CN109081794A - N- virtue acetyl-amino thiocarbamide type urease inhibitor and its preparation method and purposes - Google Patents

N- virtue acetyl-amino thiocarbamide type urease inhibitor and its preparation method and purposes Download PDF

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CN109081794A
CN109081794A CN201811135623.4A CN201811135623A CN109081794A CN 109081794 A CN109081794 A CN 109081794A CN 201811135623 A CN201811135623 A CN 201811135623A CN 109081794 A CN109081794 A CN 109081794A
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thiosemicarbazides
eims
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肖竹平
倪伟伟
李芳�
朱文艳
邹霞
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Jishou University
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    • C07—ORGANIC CHEMISTRY
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    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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    • C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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 ofNFragrant acetyl-amino thiourea compound, they have the following structure general formula:

Description

N- virtue acetyl-amino 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- virtue acetyl-amino thiocarbamide type urease inhibitor and they are anti-in preparation Gastritis, 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 China Infection rate is up to 80-90% in family.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 Caused by H.pylori.Eradicating H.pylori is the above-mentioned disease for the treatment of and the premise for preventing recurrence.Eradicate H.pylori most 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 fluorine Husky star or metronidazole).But Omeprazole has apparent side effect: in addition to it can cause the side effects such as abdominal pain, vomiting, flatulence, also It can cause liver weight increase etc.；There are also induce carcinoid of stomach, cause the danger such as renal failure.Furthermore H.pylori holds antibiotic used It is also easy to produce drug resistance, 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 A suitable microenvironment is built.Some other germ, such as proteus vulgaris (Proteus vulgaris), unusual deformation Bacillus (Proteus mirabilis), ureaplasma urealyticum (Ureaplasma urealyticum) etc., when they infect urinary tract system After 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 urinary tract knot Stone.Pathogen with urease activity or ammonia generated by urea enzyme hydrolysis urea provide nitrogen source for the vital movement of itself, A suitable microenvironment is provided using the alkalinity of ammonia for its existence.But the release of ammonia will cause cytotoxicity, cause Inflammation or ulcer, also can because caused by excessively high initiation hepatic encephalopathy of blood ammonia etc., furthermore urease itself can pass through immune response, thorn Swash the oxidative burst of human neutrophil, generate chlorine ammonia, participate in cellular damage and induce canceration, therefore urease is above-mentioned causes a disease The important virulence factor of bacterium.Therefore urease activity has been blocked, it can effectively inhibit even to kill this kind of germ, reach in treatment State the purpose of disease.Meanwhile virulence factor is that bacteria live is essential not as DNA, protein etc., therefore with Conventional antibiotic is compared, and virulence factor bacterium is inhibited to be not easy to develop drug resistance.These superiority show that urease inhibitor will It is likely 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- virtue acetyl-amino thiocarbamide (I) type urease inhibitors, It has found active higher, the lower new urea enzyme inhibitor of toxic side effect, and N- virtue acetyl-amino Thiourea series is provided The preparation method of compound.
Technical scheme is as follows:
A kind of N- virtue acetyl-amino 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- virtue acetyl-amino thiocarbamide series compound, it includes the following steps:
Step 1. takes 2-R1-3-R2-4-R3-5-R4-6-R5Substituted phenylacetic 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 phenylacetic 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-R5Replace phenyllacetyl chloride (II)；
Step 2. is by 2-R1-3-R2-4-R3-5-R4-6-R5Replace phenyllacetyl chloride (II) to be dissolved in toluene, after thiocarbamide is added, stirs Mix the ratio between 2~4h, the amount of substance: 2-R1-3-R2-4-R3-5-R4-6-R5Replace phenyllacetyl chloride (II): thiocarbamide=1:(1~4), it steams Toluene is removed, deionized water is added, is extracted with AcOEt, organic layer, washing, MgSO are merged4It 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-R5Replace phenylacetyl Base) thiosemicarbazides (I), wherein the R1、R2、R3、R4And R5Definition it is identical as the definition of above-mentioned (I) formula.
N- virtue acetyl-amino Thiourea series compound of the present invention has preferable inhibitory activity to urease, than The activity of positive control acetohydroxamic acid 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 phenylacetyl group) thiosemicarbazides (90)
204mg 2 is taken, 6- fenac is dissolved into 50mL thionyl chloride, 1h is stirred at 80 DEG C, it is cooling, it boils off Thionyl chloride adds water, is extracted with ethyl acetate three times, merges organic phase, washing, anhydrous MgSO4It is dry, boil off solvent, silica gel Column chromatographic purifying, eluant, eluent volume ratio: AcOEt: petroleum ether=1:4 obtains white solid 2, and 6- dichlorobenzoyl chloride 200mg is produced Rate 90%.2,6- dichloro phenyllacetyl chloride 120mg is dissolved in 50mL toluene, thiocarbamide 500mg is added with stirring, 2h is stirred at room temperature, is steamed It goes after toluene plus 8mL deionized water, AcOEt extraction merges organic layer, washing, anhydrous MgSO4It is dry, boil off solvent, silicagel column Chromatographic purifying, eluant, eluent volume ratio: AcOEt: petroleum ether=1:4 obtains white solid N2- (2,6- dichloro phenylacetyl group) amino sulphur Urea (90) 130mg, yield 92%.Fusing point: 157~159 DEG C；EIMS m/z:141 [M+]；1H NMR (400MHz, DMSO, δ): 9.08(s,2H),7.33(dd,1H),7.30–7.25(m,2H),3.52(s,2H)。
Embodiment 2:
By the similar method of embodiment 1, the phenylacetic acid with different substitution forms is raw material, has synthesized table 1,2 table of table, 3 institute The N- virtue acetyl-amino thiocarbamide series compound 1~99 of column.
