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CN101735113B - Urea derivatives, preparation method and use thereof - Google Patents

Urea derivatives, preparation method and use thereof Download PDF

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Publication number
CN101735113B
CN101735113B CN200910262954.9A CN200910262954A CN101735113B CN 101735113 B CN101735113 B CN 101735113B CN 200910262954 A CN200910262954 A CN 200910262954A CN 101735113 B CN101735113 B CN 101735113B
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preparation
urea derivative
chloro
compound
dehydrated alcohol
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CN101735113A (en
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朱海亮
李青山
李环球
严涛
骆银
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Nanjing University
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Nanjing University
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Abstract

The invention provides urea derivatives, which have the following general formula. In the formula, R is H or nitroso, R2 is 5-chloro-2-hydroxyphenmethyl or 3,5-dichloro-2-hydroxyphenmethyl, and R3 is p-methylphenyl, p-fluorophenyl, p-methoxyphenyl, p-chlorophenyl, p-bromophenyl, 2,4-difluorophenyl, 2-chlorophenyl, 2-(N-morpholinyl)ethyl, 3-(N-morpholinyl)propyl, n-dodecylamino, n-hexadecylamino or n-octadecylamino. The urea derivatives have an obvious inhibiting effect on the cancer cell strain (KB) of the epicuticle of human oral cavity and human leukemia cell strain (K562). Thus, the urea derivatives can be applied to the preparation of antineoplastic drugs. The invention discloses a preparation method of the urea derivatives.

Description

One class urea derivative and method for making and purposes
Technical field
The present invention relates to class urea derivative and preparation method thereof and its purposes as cancer therapy drug.
Background technology
Urea compound be a class at pesticide field, the broad-spectrum compound in medicine bioengineering field, the asymmetric unit in its structure is the common structure feature of many enzyme inhibitorss and biosimulation peptide, therefore majority has biological activity.Especially leukemia, tumour are also had to good drug effect.Thereby N-substituted ureas is proved to be and can disturbs the assembling block cell propagation of the mitotic spindle microtubule in tumour cell to make apoptosis of tumor cells by the combination with 'beta '-tubulin.Self-discovery N-replaces class urea compounds to be had after certain biological activity, people are just using it as a kind of biological target with potentiality to be exploited, carry out reasonable molecular designing and from natural bioactivity substance, find biological activity higher or more wide spectrum, higher selectivity, lower toxicity, the longer or shorter longevity of residure etc., so the present invention's design and synthesized a series of new N-substituted ureas analog derivatives.
The present invention carries out nitrosylation and then has synthesized a series of N '-nitrosourea analog derivative on above-mentioned synthetic N-substituted ureas analog derivative basis, and nitrosourea analog derivative is having significant effect aspect cancer therapy drug.N '-nitroso existence makes the key between this nitrogen-atoms and contiguous carbonyl become unstable, decomposes in vivo and generates Electron Affinities group, destroys the structure of DNA, thus the growth of anticancer.N '-nitrosourea analog derivative enters after cell and makes DNA that alkylation occur, carbamylation, thereby DNA is crosslinked etc., reaction reaches its anticancer effect.(C.Thomas Gnewuchand George Sosnovsky.Chem.Rev.1997,97,829-1013) in the U.S., there are 4 kinds of N-nitrosoureas medicines through FDA approval for cancer clinical treatment at present, be respectively Carmustine (carmustine, BCNU), Lomostine (lomustine, CCNU), Semustine (semustine MeCCNU), and Streptozotocin (U-9889, SZT).
In half a century in the past, a large amount of scientific research strengths is devoted to the research of cancer therapy drug, also there are some effective medicine listings to benefit cancer patients simultaneously, but still have many problem demanding prompt solutions, as the selectivity to cancer cells suppresses poor, some cancer therapy drugs but can cause the formation of new tumour in treatment patient cancer, and the membrane penetrating after entering in body, so, find at present there is highly selective more, focus that more hypotoxicity and the cancer therapy drug in longevity of residure of being more suitable for are still research.So the present invention has synthesized the novel urea analog derivative of a class and has been intended to find out the newtype drug with better antitumour activity.
Summary of the invention
The object of the present invention is to provide the novel urea derivative of a class and method for making and purposes.
Technical scheme of the present invention is as follows:
One class urea derivative, it has following general formula:
Figure G2009102629549D00021
In formula:
R 1for H or nitroso-group;
R 2for 5-chlorine-2-hydroxyl phenmethyl or the chloro-2-hydroxybenzene of 3,5-bis-methyl;
R 3for p-methylphenyl, to fluorophenyl, p-methoxyphenyl, rubigan, to bromophenyl, 2,4 difluorobenzene base, 2-chloro-phenyl-, 2-(N-morpholinyl) ethyl, 3-(N-morpholinyl) propyl group, n-dodecane is amino, n-hexadecane is amino or Octadecane is amino.
