CN109134328B - Amino n-caproyl methyl cyclo amido n-caproyl Met, its synthesis, activity and application - Google Patents
Amino n-caproyl methyl cyclo amido n-caproyl Met, its synthesis, activity and application Download PDFInfo
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Abstract
The invention discloses (N-amino-N-caproyl carbamoyl) -amino-N-caproyl-Met with the following formula, discloses a preparation method thereof, discloses anti-tumor activity thereof, discloses anti-tumor metastasis activity thereof and discloses anti-inflammatory activity thereof, and thus the invention discloses the application thereof in preparing anti-tumor drugs, anti-tumor metastasis drugs and anti-inflammatory drugs.
Description
Technical Field
The invention relates to (N-amino-N-caproyl carbamoylcarbamoyl) -amino-N-caproyl-Met, a preparation method thereof, antitumor activity thereof, antitumor metastasis activity thereof and anti-inflammatory activity thereof, and thus the invention relates to application thereof in preparing antitumor drugs, antitumor metastasis drugs and anti-inflammatory drugs. The invention belongs to the field of biological medicine.
Background
Invasion and metastasis processes are the basic biological features of malignant tumors and are one of the difficulties in tumor research. Cancer metastasis is the leading cause of morbidity and mortality in cancer patients, accounting for approximately 90% of cancer deaths. The present study on tumor infiltration and metastasis has been extensively discussed in different aspects. Among them, the role of urokinase-type plasminogen activator (uPA) series in tumor invasion and metastasis has become one of the hot spots in current research. The urokinase-type plasminogen activator (uPA) system, a family of serine proteases, plays a crucial role in tumor infiltration and metastasis. The system includes urokinase-type plasminogen activator (uPA), urokinase receptor (uPAR), Plasminogen Activator Inhibitor (PAI), which is involved in a variety of physiological and pathological processes including cell migration, angiogenesis, inflammation, embryonic development, tumor growth and metastasis.
The amino n-hexanoic acid can generate competitive inhibition with plasminogen activator, so that the plasminogen can not be activated into plasmin, and the amino n-hexanoic acid is a medicament for clinically treating fibrinolytic hemorrhage. Tranexamic acid binds to plasminogen and also exerts an antifibrinolytic effect. The two can respectively achieve the relevant effect of inhibiting the uPA system by preventing the uPA/uPAR interaction and inhibiting the plasmin activation. The lowest effective dose of amino-n-hexanoic acid and tranexamic acid for inhibiting the uPA system is 3.8mmol/kg and 3.2mmol/kg respectively. The inventors believe that their toxic side effects are directly related to their minimum effective dose. The inventor realizes that the novel u-PA inhibitor constructed by reasonably combining two known inhibitors of the uPA system and connecting amino acids has triple effects of resisting tumor, tumor metastasis and inflammation at low dose. Based on this knowledge, it was found that the amino-n-hexanoyl formylaminocyclohexylamido-n-hexanoic acid derivative modified with Met had not only antitumor metastasis activity but also antitumor and anti-inflammatory activities at a dose of 0.5. mu. mol/kg, as searched for over 3 years. Because the toxic and side effects of the medicine can disappear along with the reduction of the dosage, the effective dosage is reduced by at least 6400 times compared with the amino n-hexanoic acid and the tranexamic acid, and the structure modification has outstanding technical effect. Based on these findings, the inventors have proposed the present invention.
Disclosure of Invention
In a first aspect of the invention there is provided (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyl-Met of the formula.
