CN109134328A - The positive positive hexanoyl Met of hexanoyl first cyclic amide base of amino, synthesis, activity and application - Google Patents
The positive positive hexanoyl Met of hexanoyl first cyclic amide base of amino, synthesis, activity and application Download PDFInfo
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- CN109134328A CN109134328A CN201710442958.XA CN201710442958A CN109134328A CN 109134328 A CN109134328 A CN 109134328A CN 201710442958 A CN201710442958 A CN 201710442958A CN 109134328 A CN109134328 A CN 109134328A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
- C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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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
Abstract
The invention discloses (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino of following formula, it discloses its preparation method, disclose its anti-tumor activity, disclose its activity of resisting tumor metastasis, and disclose its anti-inflammatory activity activity, anti-tumor drug thus is being prepared the invention discloses it, 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-Met of-amino, are related to its preparation method, are related to
Its anti-tumor activity is related to its activity of resisting tumor metastasis, and is related to its anti-inflammatory activity activity, thus the present invention relates to
It is preparing anti-tumor drug, the application in medicine for anti transfer of tumor and anti-inflammatory drug.The invention belongs to biomedicine fields.
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), which is related to a variety of
Physiology 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, finds the ammonia modified with Met
The positive hexanoyl first cyclic amide base n-caproic acid derivative of base not only has activity of resisting tumor metastasis, Er Qietong under 0.5 μm of ol/kg dosage
When with antitumor and anti-inflammatory activity.It disappears because the toxic side effect of drug can be reduced with dosage, effective agent
Amount, which than Amino-n-hexanoic acid and tranexamic acid at least reduces by 6400 times and shows this structural modification, technical effect outstanding.According to
These discoveries, inventors herein propose the present invention.
Summary of the invention
First content of the invention is to provide (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino of following formula.
Second content of the invention is to provide the synthesis side of (the positive hexanoyl ammonia first ring acyl of the N- amino) positive hexanoyl-Met of-amino
Method, this method comprises:
(1) Boc- tranexamic acid and Amino-n-hexanoic acid methyl esters are condensed to obtain N- (Boc- ammonia first ring acyl group)-Amino-n-hexanoic acid first
Ester (1)；
(2) N- (Boc- ammonia first ring acyl group)-Amino-n-hexanoic acid methyl esters de- Boc in the ethyl acetate solution of hydrogen chloride obtains N-
Ammonia first ring acyl group-Amino-n-hexanoic acid methyl ester hydrochloride (2)；
(3) Boc- Amino-n-hexanoic acid and N- ammonia first ring sulphonyl-amino methyl hexyl are condensed (the positive hexanoyl of N-Boc- amino
Ammonia first ring acyl group)-Amino-n-hexanoic acid methyl esters (3)；
(4) compound 3 is saponified demethylation and obtains (the positive hexanoyl ammonia first ring acyl group 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 Met-OBzl are condensed (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino) positive hexanoyl-of-amino
Met-OBzl(5)；
(2) the de- Boc in the ethyl acetate solution of hydrogen chloride of compound 5 obtains (the positive hexanoyl ammonia first ring acyl group of N- amino)-ammonia
Positive hexanoyl-the Met of base (6).
Third content of the invention is that the positive hexanoyl-Met of evaluation (the positive hexanoyl ammonia first ring acyl of N- amino)-amino inhibits
C57BL/6 mouse anti-lung cancer transfer activity.
4th content of the invention is that evaluation (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino is small to S180
The inhibition application of mouse tumour growth.
5th content of the invention is that evaluation (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino is small to ICR
The inhibiting effect of mouse inflammation.
Detailed description of the invention
The synthetic route .i of Fig. 1 (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino) dicyclohexylcarbodiimide
(DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), dry tetrahydrofuran (THF)；Ii) chlorination hydroacetic acid second
Ester solution (4M)； iii)CH3OH,2N NaOH；iv)Pd/C,H2,CH3OH；Hydrochloride/ethyl acetate (4M).
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
0.66 g (3.20mmol) dicyclohexylcarbodiimide (DCC) and 0.44g (3.26mmol) I-hydroxybenzotriazole (HOBt), are stirred
Mix 30 min.Then 0.49g (2.70mmol) Amino-n-hexanoic acid methyl esters is added, and adjusts pH value of solution with N-methylmorpholine (NMM)
To 9,6h is stirred at room temperature, TLC (methylene chloride/methanol=30/1) display reaction is completed.It is concentrated under reduced pressure and removes solvent, residue
It is dissolved with 50mL ethyl acetate, filtering.Filtrate is successively saturated NaHCO with 20mL3Solution washs 3 times, and 20mL is saturated NaCl solution
Washing 3 times, 20mL are saturated KHSO4Solution washs 3 times, and 20mL is saturated NaCl solution and washs 3 times, and 20mL is saturated NaHCO3Solution is washed
It washs 3 times, 20mL is saturated NaCl solution and washs 3 times, the ethyl acetate layer dry 12h of anhydrous sodium sulfate.Filtering, filtrate decompression are dense
It is reduced to dry, 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 and removes
Solvent, residue are dissolved with anhydrous ethyl acetate, and obtained solution is concentrated under reduced pressure.The operation is repeated 3 times.Solid uses anhydrous second again
Ether sufficiently suspends, and removes ether, and 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℃；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, 2 H), 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, 4 H), 1.52~1.40 (m, 5H), 1.37~1.24 (m, 6H), 0.93 (m, 2H).