A kind ofly prepare above-mentioned R 1the method of the urea derivative of=H, it is comprised of the following step:
Step 1., in dehydrated alcohol, adds a certain amount of corresponding aldehyde and amine, and aldehyde is 1 with the ratio of the amount of substance of amine: 1.1-1: 1.3, under room temperature, react after 1h, and the solvent that pressure reducing and steaming is unnecessary and amine, in ethanol, recrystallization obtains R 3=N-R 2,
Step 2. is by the R obtaining 3=N-R 2be dissolved in dehydrated alcohol, be placed in ice bath, the NaBH of amount of substance such as slowly add wherein 4, after adding, remove ice bath, react at normal temperatures 3-6h, reaction finishes, and pressure reducing and steaming solvent, adds water, uses the chloroform extraction aqueous solution, and extraction liquid pressure reducing and steaming chloroform, obtains R 3nHR 2,
Step 3. will wait the compound R of amount of substance 3nHR 2be dissolved in chloroform with phenylcarbimide (PhNCO), stirring and refluxing 2-4h at room temperature, reaction finishes to add normal hexane to make to separate out more solids in backward reaction system, filter, by gained solid recrystallization or after reaction finishes in ethanol, pressure reducing and steaming solvent, the ethyl acetate/petroleum ether of take obtains R as eluent silica gel column chromatography 1the urea derivative of=H.
Above-mentioned method for making, in step 1, the consumption of described dehydrated alcohol is every mmole aldehyde 10-15ml dehydrated alcohol.
Above-mentioned method for making, in step 2, the consumption of described dehydrated alcohol is every mmole R 3=N-R 2use 10-15ml dehydrated alcohol.
Above-mentioned method for making, in step 3, described CHCl 3consumption be every mmole R 3nR 2add 10-15ml CHCl 3.
A kind ofly prepare above-mentioned R 1the method of the urea derivative of=NO, it is comprised of the following step:
The urea derivative of the R1=H that step 4. obtains aforesaid method step 3 is dissolved in the anhydrous acetonitrile that adds acetic acid, and acetic acid is 1.5: 1 with the ratio of the amount of substance of urea derivative, under ice bath is cooling, adds NOBF 4, NOBF 4with the ratio of the amount of substance of urea derivative be 1.5: 1, at the cooling lower reaction 8-12 hour of ice bath, reaction finishes to add frozen water in backward reaction system, with 5%NaHCO 3solution regulates pH to 5-6, adds isopyknic ethyl acetate aqueous phase extracted, merges organic phase, anhydrous magnesium sulfate drying, and the ethyl acetate/petroleum ether of then take obtains R as eluent column chromatography for separation 1the urea derivative of=NO.
Above-mentioned method for making, in step 4, described CH 3the consumption of CN is the R of every mmole 1the urea derivative of=H 6ml anhydrous acetonitrile.
Research shows: urea derivative of the present invention has obvious inhibition growth to human oral cavity upper epidermis JEG-3 (KB) and human leukemia cell line (K562), therefore can be for the preparation of anti-tumor drug.
Embodiment
By following examples, further describe the present invention, but should notice that scope of the present invention is not subject to any restriction of these embodiment.
The preparation of embodiment 1:N-p-methylphenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 1)
Figure G2009102629549D00031
In 250ml single necked round bottom flask, add 100ml dehydrated alcohol, add 3,5-dichloro-salicylaldehyde (10mmol) and to monomethylaniline (12mmol).Stirring reaction approximately 3 hours, on Rotary Evaporators, pressure reducing and steaming solvent and unnecessary amine, obtain yellow oil.Under heating condition, with 40ml ethanol, it is all dissolved, cooling recrystallization, obtains glassy yellow solid afterwards.Solid transfer is entered to 250ml single necked round bottom flask, add 100ml dehydrated alcohol it is dissolved completely, and flask is placed in to ice bath, slowly in reaction system, drip sodium borohydride (380mg, 10mmol), remove ice bath, at normal temperatures the about 6h of stirring reaction.Take off flask, in reaction system, add water, migrate out the separating funnel to 500ml, add 200ml chloroform extraction 2～3 times at every turn, after extraction liquid pressure reducing and steaming chloroform, obtain the chloro-2-[(4-methylbenzene of 2,4-bis-amino)-methyl] phenol.Transfer them in 250ml single necked round bottom flask, add 100ml chloroform and dissolve, then drip 10mmol phenylcarbimide (PhNCO) in solution, be heated to 60 ℃ of stirring and refluxing 4h, have yellow solid matter to generate.Solid filtering is gone out, with ethanol, clean 3～4 times at normal temperatures, remove impurity.40ml dehydrated alcohol in addition dissolves solid completely when being heated to 65 ℃ of left and right again, is cooled to room temperature, and recrystallization obtains brown solid target compound N-p-methylphenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 62%.Mp119-121℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：2.44(s，3H)；4.75(s，2H)；6.15(s，1H)；6.54-7.32(11H，Ar-H)；10.80(s，1H).MS(ESI)：402.1([M+H] +).Anal.calc.forC 21H 18C l 2N 2O 2：C，62.85；H，4.52；N，6.98％；found：C，62.93；H，4.54；N，6.95％.