The second aspect of the present invention provides a process for the synthesis of (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyl-Met, which comprises:
(1) condensing Boc-tranexamic acid and amino methyl hexanoate to obtain N- (Boc-tranacyl) -amino methyl hexanoate (1);
(2) removing Boc from N- (Boc-carbamoylamino-N-hexanoic acid methyl ester in ethyl acetate solution of hydrogen chloride to obtain N-carbamoylamino-N-hexanoic acid methyl ester hydrochloride (2);
(3) condensing Boc-amino N-hexanoic acid and N-aminomethyl cycloacyl-amino N-hexanoic acid methyl ester to obtain (N-Boc-amino N-hexanoyl cycloacyl) -amino N-hexanoic acid methyl ester (3);
(4) saponifying and demethylating the compound 3 to obtain (N-Boc-amino-N-caproyl carbamoylmethyl) -amino-N-hexanoic acid (4);
(5) removing Boc from the compound 4 in ethyl acetate solution of hydrogen chloride to obtain (N-amino-N-hexanoyl formyl) -amino-N-hexanoic acid (7);
(6) condensing the compound 4 and Met-OBzl to obtain (N-Boc-amino-N-hexanoyl formyl) -amino-N-hexanoyl-Met-OBzl (5);
(2) the compound 5 is subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain (N-amino-N-hexanoyl formyl) -amino-N-hexanoyl-Met (6).
The third aspect of the present invention is to evaluate the anti-lung cancer metastasis activity of (N-amino-N-hexanoyl-carbamoyl) -amino-N-hexanoyl-Met in inhibiting C57BL/6 mice.
A fourth aspect of the invention is the evaluation of the use of (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyl-Met for inhibiting tumor growth in S180 mice.
The fifth aspect of the invention is the evaluation of the inhibitory effect of (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyl-Met on ICR inflammation in mice.
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FIG. 1 (scheme for the synthesis of N-amino-N-hexanoylcyclohexyl) -amino-N-hexanoyl-Met. i) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), dry Tetrahydrofuran (THF); ii) ethyl hydrogen chloride solution (4M); iii) CH3OH,2N NaOH；iv)Pd/C,H2,CH3OH; hydrochloric acid ethyl acetate solution (4M).
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of (N-Boc-carbamoylamino-N-hexanoic acid methyl ester (1)
0.69g (2.68mmol) of Boc-tranexamic acid was suspended in 50mL of dry tetrahydrofuran, and 0.66 g (3.20mmol) of Dicyclohexylcarbodiimide (DCC) and 0.44g (3.26mmol) of 1-hydroxybenzotriazole (HOBt) were added in this order at 0 ℃ and stirred for 30 min. Then 0.49g (2.70mmol) methyl aminohexanoate was added and the solution pH was adjusted to 9 with N-methylmorpholine (NMM), stirred at rt for 6h, TLC (dichloromethane/methanol-30/1) showed completion. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in 50mL of ethyl acetate and filtered. The filtrate was successively diluted with 20mL of saturated NaHCO3The solution was washed 3 times, 20mL of saturated NaCl solution was washed 3 times, and 20mL of saturated KHSO was added4The solution was washed 3 times, 20mL of saturated NaCl solution 3 times, 20mL of saturated NaHCO3The solution was washed 3 times, 20mL of a saturated NaCl solution was washed 3 times, and the ethyl acetate layer was dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate to dryness under reduced pressure gave 0.83g (80%) of the title compound as a colorless solid. ESI-MS (m/e): 385[ M + H ]]+。
EXAMPLE 2 preparation of N-carbamoylamino-N-hexanoic acid methyl ester hydrochloride (2)