Each R group of 1 general formula I N- virtue acetyl-amino 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: part N- virtue acetyl-amino Thiourea series compound of the present invention has preferably urease Inhibitory activity, than positive control acetohydroxamic acid activity it is higher.
Inhibiting effect (IC of the table 2N- virtue acetyl-amino Thiourea series compound to sword bean urease50)
The result shows that all compounds have significant inhibiting effect to sword bean urease, it is market drug acetohydroxamic acid 130-2100 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 8,13,14,17,21,24,27,30, 33,35,37,44,49,60,66,72,82,83,87,92,98 dosage reach 5g/kg (this dosage be States Pharmacopoeia specifications it is nontoxic Dosage) 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- fluorobenzene acetyl group) thiosemicarbazides (1):
162~164 DEG C of Mp；EIMS m/z:212 [M+]；1H NMR (400MHz, DMSO, δ): 9.05 (s, 3H), 7.43- 7.36 (m, 3H), 7.14-7.06 (m, 3H), 3.52 (d, J=2.1Hz, 1H), 3.52 (s, 2H).
N2- (4- chloro acetyl) thiosemicarbazides (2):
180~182 DEG C of Mp；EIMS m/z:228 [M+]；1H NMR (400MHz, DMSO, δ): 9.04 (s, 1H), 7.38 (q,2H),3.52(s,1H)。
N2- (4- bromobenzene acetyl group) thiosemicarbazides (3):
185~187 DEG C of Mp；EIMS m/z:272 [M+]；1H NMR (400MHz, DMSO, δ): 9.05 (s, 3H), 7.61- 7.54(m,3H),7.35(dt,3H),3.52(d,1H),3.52(s,2H)。
N2- phenylacetyl group thiosemicarbazides (4):
190~192 DEG C of Mp；EIMS m/z:194 [M+]；1H NMR (400MHz, DMSO, δ): 9.09 (s, 1H), 7.34- 7.27(m,1H),7.28–7.18(m,2H),3.52(d,1H)。
N2- (4- methyl phenylacetyl group) thiosemicarbazides (5):
202~204 DEG C of Mp；EIMS m/z:208 [M+]；1H NMR (400MHz, DMSO, δ): 7.29 (dd, 1H), 7.18 (dd,1H),6.97(s,1H),3.52(d,1H),2.21(d,2H)。
N2- (4- nitrobenzene acetyl group) thiosemicarbazides (6):
187~189 DEG C of Mp；EIMS m/z:239 [M+]；1H NMR (400MHz, DMSO, δ): 8.23-8.16 (m, 3H), 7.64(dt,3H),6.80(s,3H),3.52(d,1H),3.52(s,2H)。
N2- (4- methoxybenzene acetyl group) thiosemicarbazides (7):
212~214 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 7.28 (dt, 1H), 6.84- 6.75(m,2H),3.80(s,2H),3.52(d,1H)。
N2- (4- hydroxyphenylacetyl) thiosemicarbazides (8):
225~227 DEG C of Mp；EIMS m/z:210 [M+]；1H NMR (400MHz, DMSO, δ): 9.08 (s, 2H), 7.15 (dt,2H),6.86–6.80(m,2H),4.81(s,1H),3.52(d,1H),3.52(s,1H)。
N2- (4- cyano phenylacetyl group) thiosemicarbazides (9):
175~177 DEG C of Mp；EIMS m/z:219 [M+]；1H NMR (400MHz, DMSO, δ): 7.61-7.55 (m, 3H), 7.49–7.43(m,3H),6.81(s,3H),3.52(d,1H),3.52(s,2H)。
N2- (4- amido phenylacetyl group) thiosemicarbazides (10):
175~176 DEG C of Mp；EIMS m/z:209 [M+]；1H NMR (400MHz, DMSO, δ): 9.10 (s, 3H), 7.21- 7.16(m,3H),6.56–6.50(m,3H),4.37(s,3H),3.40(s,2H),3.40(d,1H)。
N2- (4- ethoxybenzene acetyl group) thiosemicarbazides (11):
200~202 DEG C of Mp；EIMS m/z:238 [M+]；1H NMR (400MHz, DMSO, δ): 7.20 (dt, 3H), 6.85- 6.78(m,6H),4.05(q,3H),3.52(d,1H),3.52(s,2H),1.34(t,4H)。
N2- (2- methoxybenzene acetyl group) thiosemicarbazides (12):
200~202 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 7.31-7.19 (m, 2H), 7.07(td,1H),6.95(s,2H),6.79(dd,1H),3.79(s,3H),3.52(d,2H)。
N2- (2- ethoxybenzene acetyl group) thiosemicarbazides (13):
213~214 DEG C of Mp；EIMS m/z:238 [M+]；1H NMR (400MHz, DMSO, δ): 8.94 (s, 2H), 7.30- 7.19(m,2H),7.07(td,1H),6.82(dd,1H),4.08(q,2H),3.52(d,2H),1.43(t,3H)。
N2- (2- ethyl phenylacetyl group) thiosemicarbazides (14):