The preparation of embodiment 2:N-to fluorophenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 2)
Figure G2009102629549D00041
Preparation method is with embodiment 1.With para-fluoroaniline, replace monomethylaniline, obtain blackish green crystal target compound N-to fluorophenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-}-N '-phenylurea.Productive rate 66%.Mp 124-129℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.75(s，2H)；6.07(s，1H)；6.53-7.60(11H，Ar-H)；10.59(s，1H).MS(ESI)：406.1([M+H] +).Anal.calc.for C 20H 15Cl 2FN 2O 2：C，59.28；H，3.73；N，6.91％；found：C，59.27；H，3.76；N，6.89％.
The preparation of embodiment 3:N-p-methoxyphenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 3)
Figure G2009102629549D00051
Preparation method is with embodiment 1.With P-nethoxyaniline, replace monomethylaniline, obtain brown crystal target compound N-p-methoxyphenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 67%.Mp125-128℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：3.88(s，3H)；4.73(s，2H)；6.16(s，1H)；6.55-7.61(11H，Ar-H)；10.78(s，1H).MS(ESI)：418.1([M+H] +).Anal.calc.forC 21H 18Cl 2N 2O 3：C，60.44；H，4.35；N，6.71％；found：C，60.92；H，4.37；N，6.70％.
The preparation of embodiment 4:N-rubigan-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 4)
Figure G2009102629549D00052
Preparation method is with embodiment 1.With p-Chlorobenzoic acid amide, replace monomethylaniline, obtain white solid target compound N-rubigan-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 59%.Mp 123-127℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.77(s，2H)；6.10(s，1H)；6.51-7.71(11H，Ar-H)；10.73(s，1H).MS(ESI)：422.0.([M+H] +).Anal.calc.forC 20H 15Cl 3N 2O 2：C，56.96；H，3.59；N，6.64；found：C，56.83；H，3.57；N，6.62％.
The preparation of embodiment 5:N-Chloro-O-Phenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 5)
Figure G2009102629549D00061
In 250ml single necked round bottom flask, add 100ml dehydrated alcohol, add 3,5-dichloro-salicylaldehyde (10mmol) and Ortho-Chloro aniline (12mmol).Stirring reaction approximately 3 hours, on Rotary Evaporators, pressure reducing and steaming solvent and unnecessary amine, obtain yellow oil.Under heating condition, with 40ml ethanol, it is all dissolved, cooling recrystallization, obtains white solid afterwards.Solid transfer is entered to 250ml single necked round bottom flask, add 100ml dehydrated alcohol it is dissolved completely, and flask is placed in to ice bath, slowly in reaction system, drip sodium borohydride (380mg, 10mmol), remove ice bath, at normal temperatures the about 6h of stirring reaction.Take off flask, in reaction system, add water, be transferred to 500ml separating funnel, add 200ml chloroform extraction 2～3 times at every turn, after extraction liquid pressure reducing and steaming chloroform, obtain the chloro-2-[(2-chlorobenzene of 2,4-bis-amino)-methyl] phenol.Transfer them in 250ml single necked round bottom flask, adding 100ml chloroform dissolves, in solution, drip 10mmol phenylcarbimide (PhNCO) again, be heated to 60 ℃ of stirring and refluxing 4h, reaction finish after on Rotary Evaporators pressure reducing and steaming solvent, then take ethyl acetate: sherwood oil=1: 4 is elutriant, silica gel column chromatography separation obtains yellow oily target compound N-Chloro-O-Phenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 37%. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.79(s，2H)；6.04(s，1H)；6.56-7.62(11H，Ar-H)；10.80(s，1H).MS(ESI)：421.0.([M+H] +).Anal.calc.for C 20H 15Cl 3N 2O 2：C，56.96；H，3.59；N，6.64；found：C，56.90；H，3.57；N，6.66％.
The preparation of embodiment 6:N-to bromophenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 6)
Figure G2009102629549D00071
Preparation method is with embodiment 1.With para-bromoaniline, replace monomethylaniline, obtain gray solid target compound N-to bromophenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 61%.Mp 123-126℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.73(s，2H)；6.15(s，1H)；6.61-7.41(11H，Ar-H)；10.70(s，1H).MS(ESI)：467.9.([M+H] +).Anal.calc.forC 20H 15BrCl 2N 2O 2：C，51.53；H，3.24；N，6.01；found：C，51.41；H，3.27；N，6.04％.
