CN103848778A - Aminopeptidase N inhibitor and preparation method and application thereof - Google Patents
Aminopeptidase N inhibitor and preparation method and application thereof Download PDFInfo
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- CN103848778A CN103848778A CN201410123847.9A CN201410123847A CN103848778A CN 103848778 A CN103848778 A CN 103848778A CN 201410123847 A CN201410123847 A CN 201410123847A CN 103848778 A CN103848778 A CN 103848778A
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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Abstract
The invention discloses an aminopeptidase N inhibitor which has a chemical name of 2-((S)-3-(3-((S)-2-amino-3-phenylpropyl)urea)-2,6-dioxopiperidine-1-yl)-N-hydroxyacetamide hydrochloride and is a compound with a structural formula (I) described in the specification. The invention further discloses a preparation of the compound and application of the compound in preparation of antitumor medicines. The aminopeptidase N inhibitor obtained by the invention is matched with an active site of aminopeptidase N in space, thereby showing stronger antitumor activity in evaluation of in vitro and vivo antitumor activity evaluation.
Description
Technical field
The present invention relates to a kind of preparation method of aminopeptidase N inhibitor and the medicinal use at anti-tumor aspect, belong to technical field of chemistry.
Background technology
Aminopeptidase N (APN, CD13) typically refer to people's alanyl-amino peptidase (EC3.4.11.2), it is the dependent hydrolysising protease of a kind of zine ion, belong to metalloprotease M1 family, be present on cytolemma with the form of homodimer, with cell-surface antigens CD13 be same material; Aminopeptidase N has expression on the various kinds of cell surface of Various Tissues, especially abundant in the intestinal epithelial cells of small intestine and the epithelial cell of kidney proximal tubule, also has expression in liver, placenta and uterus.Aminopeptidase N can discharge from peptide, acid amides or the hydrolysis of fragrant acid amides neutral amino acids or the basic aminoacids (Ala>Phe>Tyr>Le u>Arg>Thr>Trp) of N end, the natural substrate of effect comprises: blood vessel function peptide, neuropeptide hormone, cytokine and immunomodulator etc.Studies have shown that, Aminopeptidase N plays an important role in tumorigenesis, Invasion and Metastasis, tumor-blood-vessel growth, immunologic function adjusting and virus infection.
1) APN expresses at tumor cell surface height, can degradation of cell epimatrix, and participate in the generation of tumour neovascularity as a novel signal transduction molecule; thereby promote tumor cell invasion and transfer (Bauvois; B.et al.Med Res Rev., 2006,26 (1): 88; Zhang, X.et al.Curr.Med.Chem., 2008,15 (27): 2850.).2) APN participates in the inflammatory reaction that T lymphocyte relies on, and can be expressed in antigen presenting cell surface, degraded immunologic active material (as interleukin-8); Also reduce the recognition capability of T cell to its antigen, slackened scavenger cell and NK cell identification and the kill capability to tumour cell simultaneously, immunity of organisms is declined.3) APN can make the chemokine Fmlp of HIV auxiliary receptor CCR 5 desensitization by degraded, thereby reduces the innate immune function of cell, and makes CCR5 enhanced sensitivity; promote HIV cell entry host cell (Shen W.et al.Blood; 2000,96 (8), 2887; Shipp MA, et al.Blood, 1993,82 (4), 1052.).4) APN, as the acceptor on human corona virus HCoV-229E and Transmissible gastroenteritis virus (TGEV) surface, plays an important role in upper respiratory tract infection (as: SARS) and acute enteritis.（Delmas,B.et?al.Nature,1992,357,417;Yeager,CL.et?al.Nature,1992,420.）。5) the APN Angiotensin of can degrading, participates in adjusting (Mitsui, T.et al.Biol.Pharm.Bull., 2004,27 (6): 768.) of body blood pressure.