122~124 DEG C of Mp；EIMS m/z:222 [M+]；1H NMR (400MHz, DMSO, δ): 7.35 (ddd, 1H), 7.23 (td,1H),7.18(td,1H),7.08(ddt,1H),6.83(s,2H),3.52(d,2H),2.45(qd,2H),1.15(t, 3H)。
N2- (2- fluorobenzene acetyl group) thiosemicarbazides (15):
198~199 DEG C of Mp；EIMS m/z:212 [M+]；1H NMR (400MHz, DMSO, δ): 9.00 (s, 2H), 7.48 (dddd,1H),7.36(tdd,1H),7.21(ddd,1H),7.07(td,1H),3.52(d,2H)。
N2- (2- chloro acetyl) thiosemicarbazides (16):
156~157 DEG C of Mp；EIMS m/z:228 [M+]；H NMR (400MHz, DMSO, δ): 9.01 (s, 2H), 7.54- 7.48(m,1H),7.41(dd,1H),7.30(td,1H),7.18(td,1H),3.52(d,2H)。
N2- (2- bromobenzene acetyl group) thiosemicarbazides (17):
221~222 DEG C of Mp；EIMS m/z:272 [M+]；1H NMR (400MHz, DMSO, δ): 9.01 (s, 2H), 7.56 (dd,1H),7.49(ddt,1H),7.26(td,1H),7.11(td,1H),3.52(d,2H)。
N2- (2- hydroxyphenylacetyl) thiosemicarbazides (18):
155~157 DEG C of Mp；EIMS m/z:210 [M+]；1H NMR (400MHz, DMSO, δ): 8.96 (s, 2H), 7.17 (ddt,2H),6.95(td,1H),6.78(dd,1H),6.64(s,1H),3.52(d,2H)。
N2- (2- methyl phenylacetyl group) thiosemicarbazides (19):
133~134 DEG C of Mp；EIMS m/z:208 [M+]；1H NMR (400MHz, DMSO, δ): 9.11 (s, 2H), 7.46- 7.39(m,1H),7.34–7.23(m,2H),7.18(ddd,1H),3.52(d,2H),2.10(d,3H)。
N2- (2- nitrobenzene acetyl group) thiosemicarbazides (20):
178~180 DEG C of Mp；EIMS m/z:239 [M+]；1H NMR (400MHz, DMSO, δ): 8.05 (dd, 1H), 7.71 (td,1H),7.64(td,1H),7.55(ddt,1H),7.16(s,2H),3.60(d,2H)。
N2- (2- amido phenylacetyl group) thiosemicarbazides (21):
157~158 DEG C of Mp；EIMS m/z:209 [M+]；1H NMR (400MHz, DMSO, δ): 9.03 (s, 2H), 7.19 (ddt,1H),6.91(td,1H),6.61–6.52(m,2H),4.74(s,2H),3.52(d,2H)。
N2- (2- cyano phenylacetyl group) thiosemicarbazides (22):
198~200 DEG C of Mp；EIMS m/z:219 [M+]；1H NMR (400MHz, DMSO, δ): 7.75-7.64 (m, 1H), 7.54(dtd,1H),7.17(s,1H),3.52(d,1H)。
N2- (3- methoxybenzene acetyl group) thiosemicarbazides (23):
156~158 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 7.31 (t, 1H), 7.07 (tt,1H),7.00(tt,2H),6.77(s,2H),3.71(s,3H),3.52(d,2H)。
N2- (3- ethoxybenzene acetyl group) thiosemicarbazides (24):
142~143 DEG C of Mp；EIMS m/z:238 [M+]；1H NMR (400MHz, DMSO, δ): 9.07 (s, 2H), 7.35 (t,1H),7.10–7.00(m,2H),6.95(tt,1H),4.14(q,2H),3.52(d,1H),3.52(s,1H),1.34(t, 3H)。
N2- (3- ethyl phenylacetyl group) thiosemicarbazides (25):
175~176 DEG C of Mp；EIMS m/z:222 [M+]；1H NMR (400MHz, DMSO, δ): 9.10 (s, 3H), 7.35- 7.23(m,4H),7.15(dt,1H),3.52(d,1H),3.52(s,2H),2.32–2.24(m,3H),1.27(t,4H)。
N2- (3- cyano phenylacetyl group) thiosemicarbazides (26):
211~212 DEG C of Mp；EIMS m/z:219 [M+]；1H NMR (400MHz, DMSO, δ): 9.01 (s, 2H), 7.79 (t,1H),7.77–7.68(m,2H),7.68–7.60(m,1H),3.52(d,2H)。
N2- (3- hydroxyphenylacetyl) thiosemicarbazides (27):
135~136 DEG C of Mp；EIMS m/z:210 [M+]；1H NMR (400MHz, DMSO, δ): 9.08 (s, 3H), 7.17 (t,2H),7.05(tt,2H),6.82(ddd,3H),4.85(s,2H),3.52(d,1H),3.52(s,2H)。
N2- (3- amido phenylacetyl group) thiosemicarbazides (28):
213~214 DEG C of Mp；EIMS m/z:209 [M+]；1H NMR (400MHz, DMSO, δ): 9.10 (s, 2H), 7.07 (t,1H),6.90(tt,1H),6.66(dd,2H),4.17(s,2H),3.52(s,2H)。
N2- (3- fluorobenzene acetyl group) thiosemicarbazides (29):
200~202 DEG C of Mp；EIMS m/z:212 [M+]；1H NMR (400MHz, DMSO, δ) 9.05 (s, 3H), 7.32 (td,2H),7.19(dtt,2H),6.99(dtt,3H),3.52(d,1H),3.52(s,2H)。
N2- (3- nitrobenzene acetyl group) thiosemicarbazides (30):
194~195 DEG C of Mp；EIMS m/z:240 [M+]；1H NMR (400MHz, DMSO, δ): 9.01 (s, 2H), 8.43 (tt,1H),8.20(dt,1H),7.66–7.59(m,1H),7.50(t,1H),3.52(d,1H),3.52(s,1H)。