The preparation of embodiment 7:N-(2,4 difluorobenzene base)-N-(3 ,-bis-chloro-2-hydroxybenzyls)-N '-phenylurea (compound 7)
Figure G2009102629549D00072
Preparation method is with embodiment 1.With 2,4 difluorobenzene amine, replace monomethylaniline, obtain garnet solid target compound N-(2,4 difluorobenzene base)-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 56%.Mp 123-125℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.70(s，2H)；6.47(s，1H)；6.91-7.61(10H，Ar-H)；10.64(s，1H).MS (ESI)：423.2.([M+H] +).Anal.calc.forC 20H 14F 2Cl 2N 2O 2：C，56.76；H，3.33；N，6.62；found：C，56.81；H，3.37；N，6.64％.
The preparation of embodiment 8:N-(3-morpholine propyl group)-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 8)
Figure G2009102629549D00081
Preparation method is with embodiment 1.With N-(3-aminopropyl) morpholino, for to monomethylaniline, obtain brown solid target compound N-(3-morpholine propyl group)-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 43%.Mp＝128-132℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：1.56(m，2H)；2.35(t，J＝2.7，4H)；2.46(t，J＝3.4，2H)；3.44(t，J＝2.8，2H)；3.65(t，J＝3.6，4H)；4.76(s，2H)；6.12(s，1H)；6.56-7.45(7H，Ar-H)；10.12(s，1H).MS(ESI)：439.1.([M+H] +).Anal.calc.for C 21H 25Cl 2N 3O 3：C，57.54；H，5.75；N，9.59；found：C，57.44；H，5.80；N，9.56％.
The preparation of embodiment 9:N-(2-morpholine ethyl)-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 9)
Figure G2009102629549D00091
Preparation method is with embodiment mono-.With N-(2-morpholine ethyl) morpholino, for to monomethylaniline, obtain brown solid target compound N-(2-morpholine ethyl)-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 38%.Mp 126-129℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：2.36(t，J＝2.7，4H)；2.39(t，J＝2.2，2H)；3.55(t，J＝6.0，2H)；3.65(t，J＝2.4，4H)；4.78(s，2H)；6.01(s，1H)；6.53-7.37(7H，Ar-H)；10.77(s，1H).MS(ESI)：427.1.([M+H] +).Anal.calc.for C 20H 23Cl 2N 3O 3：C，56.61；H，5.46；N，9.90；found：C，56.45；H，5.50；N，9.85％.
The preparation of embodiment 10:N-dodecyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 10)
Figure G2009102629549D00092
Preparation method is with embodiment 1.With dodecyl amine, replace monomethylaniline, obtain white solid target compound N-dodecyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 50%.Mp 134-137℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：0.89-3.64(25H，dodecyl -h)；4.84(s，2H)；6.37(S，1H)；7.01-7.40(7H，Ar-H)；10.60(s，1H).MS(ESI)：482.2.([M+H] +).Anal.calc.for C 26H 36Cl 2N 2O 2：C，65.13；H，7.57；N，5.84；found：C，65.21；H，7.55；N，5.85％.
The preparation of embodiment 11:N-hexadecyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 11)
Figure G2009102629549D00101
Preparation method is with embodiment 1.With n-hexadecyl amine, replace monomethylaniline, obtain white solid target compound N-hexadecyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 46%.Mp 129-132℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：0.87-3.71(33H，cetyl-h)；4.73(s，2H)；6.38(S，1H)；7.14-7.60(7H，Ar-H)；10.53(s，1H).MS(ESI)：535.3.([M+H] +).Anal.calc.forC 30H 44Cl 2N 2O 2：C，67.28；H，8.28；N，5.23；found：C，67.39；H，8.30；N，5.21％.
The preparation of embodiment 12:N-octadecyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea (compound 12)
Figure G2009102629549D00102
Preparation method is with embodiment 1.With positive octadecyl amine, replace monomethylaniline, obtain white cotton-shaped target compound N-octadecyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenylurea.Productive rate 45%.Mp 115-117℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：0.86-3.24(37H，stearyl-h)；4.80(s，2H)；6.42(S，1H)；7.07-7.31(7H，Ar-H)；10.65(s，1H).MS(ESI)：563.3.([M+H] +).Anal.calc.for C 32H 48Cl 2N 2O 2：C，68.19；H，8.58；N，4.97；found：C，68.07；H，8.59；N，5.00％.
The preparation of embodiment 13:N-p-methylphenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 13)
Figure G2009102629549D00111
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3 ,-dichloro-salicylaldehyde, obtains white crystal target compound N-p-methylphenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 57%.Mp 104-107℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：3.88(s，3H)；4.70(s，2H)；6.13(s，1H)；6.61-7.61(12H，Ar-H)；10.04(s，1H).MS(ESI)：368.1([M+H] +).Anal.calc.forC 21H 19ClN 2O 2：C，68.76；H，5.22；N，7.64％；found：C，68.61；H，5.26；N，7.63％.