6.00g (15.62mmol) of Compound 1 are slowly mixed with 60mL of a solution of hydrogen chloride in ethyl acetate (4M) at-10 ℃ with stirring and kept at-10 ℃ for 5h with stirring. TLC (dichloromethane/methanol-30/1) showed the reaction was complete. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated 3 times. The solid was then suspended thoroughly with anhydrous ether and the ether was removed to give a colorless solid which was used directly in the next reaction. ESI-MS (M/e):322[ M + H]+。
EXAMPLE 3 preparation of (N-Boc-amino-N-caproylcarboxamide-amino-N-hexanoic acid methyl ester (3)
Using the procedure of example 1, from 3.36g (14.55mmol) Boc-amino-n-hexanoic acid and 4.67g (14.57mmol) Compound 2, a pale yellow solid was obtained. The solid was thoroughly triturated with ethyl acetate to give 6.20g (85%) of the title compound as a colorless solid. ESI-MS (m/e): 498[ M + H]+。
EXAMPLE 4 preparation of (N-Boc-amino-N-hexanoylaminocyclic-acyl) -amino-N-hexanoic acid (4)
6.20g (12.47mmol) of Compound 3 are dissolved in 20mL of methanol and the pH is adjusted to 12 at 0 ℃ with aqueous NaOH (2M). Stirring was carried out for 4h at 0 ℃ and pH12, and TLC (dichloromethane/methanol-25/1) indicated completion of the reaction. The reaction mixture was saturated with KHSO4The solution was adjusted to pH 7 and concentrated under reduced pressure. The residue was further saturated with KHSO4The solution was adjusted to pH 2, extracted with ethyl acetate, and the ethyl acetate layers were combined and washed to neutrality with saturated NaCl solution. The ethyl acetate phase was dried over anhydrous sodium sulfate for 12 h. Filtration and concentration of the filtrate to dryness under reduced pressure gave 4.60g (76%) of the title compound as a colorless solid. ESI-MS (m/e): 484[ M + H]+。
EXAMPLE 5 preparation of (N-amino-N-hexanoylaminocyclic-acyl) -amino-N-hexanoic acid (7)
Using the method of example 2, 0.87g (84%) of the title compound was obtained as a colorless solid from 1.30g (2.69mmol) of Compound 4. 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)。
EXAMPLE 6 preparation of (N-Boc-amino-N-hexanoylaminocyclyl) -amino-N-hexanoyl-Met-OBzl (5)
Using the method of example 1, 2.08g (39%) of the title compound were obtained as a colorless solid from 4.00g (8.28mmol) of compound 4 and 3.09g (7.52mmol) of Tos. Met-OBzl. ESI-MS (m/e): 705[ M + H]+。
EXAMPLE 7 preparation of EACA-TA-EACA-Met (6)
840mg (1.19mmol) of compound 5 are dissolved in 20mL of methanol and the solution pH is adjusted to 12 at 0 ℃ with 2N NaOH. Stirring was carried out for 4h while controlling the temperature and pH at 12. TLC (dichloromethane/methanol-5/1) showed the reaction was complete. Saturation of the reaction mixtureKHSO4The solution was adjusted to pH 7 and concentrated under reduced pressure. The residue was further saturated with KHSO4The solution was adjusted to pH 2 and filtered. The resulting pale yellow solid was mixed well with 5mL of anhydrous ethyl acetate, and 8mL of ethyl hydrogen chloride acetate solution (4M) was added slowly at-10 ℃, and stirred at-10 ℃ until TLC (ethyl acetate/water/glacial acetic acid) ═ 5/1/1 indicated completion of the reaction. The solvent was removed under reduced pressure, and the residue was dissolved with anhydrous ethyl acetate. The resulting solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous ethyl acetate. This operation was repeated 3 times. Suspending the obtained solid with anhydrous diethyl ether, standing, removing diethyl ether to obtain colorless solid, and adding saturated NaHCO at 0 deg.C3The aqueous solution was adjusted to pH 7 and purified by C18 column chromatography to give 360mg (54%) of the title compound as a colorless solid. Mp 245-.