Bestatin, commodity are called ubenimex, it is a class dipeptide compound with beta-amino acids structure, it is the APN inhibitor for leukemia treating as immunostimulant of a unique listing at present, because be separates and obtain from the nutrient solution of the netted streptomycete of olive (Streptomyces olivorecticuli), originate limited.Therefore, utilize chemosynthesis means to obtain to have the small molecules APN inhibitor of anti-tumor activity to have great importance.
In patent (CN200910020656.9), alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof are reported; wherein compound 13f has stronger inside and outside anti-tumor activity; but in compound 13f structure, contain the peptide bond of easy body endoproteinase degraded, internal metabolism less stable.The chemical structural formula of compound 13f is as follows:
Summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind of aminopeptidase N inhibitor, this compound suppresses interior the inhibition in lotus H22 hepatoma mice Blood route metastasis experimental test of activity experiment, the test of inhibition tumor cell proliferation activity and body of Aminopeptidase N in vitro, and its activity is all better than compound 13f.
Another object of the present invention is to provide the preparation method of this aminopeptidase N inhibitor and in the application of preparing in antitumor drug.
For achieving the above object, the present invention adopts following technical scheme:
A kind of aminopeptidase N inhibitor, chemical name is: 2-((S)-3-(3-((S)-2-amino-3-hydrocinnamyl) urea)-2,6-dioxopiperidin-1-yl)-N-glycoloyl amine hydrochlorate, there is the compound of structure formula I:
The preparation method of described compound, reactions steps and reaction formula are as follows:
1) taking Boc protection L-glutamine (1) as starting raw material; protect to obtain intermediate (4) through cyclization, nucleophilic substitution, de-Boc; intermediate (4) prepares key intermediate isocyanic ester (5) under triphosgene effect, and synthetic route is:
Reagent in said synthesis route and reaction conditions are: (a) dicyclohexylcarbodiimide, N-hydroxy succinic acid imines, tetrahydrofuran (THF), 65 DEG C; (b) salt of wormwood, tetrabutylammonium iodide, potassiumiodide, acetone, benzyl acetate bromide, 56 DEG C; (c) trifluoroacetic acid, methylene dichloride; (d) triphosgene, sodium bicarbonate, methylene dichloride.
2) (S)-2-tertiary butyloxycarbonyl amide group-3-phenyl-propyl alcohol (6); after methylsulfonyl, azide, hydro-reduction, obtain intermediate (9); intermediate (9) obtains urea groups intermediate (10) with isocyanic ester (5) condensation; intermediate (10) is again through hydro-reduction debenzylation; with oxammonium hydrochloride condensation; finally slough Boc protecting group, obtain target compound (ZX-1), synthetic route is:
Reagent in said synthesis route and reaction conditions are: (a) methylsulfonyl chloride, triethylamine, tetrahydrofuran (THF), 0 DEG C; (b) sodium azide, DMF, 65 DEG C; (c) magnesium, methyl alcohol; (d) methylene dichloride, 0 DEG C; (e) 10% palladium charcoal, methyl alcohol, hydrogen; (f) isobutyl chlorocarbonate, triethylamine, oxammonium hydrochloride, 0 DEG C; (g) 3mol/L hydrogenchloride/ethyl acetate solution.
Those skilled in the art can change to improve yield to above-mentioned steps; they can determine synthetic route according to the ABC of this area; as selective reaction thing, solvent and temperature, thus can be by using various GPF (General Protection False bases to improve yield with the generation of avoiding side reaction.These conventional guard methods can be referring to for example T.Greene, Protecting Groups in Organic Synthesis.
The aminopeptidase N inhibitor that the present invention obtains, spatially matches with the avtive spot of Aminopeptidase N, therefore in anti-tumor activity evaluation in vivo and in vitro, all demonstrates stronger anti-tumor activity, and this compound is expected to develop into a kind of new type antineoplastic medicine.
Brief description of the drawings
Target compound anti-tumor in vivo cell lung shift experiment lung surface tubercle number prepared by Fig. 1 embodiment of the present invention 1;
Target compound anti-tumor in vivo cell lung metastasis inhibition rate prepared by Fig. 2 embodiment of the present invention 1.
