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CN103159801B - N-ferrocenyl-N '-aryl ureas compound and application thereof - Google Patents

N-ferrocenyl-N '-aryl ureas compound and application thereof Download PDF

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Publication number
CN103159801B
CN103159801B CN201110406354.2A CN201110406354A CN103159801B CN 103159801 B CN103159801 B CN 103159801B CN 201110406354 A CN201110406354 A CN 201110406354A CN 103159801 B CN103159801 B CN 103159801B
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ferrocenyl
phh
fch
aryl ureas
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CN103159801A (en
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杨诚
周红刚
孙涛
刘伟
尹春晓
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Tiancheng Nanyun Tianjin Technology Co ltd
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Tian Yun Yun (tianjin) Technology Co Ltd
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Abstract

The present invention relates to the N ferrocenyl N ' aryl ureas compound of logical formula (I),Wherein, R is selected from C1‑C4Alkyl, halogen or nitro, and R is in the ortho position of NH, meta or para position.The invention still further relates to the pharmaceutical composition with this compound as active component, and the application that the compounds of this invention and Pharmaceutical composition are in preparation treatment or the medicine that prevents AIDS.

Description

N-ferrocenyl-N '-aryl ureas compound and application thereof
Technical field
The present invention relates to a kind of N-ferrocenyl-N '-aryl ureas compound and application thereof.
Background technology
Recent years, biological metal organic chemistry has obtained quick development, by classical metal Organic chemistry and biology, medical science and molecular biotechnology connect.Such as: cis-platinum is answered For clinical treatment carcinoma of testis and oophoroma etc..Ferrocene, is reported in nineteen fifty-one the earliest, is one Neutral, chemically stable and nontoxic molecule.Lipophilicity that Ferrocene and its derivative has had and film Permeability, hypotoxicity, redox active and large volume etc., these advantages make ferrocene and derive Thing becomes molecule very popular in biologic applications field.Many ferrocene derivatives show anticancer, Sterilization, antimalarial, AntiHIV1 RT activity and DNA cut isoreactivity.Therefore, new ferrocene derivatives is developed It is significantly.
Recently, carbamide derivative is in the news as various enzyme inhibitors, includes HIV-1 albumen among these Enzyme inhibitor, p38 mitrogen-activated protein (p38MAP) inhibitors of kinases, EGFR-TK (PTK) Inhibitor etc..Therefore, developing the new carbamide derivative as enzyme inhibitor is significantly.
Document (Fischer, E.O.；Zahn, U.；Baumgartner, F.Univ.Munich, Germany, Zeitschrift fuer Naturforschung (1959), 14B, 133) report there is following structural formula Ferrocenyl carbamide derivative
But do not report its activity.
There is not document to report other N-ferrocenyl-N '-aryl ureas compounds at present, do not have document report yet The activity of this compounds of road.
Summary of the invention
The invention provides N-ferrocenyl-N '-aryl ureas compound that a class is new.The present invention also provides for Such N-ferrocenyl-N '-aryl ureas compound is in preparation treatment or the medicine that prevents AIDS Application and a kind of pharmaceutical composition treating and preventing AIDS.
N-ferrocenyl-N '-aryl ureas compound that the present invention provides has a structure that
Wherein, R is selected from C1-C4Alkyl, halogen or nitro, and R be in-NH ortho position, Meta or para position.
In above-mentioned N-ferrocenyl-N '-aryl ureas compound, the preferred methyl of R, fluorine, chlorine or bromine.
In above-mentioned N-ferrocenyl-N '-aryl ureas compound, R is preferably in the ortho position of-NH and right Position.
According to an aspect of the present invention, above-mentioned N-ferrocenyl-N '-aryl ureas compound is preferred:
According to a further aspect in the invention, above-mentioned N-ferrocenyl-N '-aryl ureas compound is preferred:
According to another aspect of the invention, above-mentioned N-ferrocenyl-N '-aryl ureas compound is preferred:
Alkyl mentioned above refers to the alkyl with the straight or branched of 1～4 carbon atom, such as first Base, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, the tert-butyl group etc..Preferably methyl.