The preparation of embodiment 14:N-to fluorophenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 14)
Figure G2009102629549D00112
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with para-fluoroaniline, replace monomethylaniline, obtain white powder target compound N-to fluorophenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 59%.Mp 103-105℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.71(s，2H)；6.17(s，1H)；6.55-7.57(12H，Ar-H)；10.07(s，1H).MS(ESI)：371.0([M+H] +).Anal.calc.for C 20H 16ClFN 2O 2：C，64.78；H，4.35；N，7.55％；found：C，64.88；H，4.39；N，7.52％.
The preparation of embodiment 15:N-p-methoxyphenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 15)
Figure G2009102629549D00121
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with P-nethoxyaniline, replace monomethylaniline, obtain brown ceramic powder shape target compound N-p-methoxyphenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 63%.Mp 110-112℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：3.88(s，3H)；4.71(s，2H)；6.04(s，1H )；6.57-7.61(12H，Ar-H)；10.01(s，1H).MS(ESI)：384.1([M+H] +).Anal.calc.for C 21H 19ClN 2O 3：C，65.88；H，5.00；N，7.32％；found：C，65.72；H，5.02；N，7.29％.
The preparation of embodiment 16:N-rubigan-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 16)
Figure G2009102629549D00131
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with p-Chlorobenzoic acid amide, replace monomethylaniline, obtain white powder target compound N-rubigan-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 43%.Mp 102-106℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.69(s，2H)；6.03(s，1H)；6.85-7.67(11H，Ar-H)；10.04(s，1H).MS(ESI)：388.0.([M+H] +).Anal.calc.for C 20H 16Cl 2N 2O 2：C，62.03；H，4.16；N，7.23％；found：C，62.17；H，4.11；N，7.27％.
The preparation of embodiment 17:N-Chloro-O-Phenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 17)
Figure G2009102629549D00132
Preparation method is with embodiment 5.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, obtain yellow oily target compound N-Chloro-O-Phenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 30%. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.70(s，2H)；6.11(s，1H)；6.09-8.08(12H，Ar-H)；10.14(s，1H).MS(ESI)：388.3.([M+H] +).Anal.calc.for C 20H 16Cl 2N 2O 2：C，62.03；H，4.16；N，7.23％；found：C，62.12；H，4.20；N，7.21％.
The preparation of embodiment 18:N-to bromophenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 18)
Figure G2009102629549D00141
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with para-bromoaniline, replace monomethylaniline, obtain brown solid target compound N-to bromophenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 59%.Mp 95-97℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.70(s，2H)；6.10(s，1H)；6.64-7.41(12H，Ar-H)；10.02(s，1H).MS(ESI)：432.0.([M+H] +).Anal.calc.forC 20H 16BrClN 2O 2：C，55.54；H，3.74；N，6.49％；found：C，55.61；H，3.76；N，6.44％.
The preparation of embodiment 19:N-(2,4 difluorobenzene base)-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 19)
Figure G2009102629549D00142
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with 2,4 difluorobenzene amine, replace monomethylaniline, obtain brown powder shape target compound N-(2,4 difluorobenzene base)-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 41%.Mp 96-101℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.77(s，2H)；6.02(1H)；6.55-7.60(11H，Ar-H)；9.95(s，1H).MS(ESI)：391.0.([M+H] +).Anal.calc.for C 20H 15F 2ClN 2O 2：C，61.78；H，3.89；N，7.21％；found：C，61.55；H，3.91；N，7.15％.
The preparation of embodiment 20:N-(3-morpholine propyl group)-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 20)
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with N-propyl group morpholino, for to monomethylaniline, obtain yellow powder shape target compound N-(3-morpholine propyl group)-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 41%.Mp 99-102℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：1.54(m，2H)；2.38(t，J＝2.7，4H)；2.47(t，J＝3.4，2H)；3.43(t，J＝2.8，2H)；3.62(t，J＝3.6，4H)；4.75(s，2H)；6.17(s，1H)；6.55-7.39(8H，Ar-H)；10.05(s，1H).MS(ESI)：405.2.([M+H] +).Anal.calc.for C 21H 26ClN 3O 3：C，62.45；H，6.49；N，10.40％；found：C，62.30；H，6.51 N，10.38％.
The preparation of embodiment 21:N-(2-morpholine ethyl)-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 21)
Figure G2009102629549D00161
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with N-ethylmorpholine, replace monomethylaniline, obtain brown ceramic powder shape target compound N-(2-morpholine ethyl)-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 34%.Mp 103-108℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：2.32(t，J＝2.7，4H)；2.33(t，J＝2.2，2H)；3.50(t，J＝6.0，2H)；3.61(t，J＝2.4，4H)；4.71(s，2H)；6.11(s，1H)；6.48-7.55(8H，Ar-H)；10.11(s，1H).MS(ESI)：391.2.([M+H] +).Anal.calc.forC 20H 24ClN 3O 3：C，61.61；H，6.20；N，10.78％；found：C，61.38；H，6.24；N，10.73％.
