CN108976147A - The positive positive hexanoyl basic amino acid of hexanoyl amino first cyclic amide base of amino, synthesis, activity and application - Google Patents
The positive positive hexanoyl basic amino acid of hexanoyl amino first cyclic amide base of amino, synthesis, activity and application Download PDFInfo
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- CN108976147A CN108976147A CN201710400008.0A CN201710400008A CN108976147A CN 108976147 A CN108976147 A CN 108976147A CN 201710400008 A CN201710400008 A CN 201710400008A CN 108976147 A CN108976147 A CN 108976147A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
Abstract
The positive positive hexanoyl basic amino acid of hexanoyl amino first cyclic amide base of amino, synthesis, activity and application, the invention discloses (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of following formula (AA is L-Lys residue and L-Arg residue in formula).It discloses their preparation method, disclose their anti-tumor activity, disclose their activity of resisting tumor metastasis, and their anti-inflammatory activity activity is disclosed, thus anti-tumor drug is being prepared the invention discloses them, the application in medicine for anti transfer of tumor and anti-inflammatory drug.
Description
Technical field
The present invention relates to (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino, are related to their preparation method, relate to
And their anti-tumor activity, it is related to their activity of resisting tumor metastasis, and be related to their anti-inflammatory activity activity, thus this
Invention is related to them and is preparing anti-tumor drug, the application in medicine for anti transfer of tumor and anti-inflammatory drug.The invention belongs to biologies
Field of medicaments.
Background technique
Invasion and transfer process are the Basic biological characteristics of malignant tumour, are one of the predicaments of tumor research work.Cancer
The main reason for disease transfer is tumor patient morbidity and is dead, accounts for about the 90% of number of cancer deaths.At present to tumor-infiltrated turn
The research of shifting has carried out deep discussion from different aspect.Wherein, plasma urokinase-type plasminogen activator (uPA) series is swollen
Effect in tumor invasion transfer becomes one of the hot spot studied now.Plasma urokinase-type plasminogen activator (uPA) system, this is
A kind of serine stretch protein enzyme family is played a crucial role in the infiltration metastasis of tumour.The system includes urokinase type fibre
Plasminogen activator (uPA), urokinase receptor (uPAR), plasminogen activator inhibitor (PAI), the system are related to a variety of lifes
Reason and pathologic process, including cell migration, angiogenesis, inflammation, embryonic development, growth and metastasis of tumours.
Amino-n-hexanoic acid can generate Reverse transcriptase with activator of plasminogen, prevent plasminogen from activating as fibrinolytic
Enzyme is the fibrinolytic bleeding drug of clinical treatment.Tranexamic acid can equally play anti-fibrinolysis activity in conjunction with plasminogen.Two
Person can reach the dependent interaction for inhibiting uPA system by preventing uPA/uPAR interaction and inhibiting plasmin activation respectively.
It is respectively 3.8mmol/kg and 3.2mmol/kg that Amino-n-hexanoic acid and tranexamic acid, which inhibit the minimum effective dose of uPA system,.Hair
Bright people thinks that their toxic side effect and their minimum effective dose height have direct relation.Inventor recognize first by two kinds
The uPA system inhibitor reasonable combination known, the novel u-PA inhibitor for reconnecting amino acid and constructing should just have under low dosage
There are antitumor, anti-tumor metastasis and anti-inflammatory triple role.It according to this understanding, was explored by 3 years, basic amino acid is used in discovery
The positive hexanoyl first cyclic amide base n-caproic acid derivative of amino of (L-Lys and L-Arg) modification not only has under 0.5 μm of ol/kg dosage
There is activity of resisting tumor metastasis, and there is antitumor and anti-inflammatory activity simultaneously.Because the toxic side effect of drug can be with agent
Amount is reduced and is disappeared, and is shown this structure so effective dose than Amino-n-hexanoic acid and tranexamic acid at least reduces by 6400 times and is repaired
It is decorated with technical effect outstanding.According to these discoveries, the present invention is inventors herein proposed.
Summary of the invention
First content of the invention is to provide (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA (formula of-amino of following formula
Middle AA is L-Lys residue and L-Arg residue).