Halogen mentioned above refers to fluorine, chlorine, bromine or iodine atom.Preferably chlorine atom, bromine atoms, special Not preferably fluorine atom.
According to a further aspect in the invention, it is provided that a kind of synthesis N-ferrocenyl-N '-aryl ureas chemical combination The method (Fig. 3) of thing:
Said method comprises the following steps:
The most under nitrogen protection, phosphorus pentachloride is dividedly in some parts the dry toluene dissolved with ferrocenecarboxylic acid 1 In solution.Being stirred at room temperature 3 hours, then wash twice with sodium hydroxide solution, suction filtration removes generation Flocculent deposit.Again with water, saturated aqueous common salt, washing.Organic phase anhydrous sodium sulfate is dried, and is spin-dried for Obtain ferrocene formyl chloride 2；
B. the aqueous solution of sodium azide is added drop-wise in the acetone dissolved with ferrocene formyl chloride 2.Room temperature is stirred After mixing 1 hour, reactant liquor is imported in water, suction filtration, be dried to obtain ferrocene acid azide 3；
C, ferrocene acid azide 3 is dissolved in dry toluene with the new arylamine that steams, under nitrogen protection micro-time Flow 1 hour.Stop reaction, by reactant liquor concentrated by rotary evaporation.
E. thick product is separated by silica gel column chromatography, and flowing is petroleum ether (60-90 DEG C) mutually: acetic acid Ethyl ester: acetone (20: 1: 1).Product 4 is obtained after concentration.
In the above-mentioned methods, described arylamine selected from 2-aminotoluene, 4-methylaniline, 2-fluoroaniline, 4-fluoroaniline, 2,4-difluoroaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 2-bromaniline, 4- Bromaniline, 2-nitroaniline, 3-nitroaniline or 4-nitroaniline.
The compound of the present invention demonstrates the activity of Inhibit HIV-1 Protease.
The pharmaceutical composition of the present invention contains the N-ferrocenyl-N '-aryl ureas compound of therapeutically effective amount For active component, and containing one or more pharmaceutically acceptable carriers.
The compound of the present invention and pharmaceutical composition can be used for the medicine of preparation treatment AIDS.
Above-mentioned pharmaceutically acceptable carrier refers to the pharmaceutical carrier that pharmaceutical field is conventional, such as: dilution Agent, excipient such as water etc., filler such as starch, sucrose etc.；Adhesive such as cellulose derivative, algae Hydrochlorate, gelatin and polyvinylpyrrolidone；Wetting agent such as glycerine；Disintegrant such as agar, calcium carbonate and Sodium acid carbonate；Sorbefacient such as quaternary ammonium compound；Surfactant such as hexadecanol；Absorption carrier Such as kaolin and soap clay；Lubricant such as talcum powder, calcium stearate and magnesium and polyethylene glycol etc..Additionally Can be so that recombinant thing to add other assistant agents such as flavouring agent, sweetener etc..
The various formulations of pharmaceutical composition of the present invention can be according to the conventional production process system of pharmaceutical field Standby.Such as make active component mix with one or more carriers, be then made into required formulation.
The invention provides N-ferrocenyl-N '-aryl ureas compound that a class is new, this compounds has The activity of Inhibit HIV-1 Protease.Wherein 1-ferrocenyl-3-rubigan urea and 1-ferrocenyl-3- The HIV-1 protease inhibiting activity IC of m-nitro base urea50Value is respectively 55.72 μMs and 42.59 μMs.
Accompanying drawing explanation
Fig. 1 illustrates the HIV-1 protease inhibiting activity IC of the compound according to embodiment 850Figure.
Fig. 2 illustrates the HIV-1 protease inhibiting activity IC of the compound according to embodiment 1250Figure.