N2- (3- methyl phenylacetyl group) thiosemicarbazides (31):
176~178 DEG C of Mp；EIMS m/z:208 [M+]；1H NMR (400MHz, DMSO, δ): 7.37 (t, 1H), 7.28- 7.22(m,2H),7.21–7.15(m,1H),6.76(s,2H),3.52(d,2H),2.36(d,2H)。
N2- (3- chloro acetyl) thiosemicarbazides (32):
154~155 DEG C of Mp；EIMS m/z:228 [M+]；1H NMR (400MHz, DMSO, δ): 9.05 (s, 2H), 7.49- 7.42(m,2H),7.38(t,1H),7.11(dtd,1H),3.52(d,1H),3.52(s,1H)。
N2- (3- bromobenzene acetyl group) thiosemicarbazides (33):
165~166 DEG C of Mp；EIMS m/z:272 [M+]；1H NMR (400MHz, DMSO, δ): 9.05 (s, 2H), 7.67 (q,1H),7.57(ddd,1H),7.24–7.16(m,2H),3.52(s,2H)。
N2- (3,5- dimethyl benzene acetyl group) thiosemicarbazides (34):
176~178 DEG C of Mp；EIMS m/z:222 [M+]；1H NMR (400MHz, DMSO, δ): 9.10 (s, 2H), 7.27 (q,1H),7.13(d,2H),3.52(d,2H),2.13(s,6H)。
N2- (3,5- diethylbenzene acetyl group) thiosemicarbazides (35):
210~211 DEG C of Mp；EIMS m/z:250 [M+]；1H NMR (400MHz, DMSO, δ): 7.02 (s, 2H), 6.76 (s,1H),3.52(d,1H),2.32–2.24(m,2H),1.27(t,3H)。
N2- (3,5- diethoxy phenylacetyl group) thiosemicarbazides (36):
145~146 DEG C of Mp；EIMS m/z:282 [M+]；1H NMR (400MHz, DMSO, δ): 9.09 (s, 1H), 6.76 (dd,1H),4.06(q,2H),3.52(d,1H),1.34(t,3H)。
N2- (3,5- dicyanobenzenes acetyl group) thiosemicarbazides (37):
188~189 DEG C of Mp；EIMS m/z:244 [M+]；1H NMR (400MHz, DMSO, δ): 8.16 (dt, 2H), 7.97 (t,1H),6.33(s,2H),3.52(d,1H),3.52(s,1H)。
N2- (3,5- difluoro phenylacetyl group) thiosemicarbazides (38):
202~203 DEG C of Mp；EIMS m/z:230 [M+]；1H NMR (400MHz, DMSO, δ): 6.87 (dd, 1H), 6.61 (s,1H),3.52(d,1H)。
N2- (3,5- dimethoxy phenylacetyl group) thiosemicarbazides (39):
168~170 DEG C of Mp；EIMS m/z:256 [M+]；1H NMR (400MHz, DMSO, δ): 9.06 (s, 2H), 6.69 (dt,2H),6.47(t,1H),3.81(s,6H),3.52(t,2H)。
N2- (3,5- dichloro phenylacetyl group) thiosemicarbazides (40):
210~212 DEG C of Mp；EIMS m/z:262 [M+]；1H NMR (400MHz, DMSO, δ): 7.27 (dt, 2H), 7.16 (t,1H),6.61(s,2H),3.52(d,1H),3.52(s,1H)。
N2- (3,5- dibromo phenylacetyl group) thiosemicarbazides (41):
182~183 DEG C of Mp；EIMS m/z:350 [M+]；1H NMR (400MHz, DMSO, δ): 7.69 (t, 1H), 7.58 (dd,2H),6.47(s,2H),3.52(d,2H)。
N2- (3,5- dinitrobenzene acetyl group) thiosemicarbazides (42):
221~223 DEG C of Mp；EIMS m/z:284 [M+]；1H NMR (400MHz, DMSO, δ): 8.91 (t, 1H), 8.64 (dd,2H),6.60(s,2H),3.52(d,1H),3.52(s,1H)。
N2- (3,5- bis- amido phenylacetyl group) thiosemicarbazides (43):
176~177 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 9.11 (s, 2H), 6.26 (dd,2H),5.84(t,1H),4.13(s,4H),3.52(d,2H)。
N2- (3,5- dihydroxy benzenes acetyl group) thiosemicarbazides (44):
183~184 DEG C of Mp；EIMS m/z:226 [M+]；1H NMR (400MHz, DMSO, δ): 8.88 (s, 1H), 9.10 (s,2H),6.56(d,4H),6.34(t,1H),3.52(d,2H)。
N2- (2,3- dichloro phenylacetyl group) thiosemicarbazides (45):
200~202 DEG C of Mp；EIMS m/z:262 [M+]；1H NMR (400MHz, DMSO, δ): 7.39-7.29 (m, 2H), 7.25(t,1H),6.97(s,2H),3.52(d,2H)。
N2- (2,3- diethylbenzene acetyl group) thiosemicarbazides (46):
210~212 DEG C of Mp；EIMS m/z:250 [M+]；1H NMR (400MHz, DMSO, δ): 7.35-7.25 (m, 1H), 6.73(s,1H),3.52(d,1H),2.66(q,1H),2.45(qd,1H),1.16(dt,3H)。
N2- (2,3- diethoxy phenylacetyl group) thiosemicarbazides (47):
186~187 DEG C of Mp；EIMS m/z:282 [M+]；1H NMR (400MHz, DMSO, δ): 7.08 (t, 1H), 6.98 (ddt,1H),6.96(s,2H),6.93(dd,1H),4.34(q,2H),4.08(q,2H),3.52(d,2H),1.61(t,3H), 1.46(t,3H).。
N2- (2,3- bis- amido phenylacetyl group) thiosemicarbazides (48):
203~204 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 6.99 (s, 2H), 6.55- 6.46(m,2H),6.38(dd,1H),4.35(s,4H),3.52(d,2H)。