Second content of the invention is to provide (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino (AA L-
Lys residue and L-Arg residue) synthetic method, this method comprises:
(1) Boc- tranexamic acid and Amino-n-hexanoic acid methyl esters are condensed to obtain Boc- ammonia first ring acyl amino methyl hexyl (1)；
(2) Boc- ammonia first ring sulphonyl-amino methyl hexyl de- Boc in the ethyl acetate solution of hydrogen chloride obtains ammonia first ring
Acyl amino methyl hexyl (2)；
(3) Boc- Amino-n-hexanoic acid and ammonia first ring acyl amino methyl hexyl (2) are condensed (the positive hexanoyl of N-Boc- amino
Ammonia first ring acyl)-Amino-n-hexanoic acid methyl esters (3)；
(4) compound 3 is saponified demethylation and obtains (the positive hexanoyl ammonia first ring acyl of N-Boc- amino)-Amino-n-hexanoic acid (4)；
(5) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 4 obtains (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
N-caproic acid (7)；
(6) compound 4 and AA-OBzl (AA is L-Lys residue and L-Arg residue) are condensed (the positive hexanoyl of N-Boc- amino
Ammonia first ring acyl) the positive caproyl amino-acid benzyl ester (5a, b) of-amino.
(7) compound 5a, b elder generation hydrogenolysis take off benzyloxycarbonyl group, de- Boc obtains (N- in the ethyl acetate solution of hydrogen chloride again
The positive caproyl ammonia first ring acyl of amino) the positive hexanoyl-AA of-amino (6a, b) (AA is L-Lys residue and L-Arg residue).
Third content of the invention is evaluation (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino (AA L-
Lys residue and L-Arg residue) inhibit C57BL/6 mouse anti-lung cancer transfer activity.
4th content of the invention is evaluation (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino (AA L-
Lys residue and L-Arg residue) inhibition application to S180 mice tumors grew.
5th content of the invention is evaluation (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino (AA L-
Lys residue and L-Arg residue) to the inhibiting effect of ICR mouse inflammation.
Detailed description of the invention
AA is that L-Lys is residual in the synthetic route .5a and 6a of Fig. 1 (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino
Base；AA is L-Arg residue in 5b and 6b.I) dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (HOBt), N- methyl
Morpholine (NMM), dry tetrahydrofuran (THF)；Ii) the ethyl acetate solution (4M) of hydrogen chloride；iii)CH3OH,2MNaOH；iv)
Pd/C,H2,CH3OH；The ethyl acetate solution (4M) of hydrogen chloride.
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares (N-Boc- ammonia first ring acyl)-Amino-n-hexanoic acid methyl esters (1)
0.69g (2.68mmol) Boc- tranexamic acid is suspended in 50mL dry tetrahydrofuran, is sequentially added at 0 DEG C
0.66g (3.20mmol) dicyclohexylcarbodiimide (DCC) and 0.44g (3.26mmol) I-hydroxybenzotriazole (HOBt), are stirred
Mix 30min.Then be added 0.49g (2.70mmol) Amino-n-hexanoic acid methyl esters, and with N-methylmorpholine (NMM) adjusting pH value of solution to
9, TLC (methylene chloride/methanol=30/1) display reaction is completed after 6h is stirred at room temperature.It is concentrated under reduced pressure and removes solvent, residue is used
The dissolution of 50mL ethyl acetate, filters to get filtrate.Filtrate is successively saturated NaHCO with 20mL3Solution washs 3 times, and 20mL is saturated NaCl
Solution washs 3 times, and 20mL is saturated KHSO4Solution washs 3 times, and 20mL is saturated NaCl solution and washs 3 times, and 20mL is saturated NaHCO3It is molten
Liquid washs 3 times, and 20mL is saturated NaCl solution and washs 3 times, the ethyl acetate layer dry 12h of anhydrous sodium sulfate.Filtering, filtrate decompression
It is concentrated to dryness, obtains 0.83g (80%) title compound, be colorless solid.ESI-MS (m/e): 385 [M+H]+。
Embodiment 2 prepares N- ammonia first ring sulphonyl-amino methyl hexyl hydrochloride (2)
By the ethyl acetate solution (4M) of 6.00g (15.62mmol) compound 1 and 60mL hydrogen chloride at -10 DEG C under stirring
It is slowly mixed together, and keeps -10 DEG C of stirring 5h.TLC (methylene chloride/methanol=30/1) display reaction is completed.It is concentrated under reduced pressure, residual
Object is dissolved with anhydrous ethyl acetate, and obtained solution is concentrated under reduced pressure.The operation is repeated 3 times.Solid is sufficiently outstanding with anhydrous ether again
It is floating, ether is removed, obtained colorless solid is directly used in react in next step.ESI-MS(m/e):322[M+H]+。
Embodiment 3 prepares (the positive hexanoyl ammonia first ring acyl of N-Boc- amino)-Amino-n-hexanoic acid methyl esters (3)
Using the method for embodiment 1, from 3.36g (14.55mmol) Boc- Amino-n-hexanoic acid and 4.67g (14.57mmol)
Compound 2 obtains faint yellow solid.The solid is sufficiently worn away with ethyl acetate, obtains 6.20g (85%) title compound, is nothing
Color solid.ESI-MS (m/e): 498 [M+H]+。
Embodiment 4 prepares (the positive hexanoyl ammonia first ring acyl of N-Boc- amino)-Amino-n-hexanoic acid (4)
6.20g (12.47mmol) compound 3 is dissolved in 20mL methanol, 0 DEG C adjusts pH to 12 with NaOH aqueous solution (2M).