Fig. 3 illustrates the flow chart of synthesis N-ferrocenyl-N '-aryl ureas compound.
Detailed description of the invention
The following examples can make those skilled in the art that the present invention is more fully understood, but not to appoint Where formula limits the present invention.
In the following specific embodiments, fusing point by the digital melting point apparatus of X-4 measure, NMR data by Brooker Avance-400MHz nuclear-magnetism measuring apparatus, infrared to be paid vertical leaf by PerkinElmer 65 type red Outer instrument records, and mass spectrometric data is measured by Brooker ESQUIRELCTM Electrospray ion trap mass spectrometry instrument. Elemental analysis data is measured by Germany's Elementar Vairo EL type elemental analyser.
The preparation of embodiment 1:1-ferrocenyl-3-o-tolyl urea
Under nitrogen protection, in one and a half hours, 11mmol phosphorus pentachloride is dividedly in some parts dissolved with 10 In the 80ml dry toluene solution of mmol ferrocenecarboxylic acid 1.After continuing to be stirred at room temperature 3 hours, use 2M Sodium hydroxide solution 50ml washes twice, and suction filtration removes the flocculent deposit produced.Again with water (4 × 50ml), Saturated aqueous common salt, washing.Organic phase anhydrous sodium sulfate is dried, and rotation steaming obtains chilli oil shape ferrocene first Acyl chlorides.The aqueous solution containing 20mmol sodium azide is added drop-wise to the 40ml third dissolved with ferrocene formyl chloride In ketone.After being stirred at room temperature 1 hour, reactant liquor imports in 300ml water, and suction filtration is dried to obtain organic crystal Shape ferrocene acid azide, yield: 1.08g (42.5%).By the ferrocene acid azide of 1mmol It is dissolved in 30ml dry toluene with the ortho-aminotoluene of 1mmol, micro-backflow one hour under nitrogen protection.Stop Only reaction, by reactant liquor concentrated by rotary evaporation.Thick product is separated by silica gel column chromatography, and flowing is oil mutually Ether (60-90 DEG C): ethyl acetate: acetone (20: 1: 1).After concentration, product is yellow powder, Productivity is 64%.
The sign data of product are as follows:
M.p.173 DEG C of decomposition；
1H-NMR (400MHz, DMSO-d6, δ in ppm): 8.15 (s, 1H, NH)；7.88 (m, 1H, PhH)；7.71 (s, 1H, NH)；7.13 (m, 2H, PhH)；6.94 (t, J=9.8Hz, 1H, PhH)；4.51 (s, 2H, FcH)；4.14 (d, J=2.8Hz, 5H, FcH)；3.96 (s, 2H, FcH)；2.23 (s, 3H, CH3)；
13C-NMR (100MHz, DMSO-d6, δ in ppm): 17.7 (CH3), 60.2 (Fc), 63.4 (Fc), 68.5 (Fc), 96.7 (Fc), 120.4 (Ph), 122.1 (Ph), 126.0 (Ph), 126.9 (Ph), 130.0 (Ph), 137.7 (Ph), 153.0 (C=O)；
Elementary analysis calculated value: C18H18FeN2O:C, 64.69；H, 5.43；N, 8.38. measured value: C, 65.00；H, 5.55；N, 8.69；
MS (ESI) m/z:335.3 (M+H+)。
The preparation of embodiment 2:1-ferrocenyl-3-p-methylphenyl urea
Synthesis step is ibid