N2- (2,3- dimethyl benzene acetyl group) thiosemicarbazides (49):
198~200 DEG C of Mp；EIMS m/z:222 [M+]；1H NMR (400MHz, DMSO, δ): 7.31 (ddt, 1H), 7.26 (t,1H),7.18(ddd,1H),6.48(s,2H),3.52(d,2H),2.27(d,3H),2.17(s,3H)。
N2- (2,3- dicyanobenzenes acetyl group) thiosemicarbazides (50):
190~192 DEG C of Mp；EIMS m/z:244 [M+]；1H NMR (400MHz, DMSO, δ): 7.97-7.87 (m, 2H), 7.80(dd,1H),6.90(s,2H),3.52(d,2H)。
N2- (2,3- dimethoxy phenylacetyl group) thiosemicarbazides (51):
188~189 DEG C of Mp；EIMS m/z:254 [M+]；1H NMR (400MHz, DMSO, δ): 7.12-7.05 (m, 1H), 7.02(dq,2H),6.96(s,2H),3.92(s,3H),3.81(s,3H),3.52(d,2H)。
N2- (2,3- dihydroxy benzenes acetyl group) thiosemicarbazides (52):
159~161 DEG C of Mp；EIMS m/z:226 [M+]；1H NMR (400MHz, DMSO, δ): 9.21 (s, 2H), 6.83 (t,1H),6.77(ddt,1H),6.72(dd,1H),5.43(s,1H),4.52(s,1H),3.52(d,2H).。
N2- (2,3- dinitrobenzene acetyl group) thiosemicarbazides (53):
169~170 DEG C of Mp；EIMS m/z:284 [M+]；1H NMR (400MHz, DMSO, δ): 8.16-8.08 (m, 2H), 7.79(t,1H),7.21(s,2H),3.60(d,2H)。
N2- (2,3- dibromo phenylacetyl group) thiosemicarbazides (54):
185~186 DEG C of Mp；EIMS m/z:350 [M+]；1H NMR (400MHz, DMSO, δ): 8 7.54 (dd, 1H), 7.35(ddt,1H),7.12(t 1H),6.86(s,2H),3.52(d,2H).。
N2- (2,3- difluoro phenylacetyl group) thiosemicarbazides (55):
175~177 DEG C of Mp；EIMS m/z:230 [M+]；1H NMR (400MHz, DMSO, δ): 7.27-7.19 (m, 1H), 7.10(td,1H),7.03(dddd,1H),6.52(s,2H),3.52(d,2H)。
N2- (2,4- dichloro phenylacetyl group) thiosemicarbazides (56):
158~160 DEG C of Mp；EIMS m/z:262 [M+]；1H NMR (400MHz, DMSO, δ): 9 7.40 (d, 1H), 7.29–7.23(m,1H),7.21(dd,1H),7.13(s,2H),3.52(d,2H)。
N2- (2,4- difluoro phenylacetyl group) thiosemicarbazides (57):
203~204 DEG C of Mp；EIMS m/z:230 [M+]；1H NMR (400MHz, DMSO, δ): 7.58-7.50 (m, 1H), 7.48(s,2H),6.85(dtd,2H),3.52(d,2H)。
N2- (2,4- diethoxy phenylacetyl group) thiosemicarbazides (58):
190~192 DEG C of Mp；EIMS m/z:282 [M+]；1H NMR (400MHz, DMSO, δ): 7.42 (dt, 1H), 6.89 (s,2H),6.67(dd,1H),6.42(d,1H),4.07(dq,4H),3.52(d,2H),1.43(t,3H),1.34(t,3H)。
N2- (2,4- diethylbenzene acetyl group) thiosemicarbazides (59):
157~158 DEG C of Mp；EIMS m/z:250 [M+]；1H NMR (400MHz, DMSO, δ): 7.04-6.97 (m, 1H), 6.38(s,1H),3.52(d,1H),2.45(qd,1H),2.32–2.24(m,1H),1.27(t,2H),1.13(t,2H).。N2- (2,4- dicyanobenzenes acetyl group) thiosemicarbazides (60):
232~234 DEG C of Mp；EIMS m/z:244 [M+]；1H NMR (400MHz, DMSO, δ): 7.94-7.86 (m, 2H), 7.84(dt,1H),7.03(s,2H),3.52(d,2H)。
N2- (2,4- bis- amido phenylacetyl group) thiosemicarbazides (61):
223~224 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 8.96 (s, 2H), 7.01 (dd,1H),6.00(dd,1H),5.77(d,1H),5.34(s,2H),4.10(s,2H),3.40(d,2H)。
N2- (2,4- dihydroxy benzenes acetyl group) thiosemicarbazides (62):
204~205 DEG C of Mp；EIMS m/z:226 [M+]；1H NMR (400MHz, DMSO, δ): 9.17 (s, 1H), 7.15 (dt,1H),7.00(s,1H),6.90(s,2H),6.45(dd,1H),6.39(d,1H),3.52(d,2H)。
N2- (2,4- dinitrobenzene acetyl group) thiosemicarbazides (63):
215~216 DEG C of Mp；EIMS m/z:284 [M+]；1H NMR (400MHz, DMSO, δ): 8.73 (d, 1H), 8.49 (dd,1H),8.02(dt,1H),6.99(s,2H),3.60(d,2H)。
N2- (2,4- dimethyl benzene acetyl group) thiosemicarbazides (64):
205~206 DEG C of Mp；EIMS m/z:222 [M+]；1H NMR (400MHz, DMSO, δ): 9.11 (s, 2H), 7.36 (dt,1H),7.15–7.09(m,1H),6.82(t,1H),3.52(d,2H),2.18(d,3H),2.11(d,3H)。
N2- (2,4- dibromo phenylacetyl group) thiosemicarbazides (65):