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)。
EXAMPLE 8 determination of the anti-metastatic Activity of Compound 6
The assay model was inoculated with Lewis mouse lung carcinoma cells (LLC, purchased from ATCC) in DMEM medium (containing 10% inactivated fetal bovine serum, 1X 10)5U/L penicillin and 100mg/L streptomycin), and the cells are enriched by passage every two days according to an adherent cell culture method. Digesting the cells when the cells are in good growth state and in logarithmic growth phase, and adjusting the cell density to 1 × 10 with physiological saline7one/mL. Staining with placental blue to count viable cells>95 percent. Inbred C57BL/6 male mice (SPF grade, body weight 20. + -.2 g) were taken and left-handed mice fixed. The right anterior limb axillary skin of the mouse was disinfected with 75% ethanol. The LLC tumor cell suspension is injected subcutaneously into the axilla of a mouse with a 1mL sterile syringe held in the right hand, and 0.2mL is injected into each mouse. Mice inoculation 10After a day, the tumor with the diameter of about 4-5mm is the tumor source. The Lewis lung cancer tumor-bearing mice are inoculated for 10 days and anesthetized by ether, and then the cervical vertebrae are removed for killing. Soaking in 75% ethanol for 10min, sterilizing, and removing tumor on clean bench. Well-grown tumor tissue was selected, minced in a sterile plate, and placed in a tissue homogenizer made of glass. Adding physiological saline with the temperature of 4 ℃ according to the ratio of the tumor mass to the volume of the physiological saline of 1 to 3(g to mL), and lightly grinding to prepare the cell suspension. The cell suspension is screened by 200-mesh cells to prepare single cell suspension. Adjusting the cell density of the single cell suspension to 1.5X 10 with physiological saline7one/mL. Staining with placental blue to count viable cells>95 percent. Left-handed inbred C57BL/6 male mice were fixed and their right anterior limb axillary skin was disinfected with 75% ethanol. The tumor cell suspension was injected subcutaneously into the mouse axilla with a 1mL sterile syringe in the right hand, 0.2mL each. 10 days after inoculation, the mice developed tumors of 4-5mm in diameter, and the inoculated mice were randomly grouped by the measured tumor volume. Each group had 12 mice. Mice on day 11 of tumor inoculation were orally administered either a normal saline solution of the putative antitumor metastatic peptide RGDS (dose of 20. mu. mol/kg/day) or compound 6 (dose of 0.5. mu. mol/kg/day) or compound 7 (dose of 5. mu. mol/kg/day) or compound 7 (dose of 10 mL/kg/day) 1 time daily for 12 consecutive days, and tumor volumes were measured and recorded every two days. The next day of the last administration, tumor volume was measured, cervical spine was removed by ether anesthesia and sacrificed, tumor of the mice was weighed, lung of the mice was taken and tumor nodules transferred from the lung of the tumor were counted. Statistical analysis of the data was performed using the t-test. The results are shown in Table 1. Compound 6 was not only effective in inhibiting tumor lung metastasis at 0.5 μmol/kg dose, but there was no significant difference in activity from RGDS at doses 400-fold higher and compound 7 at doses 10-fold higher than them. These data indicate that the present invention has significant technical effects.
TABLE 1 antitumor metastatic Activity of Compound 6
a) P <0.01 to saline, p >0.05 to RGDS and compound 7; n is 12.
EXAMPLE 9 determination of the anti-tumor growth Activity of Compound 6
Doxorubicin, compound 7 and compound 6 were all dissolved in saline prior to assay for administration to S180 mice. Taking S180 ascites tumor liquid which is inoculated in a male ICR mouse and grows vigorously for 10 days in a sterile environment, diluting the S180 ascites tumor liquid into liquid (1:2) by using normal saline, fully mixing the liquid, dyeing the tumor cell suspension by using freshly prepared 0.2% trypan blue, uniformly mixing the liquid and the liquid, counting the liquid according to a white cell counting method, wherein the blue-dyed cell is a dead cell, and the non-dyed cell is a live cell. The cell concentration is 4-large-grid viable cell number/4 × 104The cell density was calculated as x dilution factor ═ cell number/mL, and the cell survival rate was calculated as live cell number/(live cell number + dead cell number) × 100%. Homogenizing tumor solution with survival rate of more than 90% to density of 2.0 × 107Cell suspension per mL. This cell suspension was inoculated subcutaneously (0.2 mL/mouse) in the right axilla of a mouse to prepare S180 tumor-bearing mice. 24h after inoculation, S180 tumor-bearing mice were intraperitoneally injected daily with a saline solution of doxorubicin (dose 2. mu. mol/kg/day g), or orally administered daily with a saline solution of Compound 7 (dose 5. mu. mol/kg/day), or orally administered daily with a saline solution of Compound 6 (dose 0.5. mu. mol/kg/day). The administration is once daily for 12 days. The day after the last dose, tumor volume was measured, cervical spine was removed under ether anesthesia and sacrificed, then the right axillary tumor growth site of the mouse was fixed with forceps, and the skin was excised and the tumor was blunt-stripped and weighed. Efficacy was expressed as tumor weight (mean ± SD g), and data were analyzed by t-test and variance. The results are shown in Table 2. Compound 6 was not only effective at inhibiting tumor growth at 0.5 μmol/kg dose, but there was no significant difference in activity from compound 7 at doses 10-fold higher than them. These data indicate that the present invention has significant technical effects.