Productivity 69%, dark red powder, m.p.158 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.32 (s, 1H, NH)；7.73 (s, 1H, NH)；7.31 (d, J=8.0Hz, 2H, PhH)；7.06 (d, J=8.0Hz, 2H, PhH)；4.50 (s, 2H, FcH)；4.10 (s, 5H, FcH)；3.95 (s, 2H, FcH)；2.24 (s, 3H, CH3)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 20.2 (CH3), 60.4 (Fc), 63.4 (Fc), 68.6 (Fc), 96.6 (Fc), 118.0 (Ph), 129.5 (Ph), 137.2 (Ph), 152.8 (C=O)；
Elementary analysis calculated value: C18H18FeN2O:C, 64.69；H, 5.43；N, 8.38. measured value: C, 64.89；H, 5.73；N, 8.40；
MS (ESI) m/z:335.4 (M+H+)。
The preparation of embodiment 3:1-ferrocenyl-3-neighbour's fluorophenyl urea
Synthesis step is ibid
Productivity 77%, Chinese red powder, m.p.190 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.34 (s, 1H, NH)；8.21 (s, 1H, NH)；8.17 (t, J=7.8Hz, 1H, PhH)；7.21 (m, 1H, PhH)；7.11 (t, J=7.8Hz, 1H, PhH)；6.98 (m, 1H, PhH)；4.50 (s, 2H, FcH)；4.15 (s, 5H, FcH)；3.98 (s, 2H, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 61.3 (Fc), 64.2 (Fc), 69.2 (Fc), 96.6 (Fc), 115.3 (Ph), 120.6 (Ph), 122.4 (Ph), 124.9 (Ph), 128.3 (Ph), 151.4, 152.9 (Ph), 153.0 (C=O)；
Elementary analysis calculated value: C17H15FFeN2O:C, 60.38；H, 4.47；N, 8.28. measured value: C, 60.79；H, 4.71；N, 8.11；
MS (ESI) m/z:338.9 (M+H+)。
The embodiment 4:1-ferrocenyl-3-preparation to fluorophenyl urea
Synthesis step is ibid
Productivity 78%, yellow powder, m.p.190 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.46 (s, 1H, NH)；7.77 (s, 1H, NH)；7.44 (m, 2H, PhH)；7.10 (t, J=8.8Hz, 2H, PhH)；4.51 (t, J=2.0Hz, 2H, FcH)；4.14 (s, 5H, FcH)；3.94 (m, 2H, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.3 (Fc), 63.4 (Fc), 68.5 (Fc), 96.9 (Fc), 115.1 (Ph), 119.4 (Ph), 136.2 (Ph), 152.8 (C=O), 157.6,159.3 (Ph)；
Elementary analysis calculated value: C17H15FFeN2O:C, 60.38；H, 4.47；N, 8.28. measured value: C, 60.65；H, 4.53；N, 8.08；
MS (ESI) m/z:339.3 (M+H+).
The preparation of embodiment 5:1-ferrocenyl-3-(2,4-difluorophenyl) urea
Synthesis step is ibid
Productivity 82%, Chinese red powder, m.p.170 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.29 (s, 1H, NH)；8.15 (s, 1H, NH)；8.11 (m, 1H, PhH)；7.28 (m, 1H, PhH)；7.02 (t, J=8.0Hz, 1H, PhH)；4.50 (s, 2H, FcH)；4.15 (s, 5H, FcH)；3.97 (s, 2H, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 61.3 (Fc), 64.2 (Fc), 70.4 (Fc), 96.6 (Fc), 104.1 (Ph), 111.5 (Ph), 121.8 (Ph), 124.9 (Ph), 151.0,153.3 (Ph), 153.1 (C=O), 155.7,158.1 (Ph)；
Elementary analysis calculated value: C17H14F2FeN2O:C, 57.33；H, 3.96；N, 7.87. measured value: C, 57.40；H, 4.33；N, 8.24；
MS (ESI) m/z:357.1 (M+H+)。
The preparation of embodiment 6:1-ferrocenyl-3-Chloro-O-Phenyl urea
Synthesis step is ibid