0 DEG C of control and pH 12 stir 4h, and TLC (methylene chloride/methanol=25/1) display reaction is completed.Reaction mixture saturation
KHSO4Solution adjusts pH to 7, is concentrated under reduced pressure.Residue continues with saturation KHSO4Solution adjusts pH to 2, is extracted with ethyl acetate,
Ethyl acetate layer is merged, is washed with saturation NaCl solution to neutrality.The ethyl acetate phase dry 12h of anhydrous sodium sulfate.Filtering,
Filtrate decompression is concentrated to dryness, and obtains 4.60g (76%) title compound, is colorless solid.ESI-MS (m/e): 484 [M+H]+。
Embodiment 5 prepares (the positive hexanoyl ammonia first ring acyl of N- amino)-Amino-n-hexanoic acid (7)
Using the method for embodiment 2,0.87g (84%) title compound is obtained from 1.30g (2.69mmol) compound 4,
For colorless solid.Mp 236-239℃；(c=0.1, H2O).ESI-MS(m/e):384[M+H]+.IR(cm-1):
3265,3081,2927,2857,1633,1557,1470,1416,1396,1362,1327,1235,1210,726,697.1H-
NMR(300MHz,D2O): δ/ppm=3.11 (t, J=6.6Hz, 2H), 2.98 (d, J=6.6Hz, 2H), 2.93 (t, J=
7.8Hz, 2H), 2.20 (t, J=7.2Hz, 2H), 2.12 (t, J=7.2Hz, 2H), 2.09 (m, 1H), 1.76 (m, 4H), 1.67
~1.55 (m, 4H), 1.52~1.40 (m, 5H), 1.37~1.24 (m, 6H), 0.93 (m, 2H).
Embodiment 6 prepares the positive hexanoyl lysine benzyl ester (5a) of (the positive hexanoyl ammonia first ring acyl of N-Boc- amino)-amino
Using the method for embodiment 1, from 4.00g (8.28mmol) compound 4 and 2.80g (7.52mmol) HClLys
(Boc)-OBzl obtains 2.49g (41%) title compound, is colorless solid.ESI-MS (m/e): 802 [M+H]+。
Embodiment 7 prepares the positive hexanoyl arginine benzyl ester (5b) of (the positive hexanoyl ammonia first ring acyl of N-Boc- amino)-amino
Using the method for embodiment 1, from 4.00g (8.28mmol) compound 4 and 3.33g (6.92mmol) TosArg
(NO2)-OBzl obtains 1.03g (19%) title compound, it is colorless solid.ESI-MS (m/e): 775 [M+H]+。
Embodiment 8 prepares the positive hexanoyl lysine (6a) of (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
1.10g (1.37mmol) 5a is dissolved in 20mL methanol, 110mg Pd/C is added, is evacuated while stirring, room temperature is logical
10h hydrogen.TLC (methylene chloride/methanol=4/1) display reaction is completed.It is filtered to remove Pd/C, filtrate decompression concentration, residue
5mL anhydrous ethyl acetate is added to stir evenly, -10 DEG C slowly add the ethyl acetate solution (4M) of 10mL hydrogen chloride and stir extremely
TLC (ethyl acetate/water ice acetic acid=3/1/1) shows fully reacting.It being concentrated under reduced pressure, residue is dissolved with anhydrous ethyl acetate,
It is concentrated under reduced pressure, residue is dissolved with anhydrous ethyl acetate.The operation is repeated 3 times.Obtained solid is sufficiently mixed with anhydrous ether,
Stand, remove ether, obtained colorless solid 0 DEG C with saturation NaHCO3Solution adjusts pH to 7 and is obtained with C18 column chromatographic purifying