Embodiment
The present invention is further illustrated in conjunction with the embodiments, should be noted that following explanation is only in order to explain the present invention, does not limit its content.
Synthesizing of embodiment 1. the compounds of this invention (I)
1) (the S)-tertiary butyl-2, the preparation of 6-dioxopiperidin-3-base carbonyl acid amides (2)
By Boc-L-glutamine (9.86g, 40.0mmol) and N-hydroxy-succinamide (4.6g, 40.0mmol) be dissolved in 100ml tetrahydrofuran (THF) (THF), under cryosel bath condition, slowly drip the THF solution that 50ml contains dicyclohexylcarbodiimide (8.24g, 40mmol).Within approximately 1 hour, drip off, remove ice bath, stirring at room temperature is after 3 hours, back flow reaction 10 hours.Reaction solution is cooled to room temperature, removes solvent under reduced pressure.Residue adds 40ml ethyl acetate reconcentration once.Final residue thing adds after 50ml ethyl acetate, and refrigerator freezing is placed and spent the night.With 2.0g diatomite filtration, filtrate is respectively with water (20ml × 1) and saturated brine (20ml × 1) washing, and anhydrous magnesium sulfate drying, filters, and is concentrated into dry.Obtain white solid 6.8g, yield with ethyl acetate-ether recrystallization again: 74.5%, mp:213-214 DEG C (literature value 212-214 DEG C).
2) preparation of (S)-benzyl-2-(3-(tertiary butyloxycarbonyl amide group)-2,6-dioxopiperidin-1-yl) acetic ester (3)
By compound 2(4.0g, 17.5mmol), K
2cO
3(2.9g, 21mmol), tetrabutylammonium iodide (0.07g, 0.18mmol) DL is in 50ml anhydrous propanone.Under room temperature condition, slowly add benzyl acetate bromide (6.0g, 26.3mmol).Reaction solution refluxes 5 hours, is cooled to room temperature.Filter, concentrate to obtain yellow oil.Add 50ml ethyl acetate, organic phase is respectively with 0.5%Na
2cO
3(20ml × 2), 1N citric acid (20ml × 2), saturated brine are washed till neutrality, and organic phase, with anhydrous magnesium sulfate drying, is filtered, concentrated, obtains compound 3, white solid 4.41g, yield: 67.0% after ethyl acetate-ether recrystallization.mp：78.0-81.0℃；ESI-MS?m/z[M+1]
+：377.6。
3) preparation of (S)-benzyl-2-(3-isocyanic ester-2,6-dioxopiperidin-1-yl) acetic ester (5)
By compound 3(2.26g, 6.0mmol) be dissolved in 24ml methylene dichloride, until completely dissolved, slowly drip 6.0ml TFA, about 20min adds, and stirring at room temperature 3 hours is concentrated by reaction solution, then adds 20ml methylene dichloride evaporate to dryness.Residue is dissolved in the mixed solution of 30mL/30mL methylene dichloride and saturated sodium bicarbonate, under condition of ice bath, once adds the rear vigorous stirring of triphosgene (0.6g, 2.0mmol), after 1 hour, stop stirring separatory; Use afterwards dichloromethane extraction water three times, merge organic phase, anhydrous magnesium sulfate drying, filters, and concentrated solvent, to 20mL left and right, without further separation and purification, can be directly used in next step.
4) preparation of synthetic (7) of (S)-2-tertiary butyloxycarbonyl amide group-3-phenyl-methylsulfonic acid propyl ester
By (S)-2-tertiary butyloxycarbonyl amide group-3-phenyl-propyl alcohol (6) (11.3g, 45.0mmol) be dissolved in 100mL anhydrous tetrahydro furan, ice bath is cooled to 0 DEG C, add anhydrous triethylamine (4.55g, 45.0mmol), under condition of ice bath, dropwise add 20mL to be dissolved with methylsulfonyl chloride (5.15g, anhydrous tetrahydrofuran solution 45.0mmol), within approximately 0.5 hour, dropwise, remove ice bath, after room temperature reaction 4 hours, reaction solution impouring is filled in the beaker of cold water, there are a large amount of white solids to separate out, solid filtering is dry, obtain target compound compound 12.0g, yield: 81.0%, mp:105-108 DEG C.