The preparation of embodiment 22:N-dodecyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 22)
Figure G2009102629549D00162
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with positive dodecyl amine, replace monomethylaniline, obtain white powder target compound N-dodecyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 39%.Mp 110-112℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：0.89-3.67(25H，dodecyl-h)；4.78(s，2H)；6.23(S，1H)；6.40-7.31(8H，Ar-H)；10.01(s，1H).MS(ESI)：446.2.([M+H] +).Anal.calc.for C 26H 37ClN 2O 2：C，70.17；H，8.38；N，6.29％；found：C，70.16；H，8.36；N，6.25％.
The preparation of embodiment 23:N-hexadecyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 23)
Figure G2009102629549D00171
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with n-hexadecyl amine, replace monomethylaniline, obtain white solid target compound N-hexadecyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 42%.Mp 102-106℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：0.87-3.67(33H，cetyl-h)；4.77(s，2H)；6.26(s，1H)；6.49-7.61(8H，Ar-H)；10.01(s，1H).MS(ESI)：502.3.([M+H] +).Anal.calc.for C 30H 45ClN 2O 2：C，71.90；H，9.05；N，5.59；found：C，71.76；
H，9.07；N，5.56％.
The preparation of embodiment 24:N-octadecyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea (compound 24)
Figure G2009102629549D00172
Preparation method is with embodiment 1.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with Octadecane base amine, replace monomethylaniline, obtain white solid target compound N-octadecyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenylurea.Productive rate 57%.Mp 95-97℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：0.82-3.71(37H，stearyl-h)；4.79(s，2H)；6.41(s，1H)；7.07-7.30(8H，Ar-H)；10.09(s，1H).MS(ESI)：532.4.([M+H] +).Anal.calc.for C 32H 49ClN 2O 2：C，72.63；H，9.33；N，5.29；found：C，72.70；H，9.37；N，5.27％.
The preparation of embodiment 25:N-p-methylphenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenyl-N '-nitrosourea (compound 25)
The compound 1 that embodiment 1 is made takes 2mmol and is dissolved in the anhydrous acetonitrile that 12ml contains 172 μ l glacial acetic acids, is placed under condition of ice bath, adds 3mmol NOBF 4, reaction 8-12 hour, TLC monitoring, adds frozen water: ethyl acetate=1 in the backward reaction system of reaction end: 1 solution, with 5%NaHCO 3solution is adjusted pH to 5-6, ethyl acetate aqueous phase extracted 2 times, merge organic phase, anhydrous magnesium sulfate drying, then take ethyl acetate: sherwood oil=1: 4 is elutriant, silica gel column chromatography separation obtains brown particle shape target compound N-p-methylphenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenyl-N '-nitrosourea.Productive rate 34%.Mp 93-97℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：2.46(s，3H)；4.77(s，2H)；6.91-8.14(11H，Ar-H)；10.15(s，1H).MS(ESI)：430.2([M+H] +).Anal.calc.for C 21H 17Cl 2N 3O 3：C，58.62；H，3.98；N，9.77％；found：C，58.41；H，3.92；N，9.80％.
The preparation of embodiment 26:N-to fluorophenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenyl-N '-nitrosourea (compound 26)
Figure G2009102629549D00191
Preparation method is with embodiment 25.With compound 2, replace compound 1, obtain faint yellow particulate state target compound N-to fluorophenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenyl-N '-nitrosourea.Productive rate 31%.Mp 99-102℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.81(s，2H)；7.23-8.04(11H，Ar-H)；9.87(s，1H).MS(ESI)：434.2([M+H] +).Anal.calc.for C 20H 14Cl 2FN 3O 3：C，55.32；H，3.25；N，9.68％；found：C，55.51；H，3.21；N，9.70％.
The preparation of embodiment 27:N-p-methoxyphenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenyl-N '-nitrosourea (compound 27)
Figure G2009102629549D00192
Preparation method is with embodiment 25.With compound 3, replace compound 1, obtain brown oily target compound N-p-methoxyphenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenyl-N '-nitrosourea.Productive rate 39%. 1H-NMR(300MHz，DMSO-d 6，δppm)：3.81(s，3H)；4.73(s，2H)；7.19-7.81(11H，Ar-H)；10.38(s，1H).MS(ESI)：446.2([M+H] +).Anal.calc.forC 21H 17Cl 2N 3O 4：C，56.52；H，3.84；N，9.42％；found：C，55.31；H，3.82；N，9.40％.
The preparation of embodiment 28:N-to bromophenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenyl-N '-nitrosourea (compound 28)
Figure G2009102629549D00201
Preparation method is with embodiment 25.With compound 6, replace compound 1, obtain yellow oily target compound N-to bromophenyl-N-(the chloro-2-hydroxybenzyl of 3,5-bis-)-N '-phenyl-N '-nitrosourea.Productive rate 33%. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.73(s，2H)；7.11-8.02(11H，Ar-H)；10.30(s，1H).MS(ESI)：496.9.([M+H] +).Anal.calc.for C 20H 14BrCl 2N 3O 3：C，48.51；H，2.85；N，8.49；found：C，48.31；H，2.87；N，8.44％.
