (76):
252~254 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 8.86 (s, 1H), 8.03 (s,1H),6.96(dd,1H),6.82(s,2H),6.69(d,1H),6.50(d,1H),4.35(s,4H)。
N2- (3,4- dicyanobenzenes formoxyl) thiosemicarbazides (77):
232~234 DEG C of Mp；EIMS m/z:245 [M+]；1H NMR (400MHz, DMSO, δ): 8.82 (s, 1H), 8.46 (dd,1H),8.35(s,1H),8.20(d,1H),7.98(d,1H),6.69(s,2H)。
N2- (2,5- difluoro benzoyl) thiosemicarbazides (78):
194~185 DEG C of Mp；EIMS m/z:231 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.65 (s, 1H), 7.87 (ddd, J=9.0,5.7,2.0Hz, 1H), 7.35-7.21 (m, 2H), 6.67 (s, 2H).
N2- (2,5- dichloro-benzoyl base) thiosemicarbazides (79):
186~188 DEG C of Mp；EIMS m/z:263 [M+]；1H NMR (400MHz, DMSO, δ): 9.07 (s, 1H), 8.85 (s,1H),8.12(d,1H),7.59(dd,1H),7.53(d,1H),6.65(s,2H)。
N2- (2,5- dibromo benzoyl) thiosemicarbazides (80):
192~194 DEG C of Mp；EIMS m/z:351 [M+]；1H NMR (400MHz, DMSO, δ): 8.99 (s, 1H), 8.81 (s,1H),8.03(d,1H),7.62–7.53(m,2H),6.62(s,2H)。
N2- (2,5- dimethylbenzoyl) thiosemicarbazides (81):
165~166 DEG C of Mp；EIMS m/z:223 [M+]；1H NMR (400MHz, DMSO, δ): 8.86 (s, 1H), 8.20 (s,1H),7.41(dd,1H),7.30(ddd,1H),7.24(dd,1H),6.36(s,2H),2.35(d,3H),2.30(s,2H), 2.30(d,1H)。
N2- (2,5- diethoxy benzoyl) thiosemicarbazides (82):
175~176 DEG C of Mp；EIMS m/z:283 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.54 (s,1H),7.76(d,1H),7.02(dd,1H),6.96(d,1H),6.52(s,2H),4.35(q,2H),4.11(q,2H), 1.65(t,3H),1.34(t,3H)。
N2- (2,5- diethylbenzene formoxyl) thiosemicarbazides (83):
192~194 DEG C of Mp；EIMS m/z:251 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.07 (s,1H),7.50(dt,1H),7.30(dt,1H),7.23(ddt,1H),6.67(s,2H),2.66(qd,2H),2.32–2.24 (m,2H),1.27(t,3H),1.12(t,3H)。
N2- (2,5- Dimethoxybenzoyl) thiosemicarbazides (84):
158~160 DEG C of Mp；EIMS m/z:255 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.67 (s,1H),7.72(d,1H),7.05(dd,1H),6.94(d,1H),6.66(s,2H),3.82(d,6H)。
N2- (2,5- bis- amido benzoyl) thiosemicarbazides (85):
175~176 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 8.11 (s, 1H), 7.85 (s,1H),6.75(d,1H),6.59–6.49(m,2H),6.53(s,2H),4.89(s,2H),4.00(s,2H)。
N2- (2,5- dicyanobenzenes formoxyl) thiosemicarbazides (86):
178~179 DEG C of Mp；EIMS m/z:231 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.65 (s,1H),7.87(ddd,1H),7.35–7.21(m,2H),6.67(s,2H)。
N2- (2,5- dinitrobenzoyl) thiosemicarbazides (87):
196~197 DEG C of Mp；EIMS m/z:285 [M+]；1H NMR (400MHz, DMSO, δ): 8.90 (d, 1H), 8.79 (s,1H),8.51(dd,1H),8.44(s,1H),8.17(d,1H),6.50(s,2H)。
N2- (2,5- dihydroxybenzoyl) thiosemicarbazides (88):