5) preparation of synthetic (8) of (S)-2-tertiary butyl (2-azido-methyl-1-styroyl) carbamate
By compound 7(10.0g, 30.0mmol) be dissolved in 80mL DMF, be warming up to 60 DEG C, add sodiumazide (3.95g in batches, 60.0mmol), isothermal reaction is after 10 hours, by reaction solution impouring frozen water, ethyl acetate extraction (50mL × 3), merge organic phase, after anhydrous magnesium sulfate drying, filtering and concentrating obtains crude product, column chromatographic isolation and purification (eluent: petrol ether/ethyl acetate=10/1) obtains target compound 5.0g, yield: 60.3%.
6) preparation of synthetic (9) of (S)-2-tertiary butyloxycarbonyl amide group-3-phenyl-propylamine
By compound 8(4.0g, 15.0mmol) be dissolved in 80mL anhydrous methanol, under condition of ice bath, add the magnesium rod (1.08g of chopping in batches, 45.0mmol), react after 1 hour, solvent is removed under reduced pressure, residue adds cold water dilution, with ether extraction (50mL × 3), merges organic phase, saturated aqueous common salt (40mL × 3) washing, anhydrous magnesium sulfate drying, filters, by filtrate evaporate to dryness, obtain white solid 1.75g, yield: 46.6%, mp:114-116 DEG C.ESI-MS?m/z：251.1[M+H]
+；
1H-NMR(600MHz,DMSO-d
6)δ1.26-1.33(m,9H),2.62(d,J=6.7Hz,1H),2.63-2.76(m,1H),2.95-3.10(m,1H),3.51(s,1H),3.63(s,1H),6.63-6.70(m,1H),7.17-7.20(m,2H),7.26(s,2H)。
7) preparation of benzyl-2-((S)-3-(3-((S)-2-tertiary butyloxycarbonyl amide group-3-hydrocinnamyl) urea groups)-2,6-dioxopiperidin-1-yl)-acetic ester (10)
By compound 9(1.50g, 6.0mmol) be dissolved in 20mL methylene dichloride, in condition of ice bath downhill reaction liquid, drip 20mL compound 5(6.0mmol) dichloromethane solution, after dropwising, continue room temperature reaction 1 hour.Evaporated under reduced pressure solvent, residue is dissolved in 40mL ethyl acetate, successively with 1N citric acid (20mL × 1), saturated brine (20mL × 1) washing, anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness is obtained to crude product, and crude product obtains white solid 1.75g, yield 52.8% after column chromatographic isolation and purification (eluent: petrol ether/ethyl acetate=4/1).mp：168-170℃。ESI-MS?m/z：575.3[M+Na]
+1。H-NMR(600MHz，DMSO-d
6)δ1.23-1.28(m,9H),1.86-1.92(m,1H),2.05-2.07(m,1H),2.61-2.65(m,1H),2.71-2.74(m,2H),2.88-2.92(m,1H),2.93-2.98(m,1H),3.15-3.18(m,1H),3.61-3.62(m,1H),4.41-4.49(m,2H),4.52-4.56(m,1H),5.13-5.17(m,2H),6.19-6.24(m,1H),6.55(d,J=6.7Hz,1H),6.70(d,J=6.7Hz,1H),7.17-7.21(m,3H),7.26-7.28(m,2H),7.33-7.40(m,5H)。
8) preparation of 2-((S)-3-(3-((S)-2-tertiary butyloxycarbonyl amide group-3-hydrocinnamyl) urea groups)-2,6-dioxopiperidin-1-yl)-acetic acid (11)
By compound 10(1.50g, 2.72mmol) be dissolved in the anhydrous methanol of 30mL, add catalytic amount 10%Pd/C, with H
2as hydrogen donor, room temperature reaction 16 hours, after reacting completely, filters, and obtains compound 11, white solid 1.21g, yield: 96.2%, mp:104-106 DEG C after concentrating under reduced pressure.ESI-MS?m/z：485.2[M+Na]
+，
1H-NMR(600MHz，DMSO-d