187~189 DEG C of Mp；EIMS m/z:350 [M+]；1H NMR (400MHz, DMSO, δ): 9.00 (s, 2H), 7.77 (d,1H),7.49(dd,1H),7.40(dt,1H),3.52(d,2H)。
N2- (2,4- dimethoxy phenylacetyl group) thiosemicarbazides (66):
236~237 DEG C of Mp；EIMS m/z:254 [M+]；1H NMR (400MHz, DMSO, δ): 7.38 (dt, 1H), 6.93 (s,2H),6.55–6.48(m,2H),3.79(d,6H),3.52(d,2H)。
N2- (3,4- dichloro phenylacetyl group) thiosemicarbazides (67):
198~199 DEG C of Mp；EIMS m/z:262 [M+]；1H NMR (400MHz, DMSO, δ): 7.43-7.36 (m, 3H), 7.19(ddt,2H),6.63(s,3H),3.52(d,1H),3.52(s,2H)。
N2- (3,4- diethoxy phenylacetyl group) thiosemicarbazides (68):
Mp178~179 DEG C；EIMS m/z:282 [M+]；1H NMR (400MHz, DMSO, δ): 7.16 (dt, 1H), 7.00 (d, J=7.5Hz, 1H), 6.94 (ddt, 1H), 6.92 (s, 2H), 4.08 (q, 4H), 3.52 (d, 2H), 1.46 (t, 6H).
N2- (3,4- diethylbenzene acetyl group) thiosemicarbazides (69):
201~202 DEG C of Mp；EIMS m/z:250 [M+]；1H NMR (400MHz, DMSO, δ): 9.10 (s, 2H), 7.28 (dt,1H),7.18–7.08(m,2H),3.52(d,1H),3.52(s,1H),2.45(qd,4H),1.18(t,3H),1.12(t, 3H)。
N2- (3,4- dibromo phenylacetyl group) thiosemicarbazides (70):
175~176 DEG C of Mp；EIMS m/z:350 [M+]；1H NMR (400MHz, DMSO, δ): 7.71-7.66 (m, 2H), 7.48–7.43(m,1H),6.94(s,2H),3.52(d,1H),3.52(s,1H)。
N2- (3,4- dinitrobenzene acetyl group) thiosemicarbazides (71):
186~188 DEG C of Mp；EIMS m/z:284 [M+]；1H NMR (400MHz, DMSO, δ): 8.34 (dd, 1H), 8.07 (d,1H),7.93(ddt,1H),7.09(s,2H),3.52(d,1H),3.52(s,1H)。
N2- (3,4- dimethyl benzene acetyl group) thiosemicarbazides (72):
187~189 DEG C of Mp；EIMS m/z:222 [M+]；1H NMR (400MHz, DMSO, δ): 7.21-7.16 (m, 1H), 7.14(s,2H),6.46(s,2H),3.52(s,2H),2.34–2.28(m,6H)。
N2- (3,4- difluoro phenylacetyl group) thiosemicarbazides (73):
196~197 DEG C of Mp；EIMS m/z:230 [M+]；1H NMR (400MHz, DMSO, δ): 7.24-7.12 (m, 3H), 7.05(ddd,2H),6.75(s,3H),3.52(d,1H),3.52(s,2H)。
N2- (3,4- dihydroxy benzenes acetyl group) thiosemicarbazides (74):
168~170 DEG C of Mp；EIMS m/z:226 [M+]；1H NMR (400MHz, DMSO, δ): 6.79 (d, 4H), 6.74 (d,1H),5.91(s,1H),5.13(s,1H),3.52(s,2H)。
N2- (3,4- dimethoxy phenylacetyl group) thiosemicarbazides (75):
223~224 DEG C of Mp；EIMS m/z:254 [M+]；1H NMR (400MHz, DMSO, δ): 7.09 (dt, 1H), 6.88- 6.78(m,2H),3.89(d,3H),3.52(d,1H)。
N2- (3,4- bis- amido phenylacetyl group) thiosemicarbazides (76):
252~254 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 6.63 (dt, 1H), 6.51 (ddt,1H),6.47(s,2H),6.33(d,1H),4.35(s,4H),3.40(s,1H)。
N2- (3,4- dicyanobenzenes acetyl group) thiosemicarbazides (77):
232~234 DEG C of Mp；EIMS m/z:244 [M+]；1H NMR (400MHz, DMSO, δ): 8.98 (s, 2H), 8.17 (dd,1H),7.92(d,1H),7.84–7.78(m,1H),3.52(d,1H),3.52(s,1H)。
N2- (2,5- difluoro phenylacetyl group) thiosemicarbazides (78):
194~185 DEG C of Mp；EIMS m/z:23O [M+]；1H NMR (400MHz, DMSO, δ): 8.99 (s, 2H), 7.22- 7.15(m,1H),7.13–7.02(m,2H),3.52(d,2H)。
N2- (2,5- dichloro phenylacetyl group) thiosemicarbazides (79):
186~188 DEG C of Mp；EIMS m/z:263 [M+]；1H NMR (400MHz, DMSO, δ): 7.55 (dd, 1H), 7.40 (d,1H),7.35(dd,1H),6.98(s,2H),3.52(d,2H)。
N2- (2,5- dibromo phenylacetyl group) thiosemicarbazides (80):
192~194 DEG C of Mp；EIMS m/z:350 [M+]；1H NMR (400MHz, DMSO, δ): 7.62 (dd, 1H), 7.45- 7.36(m,2H),6.95(s,2H),3.52(d,2H)。
N2- (2,5- dimethyl benzene acetyl group) thiosemicarbazides (81):
165~166 DEG C of Mp；EIMS m/z:222 [M+]；1H NMR (400MHz, DMSO, δ): 9.11 (s, 1H), 7.24- 7.09(m,1H),3.52(d,1H),2.36(d,1H),2.10(d,1H)。
N2- (2,5- diethoxy phenylacetyl group) thiosemicarbazides (82):