480mg (68%) title compound is colorless solid.Mp 208-209℃.(c=0.1, H2O).ESI-MS
(m/e):512[M+H]+.IR(cm-1):3292,2927,2857,1634,1548,1437,1392,1257,1232,1207,
1168,696.1H-NMR(300MHz,D2O): δ/ppm=4.07 (dd, J1=7.8Hz, J2=5.1Hz, 1H), 3.07 (t, J=
6.3Hz, 2H), 2.95 (d, J=6.3Hz, 2H), 2.88 (t, J=7.2Hz, 4H), 2.18 (m, 4H), 2.08 (m, 1H), 1.75
(m, 5H), 1.63~1.46 (m, 9H), 1.44~1.35 (m, 3H), 1.33~1.22 (m, 8H), 0.89 (m, 2H).
Embodiment 9 prepares the positive hexanoyl arginine (6b) of (the positive hexanoyl ammonia first ring acyl of N- amino)-amino
Using the method for embodiment 8,120mg (19%) title compound is obtained from 0.92g (1.19mmol) 5b, is colourless
Solid.Mp 219-221℃.(c=0.1, H2O).ESI-MS(m/e):540[M+H]+.IR(cm-1):3282,
3084,2927,2858,1634,1549,1446,1396,1235,1208,692.1H-NMR(300MHz,D2O): δ/ppm=
4.06 (m, 1H), 3.08 (m, 4H), 2.93 (d, J=6.3Hz, 2H), 2.80 (t, J=6.6Hz, 2H), 2.18 (m, 4H), 2.06
(m, 1H), 1.71 (m, 5H), 1.62~1.50 (m, 8H), 1.40~1.35 (m, 4H), 1.29~1.20 (m, 6H), 0.87 (m,
2H)。
Embodiment 10 measures compound 6a, the activity of resisting tumor metastasis of b
Lewis murine lung cancer cell (LLC the is purchased from ATCC) inoculation of this rating model, selects DMEM culture medium (to contain 10%
Fetal calf serum through inactivating, 1 × 105U/L penicillin and 100mg/L streptomysin), it was passed according to attached cell cultural method every two days
In generation, is primary, enrichment of cell.Vitellophag when cell growth state is good and is in logarithmic growth phase, is adjusted thin with physiological saline
Born of the same parents' density is to 1 × 107A/mL.The dyeing of placenta indigo plant, makes viable count > 95%.Take inbred strais C57BL/6 male mice (SPF
Grade, 20 ± 2g of weight), the fixed mouse of left hand.It is sterilized with 75% Mice Hepatocytes Injured by Ethanol right fore skin of axillary fossa.It is sterile that the right hand holds 1mL
LLC tumor cell suspension is subcutaneously injected toward mouse armpit in syringe, and every mouse injects 0.2mL.After mouse inoculation 10 days, grow
The tumour of diameter about 4-5mm is knurl source.The Lewis lung cancer tumor-bearing mice etherization of inoculation 10 days, cervical dislocation are put to death.With
75% ethyl alcohol impregnates 10min, and knurl is removed in disinfection on superclean bench.Select well-grown tumor tissues sterile flat
It shreds, is placed in the tissue homogenizer of glass manufacture in ware.The ratio for being again 1 to 3 (g ratio mL) than physiological saline volume in tumor mass
The physiological saline that heating degree is 4 DEG C, is lightly ground and cell suspension is made.Cell suspension crosses 200 mesh cell sieve single cell suspensions.
With the cell density of physiological saline tune single cell suspension to 1.5 × 107A/mL.The dyeing of placenta indigo plant, makes viable count > 95%.