Embodiment 6 prepares (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino) positive hexanoyl-Met-OBzl of-amino (5)
Using the method for embodiment 1, from 4.00g (8.28mmol) compound 4 and 3.09g (7.52mmol) TosMet-
OBzl obtains 2.08g (39%) title compound, is colorless solid,.ESI-MS (m/e): 705 [M+H]+。
Embodiment 7 prepares EACA-TA-EACA-Met (6)
840mg (1.19mmol) compound 5 is dissolved in 20mL methanol, adjusts pH value of solution to 12 with 2N NaOH at 0 DEG C.
0 DEG C of control and pH12 stir 4h.TLC (methylene chloride/methanol=5/1) display reaction is completed.Reaction mixture saturation KHSO4
Solution adjusts pH to 7, is concentrated under reduced pressure.Residue continues with saturation KHSO4Solution adjusts pH to 2, filtering.Obtained pale yellow colored solid
Body is uniformly mixed with 5mL anhydrous ethyl acetate, is slowly added 8mL Hydrochloride/ethyl acetate (4M) at -10 DEG C, is kept for -10 DEG C
Stirring to TLC (ethyl acetate/water ice acetic acid=5/1/1) shows fully reacting.Solvent, the anhydrous second of residue is removed under reduced pressure
Acetoacetic ester dissolution.Obtained solution is concentrated under reduced pressure, and residue is dissolved with anhydrous ethyl acetate.The operation is repeated 3 times.What is obtained consolidates
Body is sufficiently suspended with anhydrous ether, stand, remove ether, obtained colorless solid 0 DEG C with saturation NaHCO3Aqueous solution adjusts pH
It is 7, with C18 column chromatographic purifying, obtains 360mg (54%) title compound, is colorless solid.Mp 245-246℃.ESI-MS(m/e):515[M+H]+.IR(cm-1): 3291,3083,2927,2857,
1634,1548,1440,1392,1234,1208,693.1H-NMR (300MHz, MeOD): δ/ppm=4.32 (dd, J1=
7.2Hz,J2=4.5Hz, 1H), 3.17 (t, J=6.0Hz, 2H), 3.04 (d, J=6.6Hz, 2H), 2.96 (t, J=7.5Hz,
2H), 2.51 (t, J=7.8Hz, 2H), 2.28 (t, J=7.5Hz, 2H), 2.26 (t, J=7.5Hz, 2H), 2.16 (m, 1H),
2.10 (s, 3H), 1.95 (m, 2H), 1.83 (m, 4H), 1.76~1.62 (m, 6H), 1.55~1.35 (m, 9H), 1.01 (m,
2H)。
The activity of resisting tumor metastasis of the measurement compound 6 of embodiment 8
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 after inoculation 10 days
Mice Inoculated is grouped by the tumour of 4-5mm at random by the gross tumor volume measured.Every group of 12 mouse.The 11st day of inoculated tumour
Mouse or the normal saline solution (dosage be 20 μm ol/kg/ days) or oral chemical combination 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 object 6
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.Neoplasm lung metastasis is not only effectively inhibited in 0.5 μm of ol/kg dosages for Compound 6, but also they are high for activity and dose ratio
Their high 10 times compounds 7 of 400 times of RGDS and dose ratio do not have significant difference.These statistics indicate that, the present invention has aobvious
The technical effect of work.
The activity of resisting tumor metastasis of 1 compound 6 of table
And physiological saline ratio p<0.01, a) with RGDS and compound 7 than p>0.05；N=12.
Embodiment 9 measures the neoplasm growth activity of compound 6
Adriamycin, compound 7 and compound 6 are all used into physiological saline solution before measurement, are administered for S180 mouse.In nothing
It is taken in collarium border and is 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) method is pressed after mixing
It counts, dye blue person is dead cell, and tinter is not living cells.By viable count/4 × 10 in cell concentration=4 block plaids4×
Extension rate=cell number/mL calculates cell density, by cell survival rate=viable count/(viable count+dead cell number) ×
100% calculates 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/mL's is thin
Born of the same parents' suspension.The cell suspension inoculation is subcutaneous (0.2mL/ is only) in mouse right axillary, manufactures S180 tumor-bearing mice.S180 after inoculation for 24 hours
Normal saline solution (dosage oral administration of compound 7 for 2 μm of ol/kg/ days g) or daily of adriamycin is injected intraperitoneally in tumor-bearing mice daily
Normal saline solution (dosage be 5 μm ol/kg/ days) or the normal saline solution of daily oral administration of compound 6 (dosage is 0.5 μ
Mol/kg/ days).It is administered once a day, successive administration 12 days.The next day measurement knurl product of last time administration, etherization are de-
Cervical vertebra is put to death, and is then fixed mouse right axillary tumor location with tweezers, is cut off skin blunt separation tumour and weigh.Use knurl weight
(mean value ± SD g) indicates curative effect, and data are examined with t and variance analysis.It the results are shown in Table 2.In 0.5 μm of ol/kg dosages for Compound
6 can not only effectively inhibit tumour growth, and activity does not have significant difference with their high 10 times compounds 7 of dose ratio.