175~176 DEG C of Mp；EIMS m/z:282 [M+]；1H NMR (400MHz, DMSO, δ): 6.97 (s, 1H), 6.96- 6.87(m,1H),4.14(q,1H),4.08(q,1H),3.52(d,1H),1.43(t,2H),1.34(t,2H)。
N2- (2,5- diethylbenzene acetyl group) thiosemicarbazides (83):
192~194 DEG C of Mp；EIMS m/z:250 [M+]；1H NMR (400MHz, DMSO, δ) 7.27 (dd, 1H), 7.20- 7.09(m,2H),6.73(s,2H),3.52(d,2H),2.49–2.41(m,2H),2.32–2.24(m,2H),1.27(t,3H), 1.13(t,3H)。
N2- (2,5- dimethoxy phenylacetyl group) thiosemicarbazides (84):
158~160 DEG C of Mp；EIMS m/z:254 [M+]；1H NMR (400MHz, DMSO, δ): 7.04 (dd, 1H), 6.94 (s,2H),6.88–6.78(m,2H),3.79(s,3H),3.71(s,3H),3.52(d,2H)。
N2- (2,5- bis- amido phenylacetyl group) thiosemicarbazides (85):
175~176 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 6.93 (s, 2H), 6.65 (dt,1H),6.43(d,1H),6.36(dd,1H),4.54(s,2H),3.80(s,2H),3.52(d,2H)。
N2- (2,5- dicyanobenzenes acetyl group) thiosemicarbazides (86):
178~179 DEG C of Mp；EIMS m/z:230 [M+]；1H NMR (400MHz, DMSO, δ): 9.06 (s, 2H), 8.14 (dd,1H),7.84(d,1H),7.78(dd,1H),3.52(d,2H)。
N2- (2,5- dinitrobenzene acetyl group) thiosemicarbazides (87):
196~197 DEG C of Mp；EIMS m/z:284 [M+]；1H NMR (400MHz, DMSO, δ): 8.72 (dt, 1H), 8.30 (dd,1H),8.15(d,1H),6.83(s,2H),3.60(d,2H)。
N2- (2,5- dihydroxy benzenes acetyl group) thiosemicarbazides (88):
196~198 DEG C of Mp；EIMS m/z:226 [M+]；1H NMR (400MHz, DMSO, δ): 9.09 (s, 1H), 8.90 (s,2H),6.84(dd,1H),6.69(d,1H),6.61(dd,1H),4.51(s,1H),3.52(d,2H)。
N2- (2,6- difluoro phenylacetyl group) thiosemicarbazides (89):
186~188 DEG C of Mp；EIMS m/z:230 [M+]；1H NMR (400MHz, DMSO, δ): 7.47 (tt, 1H), 6.97 (td,2H),6.82(s,2H),3.52(s,2H)。
N2- (2,6- dichloro phenylacetyl group) thiosemicarbazides (90):
175~177 DEG C of Mp；EIMS m/z:230 [M+]；1H NMR (400MHz, DMSO, δ): 7.33 (dd, 1H), 7.31- 7.25(m,2H),6.77(s,2H),3.52(s,2H)。
N2- (2,6- dibromo phenylacetyl group) thiosemicarbazides (91):
189~191 DEG C of Mp；EIMS m/z:350 [M+]；1H NMR (400MHz, DMSO, δ): 7.50 (d, 2H), 7.08 (t,1H),6.58(s,2H),3.52(s,2H)。
N2- (2,6- dihydroxy benzenes acetyl group) thiosemicarbazides (92):
164~166 DEG C of Mp；EIMS m/z:226 [M+]；1H NMR (400MHz, DMSO, δ): 7.05 (t, 1H), 6.93 (s,2H),6.77(s,2H),6.43(d,2H),3.52(s,2H)。
N2- (2,6- dicyanobenzenes acetyl group) thiosemicarbazides (93):
173~175 DEG C of Mp；EIMS m/z:244 [M+]；1H NMR (400MHz, DMSO, δ): 7.90 (d, 2H), 7.67 (t,1H),7.03(s,2H),3.52(s,2H)。
N2- (2,6- dimethoxy phenylacetyl group) thiosemicarbazides (94):
196~198 DEG C of Mp；EIMS m/z:254 [M+]；1H NMR (400MHz, DMSO, δ): 7.28 (t, 1H), 6.92 (s,2H),6.66(d,2H),3.80(s,6H),3.52(s,2H)。
N2- (2,6- dimethyl benzene acetyl group) thiosemicarbazides (95):
168~170 DEG C of Mp；EIMS m/z:222 [M+]；1H NMR (400MHz, DMSO, δ): 9.14 (s, 2H), 7.23 (t,1H),7.03(d,2H),3.52(s,2H),2.29(s,6H)。
N2- (2,6- diethoxy phenylacetyl group) thiosemicarbazides (96):
193~194 DEG C of Mp；EIMS m/z:282 [M+]；1H NMR (400MHz, DMSO, δ): 9.03 (s, 1H), 6.49 (d,1H),4.08(q,2H),3.52(s,1H),1.43(t,3H)。
N2- (2,6- diethylbenzene acetyl group) thiosemicarbazides (97):
177~178 DEG C of Mp；EIMS m/z:250 [M+]；1H NMR (400MHz, DMSO, δ): 9.11 (s, 1H), 6.97 (d,1H),3.52(s,1H),2.45(qd,2H),1.02(t,3H)。
N2- (2,6- dinitrobenzene acetyl group) thiosemicarbazides (98):
166~168 DEG C of Mp；EIMS m/z:284 [M+]；1H NMR (400MHz, DMSO, δ): 8.16 (d, 2H), 7.61 (t,1H),6.51(s,2H),3.52(s,2H)。
N2- (2,6- bis- amido phenylacetyl group) thiosemicarbazides (99):
186~188 DEG C of Mp；EIMS m/z:224 [M+]；1H NMR (400MHz, DMSO, δ): 8.98 (s, 2H), 6.78 (t,1H),6.06(d,2H),4.88(s,4H),3.52(s,2H)。