6)δ1.25-1.33(m,9H),1.83-1.91(m,1H),2.04-2.06(m,1H),2.61-2.64(m,1H),2.69-2.72(m,2H),2.85-2.91(m,1H),2.94-2.98(m,1H),3.14-3.18(m,1H),3.59-3.62(m,1H),4.23-4.31(m,2H),4.48-4.52(m,1H),6.19-6.26(m,1H),6.55(d,J=6.7Hz,1H),6.72(d,J=6.7Hz,1H),7.17-7.20(m,3H),7.26-7.28(m,2H)。
9) preparation of the tertiary butyl-(S)-1-(3-((S)-1-(2-azanol-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl) urea groups)-3-hydrocinnamyl-2-carboxylicesters (12)
By compound 11(0.93g, 2.0mmol) be dissolved in 30mL anhydrous tetrahydro furan, control solution temperature not higher than-20 DEG C, slowly add 0.26mL(2.2mmol) N-methylmorpholine, and after 5min, slowly add 0.3mL(2.2mmol) isobutyl chlorocarbonate.Reaction solution continues to stir after 30 minutes at-20 DEG C, and oxammonium hydrochloride (0.17g, the 2.45mmol) solution (adjusting pH to neutral with N-methylmorpholine in advance) that is dissolved in 3mL anhydrous methanol is slowly dropped in mixed anhydride reaction liquid, dropwises.Continue-20 DEG C of insulation reaction 1 hour then room temperature reaction 4 hours.After reaction finishes, with 2.0g diatomite filtration, concentrated, add 50mL ethyl acetate, successively with saturated sodium bicarbonate (10mL × 3), 1mol/L citric acid (10mL × 3), saturated aqueous common salt (10mL × 2) washing, anhydrous magnesium sulfate drying.Filter, concentrating under reduced pressure, column chromatography for separation (eluent: petrol ether/ethyl acetate=1/1) obtains compound 12, white solid 0.65g, yield: 68.1%; Mp=74-76 DEG C.ESI-MS?m/z：500.2[M+Na]
+，
1H-NMR(600MHz,DMSO-d
6)δ1.26-1.33(m,9H),1.88-1.93(m,1H),2.03(s,1H),2.63-2.66(m,1H),2.70-2.74(m,2H),2.81-2.86(m,1H),2.97(s,1H),3.15-3.17(m,1H),3.61(s,1H),4.12-4.20(m,2H),4.47-4.54(m,1H),6.22(s,1H),6.47(s,1H),6.68(s,1H),7.17-7.20(m,H),7.26-7.28(m,2H),8.80(s,1H),10.53(s,1H)。
10) preparation of 2-((S)-3-(3-((S)-2-amino-3-hydrocinnamyl) urea groups)-2,6-dioxopiperidin-1-yl)-N-hydroxyl imide salts hydrochlorate (ZX-1)
By compound 12(0.5g, 1.05mmol) be dissolved in 10mL hydrogenchloride/ethyl acetate (3mol/L) solution, room temperature reaction 3 hours, product is separated out with the form of hydrochloride, filters anhydrous diethyl ether washing, be drying to obtain target compound, called after ZX-1, white solid powder 0.36g, yield: 83.7%; Mp=88-90 DEG C.ESI-MS?m/z：378.1[M+Na]
+，
1H-NMR(600MHz,DMSO-d
6)δ1.91-1.95(m,1H),2.02-2.05(m,1H),2.67-2.73(m,1H),2.82-2.85(m,2H),2.89-2.95(m,1H),3.14-3.18(m,1H),3.22-3.25(m,1H),3.42-3.45(m,1H),4.13-4.19(m,2H),4.46-4.56(m,1H),6.69(s,1H),6.71-6.74(m,1H),7.26-7.28(m,1H),7.30-7.31(m,2H),7.33-7.36(m,2H),8.14(s,3H),8.78(s,1H),10.60(s,1H)。
Embodiment 2. target compounds suppress the activity experiment (In vitro) of Aminopeptidase N
Aminopeptidase N (APN) suppresses active test description in Lejczak, and the .Biochemistry such as B, in 1989,28,3549.Substrate L-leucyl-p-NA is degraded by APN, and being created in 405nm has the p-NA of absorption, and the concentration of p-NA and the size of enzymic activity are proportionate.By detect 405nm place optical density is determined the content of p-NA, thereby determine the activity of aminopeptidase, indirectly reflect the size of inhibitor to inhibition of enzyme activity degree.