196~198 DEG C of Mp；EIMS m/z:227 [M+]；1H NMR (400MHz, DMSO, δ): 9.04 (s, 1H), 8.76 (s,1H),7.52(d,1H),6.88(dd,1H),6.79(d,1H),6.67(s,2H),5.24(s,1H),4.54(s,1H)。
N2- (2,6- difluoro benzoyl) thiosemicarbazides (89):
186~188 DEG C of Mp；EIMS m/z:231 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.65 (s,1H),7.87(ddd,1H),7.35–7.21(m,2H),6.67(s,2H)。
N2- (2,6- dichloro-benzoyl base) thiosemicarbazides (90):
175~177 DEG C of Mp；EIMS m/z:231 [M+]；1H NMR (400MHz, DMSO, δ): 9.07 (s, 1H), 8.85 (s,1H),8.12(d,1H),7.59(dd,1H),7.53(d,1H),6.65(s,2H)。
N2- (2,6- dibromo benzoyl) thiosemicarbazides (91):
189~191 DEG C of Mp；EIMS m/z:351 [M+]；1H NMR (400MHz, DMSO, δ): 8.99 (s, 1H), 8.81 (s,1H),8.03(d,1H),7.62–7.53(m,2H),6.62(s,2H)。
N2- (2,6- dihydroxybenzoyl) thiosemicarbazides (92):
164~166 DEG C of Mp；EIMS m/z:227 [M+]；1H NMR (400MHz, DMSO, δ): 9.04 (s, 1H), 8.76 (s,1H),7.52(d,1H),6.88(dd,1H),6.79(d,1H),6.67(s,2H),5.24(s,1H),4.54(s,1H)。
N2- (2,6- dicyanobenzenes formoxyl) thiosemicarbazides (93):
173~175 DEG C of Mp；EIMS m/z:245 [M+]；1H NMR (400MHz, DMSO, δ): 8.72 (s, 1H), 8.26- 8.21(m,1H),8.17(s,1H),8.00(d,2H),6.68(s,2H)。
N2- (2,6- Dimethoxybenzoyl) thiosemicarbazides (94):
196~198 DEG C of Mp；EIMS m/z:255 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.67 (s,1H),7.72(d,1H),7.05(dd,1H),6.94(d,1H),6.66(s,2H),3.82(d,6H)。
N2- (2,6- dimethylbenzoyl) thiosemicarbazides (95):
168~170 DEG C of Mp；EIMS m/z:223 [M+]；1H NMR (400MHz, DMSO, δ): 8.86 (s, 1H), 8.20 (s,1H),7.41(dd,1H),7.30(ddd,1H),7.24(dd,1H),6.36(s,2H),2.35(d,3H),2.30(s,2H), 2.30(d,1H).。
N2- (2,6- diethoxy benzoyl) thiosemicarbazides (96):
193~194 DEG C of Mp；EIMS m/z:283 [M+]；1H NMR (400MHz, DMSO, δ): 8.76 (s, 1H), 8.55 (s,1H),7.73(d,1H),7.08(dd,1H),6.94(d,1H),6.67(s,2H),4.35(q,2H),4.11(q,2H), 1.65(t,3H),1.34(t,3H)。
N2- (2,6- diethylbenzene formoxyl) thiosemicarbazides (97):
177~178 DEG C of Mp；EIMS m/z:251 [M+]；1H NMR (400MHz, DMSO, δ): 8.80 (s, 1H), 8.07 (s,1H),7.50(dt,1H),7.30(dt,1H),7.23(ddt,1H),6.67(s,2H),2.66(qd,2H),2.32–2.24 (m,2H),1.27(t,3H),1.12(t,3H)。
N2- (2,6- dinitrobenzoyl) thiosemicarbazides (98):
166~168 DEG C of Mp；EIMS m/z:285 [M+]；1H NMR (400MHz, DMSO, δ): 8.91 (d, 1H), 8.75 (s,1H),8.51(dd,1H),8.46(s,1H),8.17(d,1H),6.66(s,2H)。
N2- (2,6- bis- amido benzoyl) thiosemicarbazides (99):
186~188 DEG C of Mp；EIMS m/z:225 [M+]；1H NMR (400MHz, DMSO, δ): 8.11 (s, 1H), 7.85 (s,1H),6.75(d,1H),6.59–6.49(m,2H),6.53(s,2H),4.89(s,2H),4.00(s,2H)。

Claims (3)

1. a kind ofNAroylamino thiourea compound, it is characterized in that they have the following structure general formula:
In Formulas I, R1、R2、R3、R4And R5Definition be derived from any group of following each group:
(1) R1=R2=R4=R5=H, R3=F、Cl、Br、H、Me、NO2、NH2, CN, OH, OEt or OMe；
(2) R2=R3=R4=R5=H, R1=OMe、F、Cl、Br、Me、Et、NO2、NH2, OEt, CN or OH；
(3) R1=R3=R4=R5=H, R2=OMe、F、Cl、Me、Br、CN、Et、OH、OEt、NH2Or NO2；
(4) R1=R3=R5=H, R2=R4=Cl、Br、Me、OMe、OH、NO2、Et、OEt、CN、NH2Or F；
(5) R3=R4=R5=H, R1=R2=Cl、F、Br、Me、OH、Et、OEt、NH2, CN, OMe or NO2；
(6) R2=R4=R5=H, R1=R3=Cl、Me、OMe、OH、Br、F、NH2, Et, OEt, CN or NO2；
(7) R1=R4=R5=H, R2=R3=F、Cl、Br、OMe、OH、CN、NO2、Et、OEt、NH2Or Me；
(8) R2=R3=R5=H, R1=R4=Cl、F、Br、Me、Et、OEt、OH、CN、OMe、NH2Or NO2；
(9) R2=R3=R4=H, R1=R5=F、Cl、Br、Et、OEt、NH2、OMe、OH、CN、NO2Or Me.
2. it is a kind of prepare it is described in claim 1NThe method of aroylamino thiocarbamide series compound, it is characterized in that: it is under Column step composition:
Step 1: taking 2-R1-3-R2-4-R3-5-R4-6-R5Substituted benzoic acid (II) is dissolved into thionyl chloride (III), and stirring adds Heat, the ratio between amount of substance are as follows: 2-R1-3-R2-4-R3-5-R4-6-R5Substituted benzoic acid (II): thionyl chloride (III)=1:(1~ 10), control reaction temperature reacts 1 ~ 2h between 80 ~ 120 DEG C, cooling, boils off thionyl chloride, adds water, is extracted with ethyl acetate Three times, merge organic phase, washing, anhydrous MgSO4It is dry, solvent is boiled off, silica gel column chromatography purifies, eluant, eluent volume ratio: AcOEt: petroleum ether=1:3~1:9 obtains white solid 2- R1-3-R2-4-R3-5-R4-6-R5 Substituted benzoyl chloride (II)；
Step 2: by 2- R1-3-R2-4-R3-5-R4-6-R5 Substituted benzoyl chloride (II) is dissolved in toluene, after thiocarbamide is added, stirring 2 ~4h, the ratio between amount of substance: 2- R1-3-R2-4-R3-5-R4-6-R5Substituted benzoyl chloride (II): thiocarbamide=1:(1~4), it boils off Toluene adds deionized water, is extracted with AcOEt, merges organic layer, washing, MgSO4It is dry, solvent is boiled off, silica gel column chromatography is pure Change, eluant, eluent volume ratio: AcOEt: petroleum ether=4:1~1:6 obtainsN2-(2- R1-3-R2-4-R3-5-R4-6-R5Substituted benzene formyl Base) amido thiocarbamide (I), wherein the R1、R2、R3、R4And R5Definition it is identical as the definition of above-mentioned (I) formula.
3. described in claim 1NAroylamino thiocarbamide series compound is preparing gastritis, gastric ulcer or anti-urinary tract knot Application in stone drug.
CN201811135581.4A 2018-09-28 2018-09-28 N- aroylamino thiocarbamide type urease inhibitor and its preparation method and purposes Pending CN109081795A (en)

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