Claims (3)

1. a kind ofNFragrant acetyl-amino 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 fragrant acetyl-amino thiocarbamide series compound, it is characterized in that: it by The following steps composition:
Step 1. takes 2-R1-3-R2-4-R3-5-R4-6-R5Substituted phenylacetic 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 phenylacetic acid (II): thionyl chloride (III)=1:(1~ 2), 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-R5Replace phenyllacetyl chloride (II)；
Step 2 is by 2- R1-3-R2-4-R3-5-R4-6-R5Phenyllacetyl chloride (II) is replaced to be 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-R5Replace phenyllacetyl chloride (II): thiocarbamide=1:(1~4), boil off first Benzene adds deionized water, is extracted with AcOEt, merges organic layer, washing, MgSO4It is dry, solvent is boiled off, silica gel column chromatography purifies, Eluant, eluent volume ratio: AcOEt: petroleum ether=4:1~1:6 obtainsN2-(2- R1-3-R2-4-R3-5-R4-6-R5Substituted benzoyl) Hydrazine sulfo-amino thiocarbamide (I), wherein the R1、R2、R3、R4And R5Definition it is identical as the definition of above-mentioned (I) formula.
3. described in claim 1NFragrant acetyl-amino thiocarbamide series compound is preparing gastritis, gastric ulcer or anti-urinary tract Application in calculus drug.
CN201811135623.4A 2018-09-28 2018-09-28 N- virtue acetyl-amino thiocarbamide type urease inhibitor and its preparation method and purposes Pending CN109081794A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005041853A2 (en) * 2003-10-28 2005-05-12 Ems S.A. Antibacterial and/or antiprotozoal nitroimidazole derivative compounds with urease inhibitor activity, process for preparing these compounds and use in pharmaceutical compositions and medicines.
WO2012100734A1 (en) * 2011-01-24 2012-08-02 Glaxo Group Limited Compounds useful as retinoid-related orphan receptor gamma modulators
CN105828798A (en) * 2013-12-19 2016-08-03 拜尔斯道夫股份有限公司 Use of alkylamidothiazoles in cosmetic or dermatological preparations for the prevention and treatment of sensitive skin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005041853A2 (en) * 2003-10-28 2005-05-12 Ems S.A. Antibacterial and/or antiprotozoal nitroimidazole derivative compounds with urease inhibitor activity, process for preparing these compounds and use in pharmaceutical compositions and medicines.
WO2012100734A1 (en) * 2011-01-24 2012-08-02 Glaxo Group Limited Compounds useful as retinoid-related orphan receptor gamma modulators
CN105828798A (en) * 2013-12-19 2016-08-03 拜尔斯道夫股份有限公司 Use of alkylamidothiazoles in cosmetic or dermatological preparations for the prevention and treatment of sensitive skin

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
SELVI, SRINIVASAN 等: "Synthetic utility of Vilsmeier reagents: formation of vinamidinium salts from acyl ureas", 《TETRAHEDRON LETTERS》 *
TIAGO O. BRITO 等: "Design, syntheses and evaluation of benzoylthioureas as urease inhibitors of agricultural interest", 《RSC ADVANCES》 *
UPUL K. BANDARAGE 等: "Convenient synthesis of N-(4-(2-aminopyridin-4-yl)thiazol-2-yl)-2-phenylacetamides", 《TETRAHEDRON LETTERS》 *
YURI F. REGO 等: "A review on the development of urease inhibitors as antimicrobial agents against pathogenic bacteria", 《JOURNAL OF ADVANCED RESEARCH》 *

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