Concrete grammar and operation steps are referring to CN100560568C " cyclin imide peptidyl metalloprotease inhibitor and application thereof ".Experimental result is in table 1.
The external Inhibiting enzyme activity test-results of table 1 target compound
In a table, numerical value is the mean value of three tests, the numeric representation standard deviation after " ± ".
Above-mentioned test result shows, target compound suppresses, in the test of APN enzymic activity, the APN of the kidney derived APN of pig and ES-2 cell expressing is all demonstrated to the activity that is better than positive control bestatin and lead compound 13f in vitro.
Embodiment 3. target compound inhibition tumor cell proliferation activity tests (In vitro)
In Vitro Anti to the tumour cell increment test of compound adopts Thiazolyl blue detection method (mtt assay), the cell suspension of human oophoroma cell line (ES-2) or human breast cancer cell strain (MDA-MB-231) is inoculated in respectively 96 orifice plates, in every hole, add the substratum containing different concns compound, after hatching, with MTT dyeing, after continuing to hatch, in microplate reader, measure the absorbancy (OD value) in every hole at 570nm place, calculate inhibitory rate of cell growth, thus the activity of deterministic compound.
1.[material] ES-2 cell strain, MDA-MB-231 cell strain, the blue MTT of tetramethyl-azo azoles, 10% foetal calf serum, 96 orifice plates.
2.[method]
Cell cultures clear cell carcinoma of ovary ES-2 cell strain and mammary cancer MDA-MB-231 cell strain all adopt cellar culture.When experiment, all use logarithmic phase cell.
Growth of Cells detects (mtt assay) ES-2 cell and MDA-MB-231 cell suspension is all adjusted to 1 × 10
5/ ml, is inoculated in respectively 96 orifice plates (50 μ l/ hole), 5 × 10
3individual cells/well.After bed board 4h, in every hole, add the substratum of 50 μ l containing different concns compound, compound final concentration in hole is respectively: 4000,800,160,32,6.4 μ mol/L, each concentration is established three multiple holes, do not add the hole reading of cell as blank, add the hole that cell do not add compound and make compound blank well, Bestatin makes compound positive control.In 37 DEG C, in 5% carbonic acid gas, hatch 48h, every hole adds the MTT staining fluid of 10 μ l0.5%, continues to hatch after 4h, 2500rpm, centrifugal 30min, then abandons substratum in plate hole, adds dimethyl sulfoxide (DMSO), 200 μ l/ holes.The absorbancy OD value of measuring every hole in microplate reader in 570nm place, inhibitory rate of cell growth is calculated as follows:
Inhibiting rate (%)=(the average OD value of the average OD value-experimental port of control wells) average OD value × 100% of/control wells
According to the concentration of compound and corresponding inhibiting rate, utilize origin7.5 software matching beneficial effect curve, calculate the IC of compound
50. experimental result is in table 2.
Table 2. target compound extracorporeal anti-tumor cell proliferation experiment result
In a table, numerical value is the mean value of three tests, the numeric representation standard deviation after " ± ".
Upper table test data shows, target compound demonstrates the activity that is better than positive control bestatin and lead compound 13f in the test of anti-tumour cell proliferative in vitro, has good DEVELOPMENT PROSPECT.