Productivity 81%, yellow powder, m.p.193 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.57 (s, 1H, NH)；8.20 (d, J= 8.0Hz, 1H, PhH)；8.10 (s, 1H, NH)；7.44 (d, J=8.0Hz, 1H, PhH)；7.27 (t, J= 8.0Hz, 1H, PhH)；6.99 (m, 1H, PhH)；4.51 (t, 2H, J=1.2Hz, FcH)；4.16 (s, 5H, FcH)；3.98 (t, 2H, J=1.6Hz, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.7 (Fc), 63.7 (Fc), 68.6 (Fc), 96.0 (Fc), 120.7 (Ph), 121.2 (Ph), 122.7 (Ph), 127.5 (Ph), 129.0 (Ph), 136.1 (Ph), 152.4 (C=O)；
Elementary analysis calculated value: C17H15ClFeN2O:C, 57.58；H, 4.26；N, 7.90. measured value: C, 57.80；H, 4.62；N, 7.49；
MS (ESI) m/z:355.1 (M+H+)。
The preparation of embodiment 7:1-ferrocenyl-3-m-chloro phenylurea
Synthesis step is ibid
Productivity 92%, yellow powder, m.p.193 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.68 (s, 1H, NH)；7.91 (s, 1H, NH)；7.72 (s, 1H, PhH)；7.25 (m, 2H, PhH)；6.98 (d, J=8.8Hz, 1H, PhH)；4.52 (s, 2H, FcH)；4.14 (s, 5H, FcH)；3.96 (s, 2H, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.7 (Fc), 63.6 (Fc), 68.7 (Fc), 96.3 (Fc), 116.3 (Ph), 117.3 (Ph), 121.1 (Ph), 130.4 (Ph), 133.3 (Ph), 141.6 (Ph), 152.6 (C=O)；
Elementary analysis calculated value: C17H15ClFeN2O:C, 57.58；H, 4.26；N, 7.90. measured value: C, 58.01；H, 4.12；N, 7.58；
MS (ESI) m/z:355.3 (M+H+)。
The preparation of embodiment 8:1-ferrocenyl-3-rubigan urea
Synthesis step is ibid
Productivity 82%, yellow powder, m.p.205 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.59 (s, 1H, NH)；7.84 (s, 1H, NH)；7.47 (d, 2H, J=12.0Hz PhH)；7.30 (d, J=8.8Hz, 2H, PhH)；4.50 (s, 2H, FcH)；4.13 (s, 5H, FcH)；3.95 (s, 2H, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.5 (Fc), 63.5 (Fc), 68.7 (Fc), 96.4 (Fc), 119.2 (Ph), 124.8 (Ph), 128.5 (Ph), 139.2 (Ph), 152.6 (C=O)；
Elementary analysis calculated value: C17H15ClFeN2O:C, 57.58；H, 4.26；N, 7.90. measured value: C, 57.86；H, 4.44；N, 8.15；
MS (ESI) m/z:355.0 (M+H+)。
The preparation of embodiment 9:1-ferrocenyl-3-o-bromophenyl urea
Synthesis step is ibid
Productivity 81%, yellow powder, m.p.203 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.66 (s, 1H, NH)；8.12 (d, J= 8.0Hz, 1H, PhH)；8.10 (s, 1H, NH)；7.44 (d, J=8.0Hz, 1H, PhH)；7.27 (t, J= 8.0Hz, 1H, PhH)；6.99 (m, 1H, PhH)；4.51 (t, 2H, J=1.2Hz, FcH)；4.16 (s, 5H, FcH)；3.98 (t, 2H, J=1.6Hz, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.7 (Fc), 63.7 (Fc), 68.8 (Fc), 96.5 (Fc), 112.2 (Ph), 121.5 (Ph), 123.5 (Ph), 128.0 (Ph), 132.3 (Ph), 137.1 (Ph), 152.3 (C=O)；
Elementary analysis calculated value: C17H15BrFeN2O:C, 51.17；H, 3.79；N, 7.02. measured value: C, 51.46；H, 4.08；N, 7.44；
MS (ESI) m/z:399.1 (M+H+)。
The preparation of embodiment 10:1-ferrocenyl-3-p-bromophenyl urea
Synthesis step is ibid
Productivity 86%, yellow powder, m.p.200 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.85 (s, 1H, NH)；8.59 (s, 1H, NH)；7.43 (s, 2H, PhH)；7.41 (s, 2H, PhH)；4.50 (s, 2H, FcH)；4.12 (s, 5H, FcH)； 3.92 (d, 2H, J=9.2Hz, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.6 (Fc), 63.5 (Fc), 68.6 (Fc), 96.4 (Fc), 113.1 (Ph), 119.9 (Ph), 131.4 (Ph), 139.1 (Ph), 152.4 (C=O)；