The preparation of embodiment 29:N-p-methylphenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenyl-N '-nitrosourea (compound 29)
Figure G2009102629549D00211
Preparation method is with embodiment 25.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with compound 13, replace compound 1, obtain yellow powder shape target compound N-p-methylphenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenyl-N '-nitrosourea.Productive rate 37%.Mp 94-97℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：2.48(s，3H)；4.77(s，2H)；6.87-8.10(12H，Ar-H)；10.21(s，1H).MS(ESI)：396.1([M+H] +).Anal.calc.for C 21H 18ClN 3O 3：C，63.72；H，4.58；N，10.62％；found：C，63.63；H，4.60；N，10.63％.
The preparation of embodiment 30:N-to fluorophenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenyl-N '-nitrosourea (compound 30)
Figure G2009102629549D00212
Preparation method is with embodiment 25.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with compound 14, replace compound 1, obtain brown oily target compound N-to fluorophenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenyl-N '-nitrosourea.Productive rate 31%. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.91(s，2H)；7.15-7.76(12H，Ar-H)；10.10(s，1H).MS(ESI)：40.1([M+H] +).Anal.calc.forC 20H 15ClFN 3O 3：C，60.08；H，3.78；N，10.51％；found：C，60.25；H，3.91；N，10.50％.
The preparation of embodiment 31:N-p-methoxyphenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenyl-N '-nitrosourea (compound 31)
Figure G2009102629549D00221
Preparation method is with embodiment 25.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with compound 15, replace compound 1, obtain yellow powder powder target compound N-p-methoxyphenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenyl-N '-nitrosourea.Productive rate 43%.Mp 83-86℃. 1H-NMR(300MHz，DMSO-d 6，δppm)：3.89(s，3H)；4.77(s，2H)；7.31-7.91(12H，Ar-H)；10.11(s，1H).MS(ESI)：413.1([M+H] +).Anal.calc.for C 21H 18ClN 3O 4：C，61.24；H，4.41；N，10.20％；found：C，61.42；H，4.42；N，10.21％.
The preparation of embodiment 32:N-to bromophenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenyl-N '-nitrosourea (compound 32)
Figure G2009102629549D00231
Preparation method is with embodiment 25.With 5-chloro-salicylic aldehyde, replace 3,5-dichloro-salicylaldehyde, with compound 18, replace compound 1, obtain yellow oily target compound N-to bromophenyl-N-(5-chlorine-2-hydroxyl benzyl)-N '-phenyl-N '-nitrosourea.Productive rate 41%. 1H-NMR(300MHz，DMSO-d 6，δppm)：4.73(s，2H)；7.13-8.00(12H，Ar-H)；10.22(s，1H).MS(ESI)：461.0.([M+H] +).Anal.calc.forC 20H 15BrClN 3O 3：C，52.14；H，3.28；N，9.12％；found：C，52.31；H，3.27；N，9.14％.
Embodiment 33: urea class and N '-nitrosoureas derivatives antitumor activity
Adopt MTT[3-(4,5)-bis-methyl-2-thiazoles-(2,5)-phenyl bromination tetrazole is blue] method measures the minimum inhibitory concentration (minimalinhibitory concentration, MIC) of above-claimed cpd to human oral cavity upper epidermis JEG-3 (KB) and human leukemia cell line (K562).
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin sulphate solution (200,000 U/ml) 0.5ml, add after tri-distilled water dissolving the NaHCO with 5.6% 3solution adjusts pH value to 7.2-7.4, is finally settled to 1000ml.Filtration sterilization.2. attached cell: the same, then add NaHCO 32.00g, HEPES 2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00g, KCl 0.40g, Na 2hPO 412H 2o0.06g, KH 2pO 40.06g, NaHCO 30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: test sample is dissolved and is made into storing solution with a small amount of tri-distilled water, general by 10 times of preparation storing solutions of experiment maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then add tri-distilled water dissolving.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05%-0.1%.Storing solution is stored in-20 ℃ of refrigerators standby.
(5) cultivation of Leukemia K562 cell: be suspension growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, is placed in 37 ℃, 5%CO 2in incubator, cultivate, every 3-4 days, go down to posterity once.While going down to posterity, nutrient solution in former bottle is transferred in centrifuge tube, the centrifugal 5min of 1000rpm, discards original fluid, add equivalent fresh medium, piping and druming evenly, pipettes in right amount to fresh culture bottle, then supplements fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) cultivation of human oral cavity upper epidermis cancer cells KB: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/ml Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 ℃, 5%CO 2in incubator, cultivate, every 3-4 days, go down to posterity once.While going down to posterity, first discard original fluid, then wash with D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium to stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette in right amount to fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(7) cell is hatched: 2 kinds of tumour cells in the vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 * 10 5individual ml -1.In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 ℃, 5%CO 2in incubator, cultivate 24h.Cultivate after 24h, by design, add liquid respectively.