Embodiment 4. target compounds suppress lotus H22 hepatoma mice Blood route metastasis test (In vivo)
Concrete grammar and operation steps are referring to CN1528745A " pyrrolidinyl metalloprotease inhibitor and preparation method thereof ".Experimental result is shown in Fig. 1 and Fig. 2.
Experimental result shows, target compound, suppressing to demonstrate the activity that is better than positive control bestatin and lead compound 13f in the test of lotus H22 hepatoma mice Blood route metastasis, has good DEVELOPMENT PROSPECT.
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (4)
1. an aminopeptidase N inhibitor, chemical name is: 2-((S)-3-(3-((S)-2-amino-3-hydrocinnamyl) urea)-2,6-dioxopiperidin-1-yl)-N-glycoloyl amine hydrochlorate, there is the compound of structure formula I:
2. the preparation method of a kind of aminopeptidase N inhibitor claimed in claim 1, is characterized in that, comprises the following steps:
1) taking Boc protection L-glutamine (1) as starting raw material; protect to obtain intermediate (4) through cyclization, nucleophilic substitution, de-Boc; intermediate (4) prepares intermediate isocyanic ester (5) under triphosgene effect, and synthetic route is:
Reagent in said synthesis route and reaction conditions are: (a) dicyclohexylcarbodiimide, N-hydroxy succinic acid imines, tetrahydrofuran (THF), 65 DEG C; (b) salt of wormwood, tetrabutylammonium iodide, potassiumiodide, acetone, benzyl acetate bromide, 56 DEG C; (c) trifluoroacetic acid, methylene dichloride; (d) triphosgene, sodium bicarbonate, methylene dichloride;
2) (S)-2-tertiary butyloxycarbonyl amide group-3-phenyl-propyl alcohol (6); after methylsulfonyl, azide, hydro-reduction, obtain intermediate (9); intermediate (9) obtains urea groups intermediate (10) with isocyanic ester (5) condensation; intermediate (10) is again through hydro-reduction debenzylation; with oxammonium hydrochloride condensation; finally slough Boc protecting group, obtain target compound, synthetic route is:
Reagent in said synthesis route and reaction conditions are: (a) methylsulfonyl chloride, triethylamine, tetrahydrofuran (THF), 0 DEG C; (b) sodium azide, DMF, 65 DEG C; (c) magnesium, methyl alcohol; (d) methylene dichloride, 0 DEG C; (e) 10% palladium charcoal, methyl alcohol, hydrogen; (f) isobutyl chlorocarbonate, triethylamine, oxammonium hydrochloride, 0 DEG C; (g) 3mol/L hydrogenchloride/ethyl acetate solution.
3. aminopeptidase N inhibitor claimed in claim 1 is in the application of preparing in antitumor drug.
4. application as claimed in claim 3, is characterized in that, the application of described aminopeptidase N inhibitor in the medicine of preparing ovarian cancer resistance and mammary cancer.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108977498A (en) * | 2018-06-19 | 2018-12-11 | 潍坊医学院 | A kind of the Inhibiting enzyme activity measuring method and application of aminopeptidase N inhibitor |
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| CN1974554A (en) * | 2006-12-12 | 2007-06-06 | 山东大学 | Cyclin imide peptidyl metalloprotease inhibitor and its application |
| CN101538311A (en) * | 2009-04-16 | 2009-09-23 | 山东大学 | Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof |
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| CN1974554A (en) * | 2006-12-12 | 2007-06-06 | 山东大学 | Cyclin imide peptidyl metalloprotease inhibitor and its application |
| CN101538311A (en) * | 2009-04-16 | 2009-09-23 | 山东大学 | Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108977498A (en) * | 2018-06-19 | 2018-12-11 | 潍坊医学院 | A kind of the Inhibiting enzyme activity measuring method and application of aminopeptidase N inhibitor |
| CN108977498B (en) * | 2018-06-19 | 2022-09-20 | 潍坊医学院 | Method for determining enzyme inhibition activity of aminopeptidase N inhibitor and application thereof |
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| CN103848778B (en) | 2016-01-06 |
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