Elementary analysis calculated value: C17H15BrFeN2O:C, 51.17；H, 3.79；N, 7.02. measured value: C, 51.21；H, 3.66；N, 7.39；
MS (ESI) m/z:399.1 (M+H+)。
The preparation of embodiment 11:1-ferrocenyl-3-O-Nitrophenylfluorone urea
Synthesis step is ibid
Productivity 74%, crocus powder, m.p.210 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 9.47 (s, 1H, NH)；9.08 (s, 1H, NH)；8.37 (d, J=8.4Hz, 1H, PhH)；8.09 (d, J=8.4Hz, 1H, PhH)；7.68 (t, J= 8.3Hz, 1H, PhH)；7.17 (t, J=7.2Hz, 1H, PhH)；4.52 (s, 2H, FcH)；4.16 (s, 5H, FcH)；3.97 (s, 2H, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.8 (Fc), 63.8 (Fc), 68.7 (Fc), 95.8 (Fc), 121.7 (Ph), 122.0 (Ph), 125.3 (Ph), 135.0 (Ph), 135.3 (Ph), 137.0 (Ph), 152.0 (C=O)；
Elementary analysis calculated value: C17H15FeN3O3: C, 51.91；H, 4.14；N, 11.51. measured value: C, 52.03；H, 4.51；N, 11.90；
MS (ESI) m/z:366.2 (M+H+)。
The preparation of embodiment 12:1-ferrocenyl-3-m-nitro base urea
Synthesis step is ibid
Productivity 73%, red powder, m.p.180 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 8.99 (s, 1H, NH)；8.56 (s, 1H, PhH)；8.01 (s, 1H, NH)；7.79 (d, J=8.0Hz, 1H, PhH)；7.68 (d, J=8.0Hz, 1H, PhH)；7.54 (t, J=8.0Hz, 1H, PhH)；4.55 (s, 2H, FcH)；4.15 (d, J=6.4Hz, 5H, FcH)；3.97 (s, 2H, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.7 (Fc), 63.7 (Fc), 68.6 (Fc), 96.1 (Fc), 111.7 (Ph), 115.8 (Ph), 123.9 (Ph), 129.9 (Ph), 141.1 (Ph), 148.1 (Ph), 152.5 (C=O)；
Elementary analysis calculated value: C17H15FeN3O3: C, 51.91；H, 4.14；N, 11.51. measured value: C, 52.33；H, 4.04；N, 11.89；
MS (ESI) m/z:366.1 (M+H+)。
The preparation of embodiment 13:1-ferrocenyl-3-p-nitrophenyl urea
Synthesis step is ibid
Productivity 81%, dark red powder, m.p.199 DEG C of decomposition；
1H NMR (400MHz, DMSO-d6, δ in ppm): 9.21 (s, 1H, NH)；8.15 (d, J= 14.8Hz, 2H, PhH)；7.95 (s, 1H, NH)；7.66 (d, J=9.2Hz, 2H, PhH)；4.55 (t, J= 1.6Hz, 2H, FcH)；4.14 (s, 5H, FcH)；3.98 (t, J=1.6Hz, 2H, FcH)；
13C NMR (100MHz, DMSO-d6, δ in ppm): 60.7 (Fc), 63.7 (Fc), 68.6 (Fc), 95.7 (Fc), 117.1 (Ph), 125.0 (Ph), 140.6 (Ph), 146.5 (Ph), 152.0 (C=O)；
Elementary analysis calculated value: C17H15FeN3O3: C, 51.91；H, 4.14；N, 11.51. measured value: C, 52.23；H, 4.08；N, 11.98；
MS (ESI) m/z:366.1 (M+H+)。
HIV-1 protease inhibitory activity detection method is as follows:
Utilize FRET (fluorescence resonance energy transfer, FRET) Technology measures the activity of the inhibitor for HIV-1 protease, according to HIV-1 protease site Design substrate: MCA-gama-abu-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Glu-Lys-Dnp, When HIV-1 protease is not acted on by inhibitor, HIV-1 protease can cut substrate, cancellation Group (Dnp) absorbs 320nm wavelength away from fluorophor (MCA), fluorophor, inspires The wavelength of 405nm, by detector fluorescence intensity, if HIV-1 protease is had by inhibitor Effect, quenching group will not be cut out, and fluorophor absorbs the ripple rear portion energy of 320nm and can turn Moving to