TABLE 2 Effect of Compound 6 on tumor growth in S180 mice
a) P <0.01 to saline, p >0.05 to compound 7; n is 12.
EXAMPLE 10 determination of anti-inflammatory Activity of Compound 6
Since xylene-induced ear swelling in mice is recognized as an acute inflammation model, the present invention measures the therapeutic effect of compound 6 on a xylene-induced ear swelling model in mice. Because aspirin is a positive drug for treating acute inflammation, aspirin is selected as a positive control in the present invention. ICR male mice (body weight 42 + -3 g) were allowed to rest for 2 days at 22 deg.C, with free access to water and food. Thereafter, 12 mice were randomly divided into a saline group (dose of 0.2 mL/mouse), an aspirin group (dose of 1.11 mmol/kg), a compound 7 group (dose of 5. mu. mol/kg) and a compound 6 group (dose of 0.5. mu. mol/kg), each group. Mice were tested either orally in normal saline, orally in aspirin, orally in compound 7, or orally in compound 6a, as indicated by group. After 30min of administration, the left auricle of the mouse was evenly smeared with 30 μ L of xylene, and after 2h, the mouse was subjected to ether anesthesia, the neck was cut off, the left and right ears were cut off, round ears were taken at the same positions of the two ears by a 7mm punch, and the difference in swelling between the two ears was weighed and found to be the swelling degree. Namely the swelling degree is equal to the weight of the left ear disk to the weight of the right ear disk. The results are shown in Table 3. Compound 6 was not only effective in inhibiting xylene-induced ear swelling in mice at the 0.5 μmol/kg dose, but there was no significant difference in activity from compound 7 at doses 10-fold higher than them. These data indicate that the present invention has significant technical effects.
TABLE 3 Effect of Compound 6 on xylene-induced ear swelling in mice
a) P <0.01 to saline, p >0.05 to compound 7; n is 12.
Claims (4)
1. (N-amino-N-hexanoylaminomethylcyclohexyl-formyl) -amino-N-hexanoyl-Met of the formula,
2. a process for the preparation of (N-amino-N-hexylaminomethylcyclohexylcyclohexylformyl) -amino-N-hexanoyl-Met according to claim 1, which comprises:
(1) condensing Boc-aminomethyl cyclohexanoic acid and amino methyl hexanoate to obtain Boc-aminomethyl cyclohexyl formyl amino methyl hexanoate (1);
(2) removing Boc from Boc-aminomethyl cyclohexyl formyl amino methyl hexanoate in ethyl acetate solution of hydrogen chloride to obtain aminomethyl cyclohexyl formyl amino methyl hexanoate (2);
(3) condensing Boc-amino n-hexanoic acid and aminomethyl cyclohexyl formyl amino n-hexanoic acid methyl ester to obtain Boc-amino n-hexanoyl aminomethyl cyclohexyl formyl amino n-hexanoic acid methyl ester (3);
(4) saponifying and demethylating the compound 3 to obtain Boc-amino-n-hexanoyl aminomethyl cyclohexyl formyl amino-n-hexanoic acid (4);
(5) condensing the compound 4 and Met-OBzl to obtain Boc-amino-n-hexanoyl aminomethyl cyclohexyl amino-n-hexanoyl-Met-OBzl (5);
(6) the compound 5 is subjected to Boc removal and OBzl removal in an ethyl acetate solution of hydrogen chloride to obtain (N-amino-N-hexylamido methyl cyclohexyl formyl) -amino-N-hexanoyl-Met (6).
3. Use of (N-amino-N-hexylaminomethylcyclohexylcyclohexylformyl) -amino-N-hexanoyl-Met according to claim 1 for the preparation of a medicament against tumor metastases.
4. Use of (N-amino-N-hexylaminomethylcyclohexylcyclohexylformyl) -amino-N-hexanoyl-Met according to claim 1 for the preparation of an antitumor medicament.
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