(8) dosing: test liquid is joined respectively in each hole according to the concentration gradient of ultimate density, and each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds respectively different concns), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in to 37 ℃, 5%CO 2in incubator, cultivate 48h.The activity of positive control medicine is measured according to the method for test sample.
(9) mensuration of survivaling cell: in having cultivated 96 orifice plates after 48h, every hole adds MTT 40 μ l (being made into 4mg/ml with D-Hanks damping fluid).At 37 ℃, place after 4h, remove supernatant liquor.Every hole adds 150 μ lDMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, utilize automatic microplate reader at 570nm wavelength place, to detect the optical density(OD) (OD value) in each hole.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD experiment-OD blank)/(OD contrast-OD blank)] * 100%
(OD experimentthe average optical that represents testing drug group, OD contrastthe average optical that represents control group, OD blankthe average optical that represents control group).
Half-inhibition concentration (IC 50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, on typical curve, try to achieve its corresponding drug level.
The IC recording 50be shown in Table 1
Table 1
Figure G2009102629549D00251
Figure G2009102629549D00261

Claims (8)

1. a class urea derivative, is characterized in that it has following general formula:
Figure FDA0000380158490000011
In formula:
R 1for H or nitroso-group;
R 2for 5-chlorine-2-hydroxyl phenmethyl or the chloro-2-hydroxybenzene of 3,5-bis-methyl;
R 3for p-methylphenyl, to fluorophenyl, p-methoxyphenyl, rubigan, to bromophenyl, 2,4 difluorobenzene base, 2-chloro-phenyl-, 2-(N-morpholinyl) ethyl or 3-(N-morpholinyl) propyl group.
2. prepare R claimed in claim 1 for one kind 1the method of the urea derivative of=H, is characterized in that it is comprised of the following step:
Step 1., in dehydrated alcohol, adds a certain amount of corresponding aldehyde and amine, and aldehyde is 1:1.1-1:1.3 with the ratio of the amount of substance of amine, under room temperature, react after 1h, and the solvent that pressure reducing and steaming is unnecessary and amine, in ethanol, recrystallization obtains R 3-N=R 2,
Step 2. is by the R obtaining 3-N=R 2be dissolved in dehydrated alcohol, be placed in ice bath, the NaBH of amount of substance such as slowly add wherein 4, after adding, remove ice bath, react at normal temperatures 3-6h, reaction finishes, and pressure reducing and steaming solvent, adds water, uses the chloroform extraction aqueous solution, and extraction liquid pressure reducing and steaming chloroform, obtains R 3nHR 2,
Step 3. will wait the compound R of amount of substance 3nHR 2be dissolved in chloroform with phenylcarbimide (PhNCO), stirring and refluxing 2-4h at room temperature, reaction finishes to add normal hexane to make to separate out more solids in backward reaction system, filter, by gained solid recrystallization or after reaction finishes in ethanol, pressure reducing and steaming solvent, the ethyl acetate/petroleum ether of take obtains R as eluent silica gel column chromatography 1the urea derivative of=H,
R wherein 2and R 3implication identical with claim 1.
3. method for making according to claim 2, is characterized in that: in step 1, the consumption of described dehydrated alcohol is every mmole aldehyde 10-15ml dehydrated alcohol.
4. method for making according to claim 2, is characterized in that: in step 2, the consumption of described dehydrated alcohol is every mmole R 3-N=R 2use 10-15ml dehydrated alcohol.
5. method for making according to claim 2, is characterized in that: in step 3, and described CHCl 3consumption be every mmole R 3-N=R 2add 10-15ml CHCl 3.
6. prepare R claimed in claim 1 for one kind 1the method of the urea derivative of=NO, is characterized in that it is comprised of the following step:
The R that method claimed in claim 2 is made 1the urea derivative of=H is dissolved in the anhydrous acetonitrile that adds acetic acid, and acetic acid is 1.5:1 with the ratio of the amount of substance of urea derivative, under ice bath is cooling, adds NOBF 4, NOBF 4with the ratio of the amount of substance of urea derivative be 1.5:1, at the cooling lower reaction 8-12 hour of ice bath, reaction finishes to add frozen water in backward reaction system, with 5%NaHCO 3solution regulates pH to 5-6, adds isopyknic ethyl acetate aqueous phase extracted, merges organic phase, anhydrous magnesium sulfate drying, and then column chromatography for separation obtains R 1the urea derivative of=NO.
7. method for making according to claim 6, is characterized in that: described CH 3the consumption of CN is the R of every mmole 1the urea derivative of=H 6ml anhydrous acetonitrile.
8. the application of urea derivative claimed in claim 1 in preparing antitumor drug.
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