Left hand fixes inbred strais C57BL/6 male mice, is sterilized with 75% Mice Hepatocytes Injured by Ethanol right fore skin of axillary fossa.The right hand holds 1mL
Tumor cell suspension, every injection 0.2mL is subcutaneously injected in mouse armpit in asepsis injector.Mouse grows diameter 4- after inoculation 10 days
Mice Inoculated is grouped by the tumour of 5mm at random by the gross tumor volume measured.Every group of 12 mouse.The 11st day of inoculated tumour is small
Mouse or the normal saline solution (dosage be 20 μm ol/kg/ days) or oral administration of compound for taking orally generally acknowledged anti tumor translocation peptide RGDS
(dosage is 5 μ to the normal saline solution (dosage be 0.5 μm ol/kg/ days) or the normal saline solution of oral administration of compound 7 of 6a, b
Mol/kg/ days) or oral normal saline (dosage be 10mL/kg/ days), daily to 1 medicine, successive administration 12 days, every three days
Measure and record gross tumor volume.The next day measurement knurl product of last time administration, etherization cervical dislocation are put to death, and the swollen of mouse is taken
Tumor weighing takes the lung of mouse and calculates the burrknot number of tumour lung transfer.It is examined with t for statistical analysis to data.As a result see
Table 1.Not only effectively inhibit neoplasm lung metastasis in 0.5 μm of ol/kg dosages for Compound 6a, b, and activity and dose ratio they
High 400 times of RGDS and their high 10 times compounds 7 of dose ratio do not have significant difference.These statistics indicate that, the present invention has
Significant technical effect.
The activity of resisting tumor metastasis of table 1 compound 6a, b
And physiological saline ratio p<0.01, a) with RGDS and compound 7 than p>0.05；N=12.
Embodiment 11 measures compound 6a, the neoplasm growth activity of b
Adriamycin, compound 7 and compound 6a, b are used into physiological saline solution before measurement, are administered for S180 mouse.
Taken in gnotobasis and be inoculated in male ICR mouse 10 days eugonic S180 ascitic tumor fluids, with normal saline dilution at (1:
2) liquid is sufficiently mixed, and by 0.2% Trypan Blue of tumor cell suspension Fresh, white blood cell count(WBC) is pressed after mixing
Method counts, and dye blue person is dead cell, and tinter is not living cells.By viable count/4 in cell concentration=4 block plaids ×
104× extension rate=cell number/mL calculates cell density, by cell survival rate=viable count/(viable count+dead cell
Number) × 100% calculating cell survival rate.It is 2.0 × 10 that density, which is made, with homogenate method in tumor liquid by survival rate greater than 90%7A/
The cell suspension of mL.The cell suspension inoculation is subcutaneous (0.2mL/ is only) in mouse right axillary, manufactures S180 tumor-bearing mice.Inoculation is for 24 hours
The normal saline solution (dosage is 2 μm of ol/kg/ days g) or daily oral of adriamycin is injected intraperitoneally in S180 tumor-bearing mice daily afterwards
The normal saline solution (dosage be 5 μm ol/kg/ days) of compound 7 or the daily normal saline solution (agent of oral administration of compound 6a, b
Amount for 0.5 μm ol/kg/ days).It is administered once a day, successive administration 12 days.The next day measurement knurl product of last time administration, second
Ehterization cervical dislocation is put to death, and is then fixed mouse right axillary tumor location with tweezers, is cut off skin blunt separation tumour and claim
Weight.Curative effect is indicated with knurl weight (mean value ± SD g), and data are examined with t and variance analysis.It the results are shown in Table 2.In 0.5 μm of ol/kg agent
Lower compound 6a is measured, b can not only effectively inhibit tumour growth, and their high 10 times compounds 7 do not have activity with dose ratio
There is significant difference.These statistics indicate that, the present invention has significant technical effect.
Influence of the 2 compound 6a-b of table to S180 mice tumors grew
And physiological saline ratio p<0.01, a) with compound 7 than p>0.05；N=12.