These statistics indicate that, the present invention has significant technical effect.
Influence of 2 compound 6 of table to S180 mice tumors grew
And physiological saline ratio p<0.01, a) with compound 7 than p>0.05；N=12.
The anti-inflammatory activity of the measurement compound 6 of embodiment 10
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 6 therapeutic effect.Because aspirin is the positive drug for treating acute inflammation, institute
Select aspirin as positive control drug using the present invention.ICR male mice (42 ± 3g of weight) is quiet in the environment that temperature is 22 DEG C
Breath 2 days, free water and feed.Later, physiological saline group (dosage is 0.2mL/), aspirin group (dosage are randomly divided into
For 1.11 mmol/kg), 7 groups of compound (dosage is 5 μm of ol/kg) and 6 groups of compound (dosage is 0.5 μm of ol/kg), every group 12
Mouse.Mouse is by place group or oral normal saline or oral aspirin or oral administration of compound 7, or oralization when measurement
Close object 6a.After 30min is administered, the left auricle toward mouse uniformly smears 30 μ L dimethylbenzene, and mouse receives etherization after 2h, and break neck
It puts to death, cuts two ears of left and right, take round auricle in the same position of two ears with the punch of 7mm, weigh, find out two ear swellings
Difference is as swelling.That is swelling=left ear disk weight-auris dextra disk weight.It the results are shown in Table 3.In 0.5 μm of ol/kg dosage
Lower compound 6 not only effectively inhibits mouse ear swelling caused by dimethylbenzene, but also activity and their high 10 times changes of dose ratio
Closing object 7 does not have significant difference.These statistics indicate that, the present invention has significant technical effect.
The influence of mouse ear swelling caused by 3 compound of table, 6 paraxylene
And physiological saline ratio p<0.01, a) with compound 7 than p>0.05；N=12.
Claims (4)
1. (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino of following formula,
2. the preparation method of (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino of claim 1, this method comprises:
(1) Boc- tranexamic acid and Amino-n-hexanoic acid methyl esters are condensed to obtain N- (Boc- ammonia first ring acyl group)-Amino-n-hexanoic acid methyl esters
(1)；
(2) N- (Boc- ammonia first ring acyl group)-Amino-n-hexanoic acid methyl esters de- Boc in the ethyl acetate solution of hydrogen chloride obtains N- ammonia first
Ring sulphonyl-amino methyl hexyl hydrochloride (2)；
(3) Boc- Amino-n-hexanoic acid and N- ammonia first ring sulphonyl-amino methyl hexyl are condensed (the positive hexanoyl ammonia first of N-Boc- amino
Ring acyl group)-Amino-n-hexanoic acid methyl esters (3)；
(4) compound 3 is saponified demethylation and obtains (the positive hexanoyl ammonia first ring acyl group 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 Met-OBzl are condensed (the positive hexanoyl ammonia first ring acyl group of N-Boc- amino) positive hexanoyl-Met- of-amino
OBzl(5)；
(7) compound 5 takes off Boc in the ethyl acetate solution of hydrogen chloride and obtains (the positive hexanoyl ammonia first ring acyl group of N- amino)-amino is just
Hexanoyl-Met (6).
3. (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino of claim 1 is in preparing medicine for anti transfer of tumor
Application.
4. (the positive hexanoyl ammonia first ring acyl of N- amino) positive hexanoyl-Met of-amino of claim 1 answering in the preparation of antitumor drugs
With.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0641776A2 (en) * | 1993-09-08 | 1995-03-08 | Takeda Chemical Industries, Ltd. | Thioglycerol derivatives |
| US5602098A (en) * | 1993-05-18 | 1997-02-11 | University Of Pittsburgh | Inhibition of farnesyltransferase |
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- 2017-06-13 CN CN201710442958.XA patent/CN109134328B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5602098A (en) * | 1993-05-18 | 1997-02-11 | University Of Pittsburgh | Inhibition of farnesyltransferase |
| EP0641776A2 (en) * | 1993-09-08 | 1995-03-08 | Takeda Chemical Industries, Ltd. | Thioglycerol derivatives |
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