quenching group, the excitation wave intensity of 405nm will weaken, and detects inhibitor to HIV-1 with this The inhibition of protease.According to fluorescence intensity change during testing compound presence or absence, permissible Calculate suppression degree or the residual activity of compound for protein enzymatic activity, thus complete protease inhibitors Preliminary screening.Circular is, in enzymatic reaction, the growing amount according to reflection process product is (the most glimmering Luminous intensity) and the curve in reaction time, the change of product formation in the slope of a curve representation unit time, So the slope of any point is exactly the reaction rate of this corresponding time on curve, at base consumption less than 10% In the range of (reaction started in the shortest time), the slope of curve is the first rate (V0) of enzyme reaction, has not In the presence of inhibitor, the reaction first rate (Vi) of enzyme has decline in various degree, the residual activity of enzyme (Vi/V0) less than 10%, for positive findings.This experiment utilize the method for fluorescent quenching to get rid of false positive, Reaction system adds protease and substrate reactions a period of time, and fluorescent value reaches maximum Qmax, and addition presses down Detecting the change of fluorescent value Qave after preparation, fluorescent quenching rate Qi ((Qmax-Qave)/Qmax) is higher than 20% is false positive.Utilize the method can complete the screening operation to a large amount of samples at short notice, we Apply this model discrimination and research anti-HIV-1 compounds and made some progress.This model can also For the known material having Anti-HIV-1 Active, to check whether its action site is protease.Table 1 illustrates The determination of activity result of compound in embodiment 1～13.Wherein the measurement concentration of residual activity is 1mM.
The determination of activity result of the compound of table 1 embodiment 1～13
Numbering Structure Residual activity Cancellation rate
1 Comparison 41.77% 6.68%
2 Embodiment 1 23.62% 2.38%
3 Embodiment 2 27.36% 22.49%
4 Embodiment 3 14.76% 1.42%
5 Embodiment 4 15.95% 1.49%
6 Embodiment 5 22.04% 1.95%
7 Embodiment 6 30.85% 3.39%
8 Embodiment 7 18.25% 6.13%
9 Embodiment 8 2.68% 2.29%
10 Embodiment 9 29.63% 2.43%
11 Embodiment 10 18.02% 5.54%
12 Embodiment 11 20.76% 40.82%
13 Embodiment 12 -0.74% 21.80%
14 Embodiment 13 1.19% 59.21%
The inhibiting rate of the compound in the embodiment 1 enumerated in table 1～embodiment 13 can be by (1-remains Activity) calculate, it can be seen that above-claimed cpd all has inhibitory activity to HIV-1 protease, this Bright selection residual activity value be less than 10%, cancellation rate less than or close to 20% embodiment 8 and embodiment 12 In compound be that preferred compound carries out IC50The test of value.