Embodiment 12 measures compound 6a, the anti-inflammatory activity of b
Because mouse ear swelling caused by dimethylbenzene is acknowledged as acute inflammation model, the present invention causes in dimethylbenzene
Mouse ear swelling model on measure compound 6a, the therapeutic effect of b.Because aspirin is the positive for treating acute inflammation
Medicine, so the present invention selects aspirin for positive control drug.The ring that ICR male mice (42 ± 3g of weight) is 22 DEG C in temperature
Border tranquillization 2 days, free water and feed.Later, physiological saline group (dosage is 0.2mL/), aspirin group are randomly divided into
(dosage 1.11mmol/kg), (dosage is 0.5 μm of ol/ for 7 groups of compound (dosage is 5 μm of ol/kg) and compound 6a, b group
Kg), every group of 12 mouse.Mouse is by place group or oral normal saline or oral aspirin or oral administration of compound when measurement
7 or oral administration of compound 6a, b.After 30min is administered, the left auricle toward mouse uniformly smears 30 μ L dimethylbenzene, and mouse receives after 2h
Etherization, the neck that breaks are put to death, and are cut two ears of left and right, are taken round auricle in the same position of two ears with the punch of 7mm, weigh,
Two ear swelling differences are found out as swelling.That is swelling=left ear disk weight-auris dextra disk weight.It the results are shown in Table 3.?
0.5 μm of ol/kg dosages for Compound 6a, b can not only effectively inhibit mouse ear swelling caused by dimethylbenzene, and activity and agent
Amount does not have significant difference than their high 10 times compounds 7.These statistics indicate that, the present invention has significant technical effect.
The influence of mouse ear swelling caused by 3 compound 6a, b paraxylene of table
And physiological saline ratio p<0.01, a) with compound 7 than p>0.05；N=12.
Claims (5)
1. (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of following formula,
AA is L-Lys residue and L-Arg residue in formula.
2. the preparation method of (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of claim 1, this method comprises:
(1) Boc- tranexamic acid and Amino-n-hexanoic acid methyl esters are condensed to obtain Boc- ammonia first ring acyl amino methyl hexyl (1)；
(2) Boc- ammonia first ring sulphonyl-amino methyl hexyl de- Boc in the ethyl acetate solution of hydrogen chloride obtains ammonia first ring acyl group
Amino-n-hexanoic acid methyl esters (2)；
(3) Boc- Amino-n-hexanoic acid and ammonia first ring acyl amino methyl hexyl (2) are condensed (the positive hexanoyl ammonia first of N-Boc- amino
Ring acyl)-Amino-n-hexanoic acid methyl esters (3)；
(4) compound 3 is saponified demethylation and obtains (the positive hexanoyl ammonia first ring acyl of N-Boc- amino)-Amino-n-hexanoic acid (4)；
(5) compound 4 in the ethyl acetate solution of hydrogen chloride take off Boc obtain (the positive hexanoyl ammonia first ring acyl of N- amino)-amino just oneself
Sour (7)；
(6) compound 4 and AA-OBzl (AA is L-Lys residue and L-Arg residue) are condensed (the positive hexanoyl ammonia first of N-Boc- amino
Ring acyl) the positive caproyl amino-acid benzyl ester (5a, b) of-amino；
(7) compound 5a, b elder generation hydrogenolysis take off benzyloxycarbonyl group, de- Boc obtains (N- amino in the ethyl acetate solution of hydrogen chloride again
Positive caproyl ammonia first ring acyl) the positive hexanoyl-AA of-amino (6a, b), AA is L-Lys residue and L-Arg residue.
3. (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of claim 1 is in preparing medicine for anti transfer of tumor
Using.
4. (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-AA of-amino of claim 1 answering in the preparation of antitumor drugs
With.
5. (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-AA of-amino application in preparing anti-inflammatory drugs of claim 1.
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| US20170007707A1 (en) * | 2013-07-04 | 2017-01-12 | Novo Nordisk A/S | Derivatives of GLP-1 Like Peptides, and Uses Thereof |
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2017
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| CN102702065A (en) * | 2003-12-30 | 2012-10-03 | 什诺波特有限公司 | Synthesis of acyloxyalkyl carbamate prodrugs and intermediates thereof |
| WO2006064133A2 (en) * | 2004-12-15 | 2006-06-22 | Centre National De La Recherche Scientifique | Novel multimeric cd40 ligands, method for preparing same and use thereof for preparing drugs |
| CN101835449A (en) * | 2007-08-31 | 2010-09-15 | Dsmip资产有限公司 | 4-amidino benzylamines for cosmetic and/or dermatological use |
| US20170007707A1 (en) * | 2013-07-04 | 2017-01-12 | Novo Nordisk A/S | Derivatives of GLP-1 Like Peptides, and Uses Thereof |
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