IC50The assay method of value is as follows:
The IC of the compound in test preferred embodiment 8 and embodiment 1250Value, method particularly includes:
Quenched fluorogenic substrate peptide used by test is MCA-gama-abu-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Glu-Lys-Dnp, HIV-1 protease with Quenched fluorogenic substrate peptide mixing insulation can make the specific fracture of Tyr-Pro key in peptide substrate, fluorescence simultaneously A time dependent linear enhancing relation is there is in intensity with the degree of substrate hydrolysis.Measure on 96 orifice plates Carry out, utilize microwell plate fluophotometer to carry out detecting (Thermo Scientific Fluoroskan Ascent FL), excite and launch wavelength and be respectively 340nm and 396nm.
Compound in embodiment 8 and embodiment 12 is configured to highly concentrated solution (generally 200 μMs), Then carry out 1/2 concentration gradient and be diluted to series concentration solution, activity under 12 concentration of general mensuration, institute Some negative control groups are carried out at 37 DEG C, and insulation solution composition is that HIV-1 protease detects cushioning liquid (20mM sodium acetate, pH=5.2,1M sodium chloride, 1mM dithiothreitol (DTT) and 1mM ethylenediamine tetraacetic Acetic acid), 20 μMs of peptide substrates and 500nM HIV-1 protease.All of experimental group is carried out at 37 DEG C, In protease detection cushioning liquid containing 20 μMs of peptide substrates, it is mixed into 1 μ L compound solution and (uses two Methyl sulfoxide makees solvent), finally add 500nM HIV-1 protease.Whole mixture (100 μ l) Before adding HIV-1 protease, insulation 10 minutes the most in advance.Initial rate is tested after one minute. Initial velocity V0 can be approximated to be the slope in reaction time and fluorescence intensity linear relationship.Each testedization The concentration of compound all calculates the residual activity of Vi/V0, i.e. HIV-1 protease.When residual activity is less than 10%, this compound is a good result.IC50Value is calculated by GraphPad Prism 5 software Arrive, i.e. utilize software GraphPad Prism 5 software analysis to make residual activity value and compound concentration The curve of logarithm value, calculates IC50(half-inhibition concentration) value.
The method is utilized to calculate the IC of compound in embodiment 850Value is 55.72 μMs (Fig. 1), implements The IC of compound in example 1250Value is 42.59 μMs (Fig. 2).
Although an embodiment of the present invention has been shown and described, for those of ordinary skill in the art For, it is possible to understand that without departing from the principles and spirit of the present invention can be to these embodiments Carry out multiple change, revise, replace and modification, the scope of the present invention by claims and etc. Jljl limits.

Claims (10)

1. a N-ferrocenyl-N'-aryl ureas compound, its structural formula is as follows:
Wherein, R is selected from C1-C4Alkyl, halogen or nitro, and R be in-NH-ortho position, Meta or para position.
Compound the most according to claim 1, wherein R is methyl.
Compound the most according to claim 1, wherein R is fluorine, chlorine or bromine.
Compound the most according to claim 1, wherein R is in ortho position or the contraposition of-NH-.
Compound the most according to claim 1, wherein said compound is:
Compound the most according to claim 1, wherein said compound is:
Compound the most according to claim 1, wherein said compound is:
8. the N-ferrocenyl-N'-aryl ureas compound according to any one of claim 1 to 7 is in system Application in the standby medicine treated or prevent AIDS.
9. the N-ferrocenyl-N'-aryl ureas compound according to any one of claim 1 to 7 is in system Application in the medicine of standby Inhibit HIV-1 Protease.
10. a pharmaceutical composition, wherein said pharmaceutical composition includes that the right of therapeutically effective amount is wanted Ask the compound according to any one of 1～7 and pharmaceutically acceptable carrier.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2003074731A2 (en) * 2002-03-07 2003-09-12 Molecular Sensing Plc Nucleic acid probes, their synthesis and use
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