CN108976146B - Amino n-hexanoyl methyl cyclamido n-hexanoyl aromatic amino acid, synthesis, activity and application thereof - Google Patents
Amino n-hexanoyl methyl cyclamido n-hexanoyl aromatic amino acid, synthesis, activity and application thereof Download PDFInfo
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Abstract
The invention discloses an amino N-caproyl carbamoylamino N-caproyl aromatic amino acid, a synthesis method, an activity and an application thereof, and discloses (N-amino N-caproyl carbamoylamino) -amino N-caproyl-AA (wherein AA is an L-Phe residue, an L-Tyr residue and an L-Trp residue). Discloses a preparation method thereof, discloses the antitumor activity thereof, discloses the anti-tumor metastasis activity thereof and discloses the anti-inflammatory activity thereof, so that the invention discloses the application thereof in preparing antitumor drugs, anti-tumor metastasis drugs and anti-inflammatory drugs.
Description
Technical Field
The invention relates to (N-amino-N-caproyl carbamoyl) -amino-N-caproyl-AA, a preparation method thereof, antitumor activity thereof, antitumor metastasis activity thereof and anti-inflammatory activity thereof, and thus 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 the amino n-hexanoic acid and tranexamic acid uPA preparation 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 amino-n-hexanoyl formylaminocyclohexylamido-n-hexanoic acid derivatives modified with aromatic side chain amino acids (L-Phe, L-Tyr and L-Trp) had not only antitumor metastasis activity but also antitumor and anti-inflammatory activities at a dose of 0.5. mu. mol/kg, after 3 years of exploration. Because the toxic and side effects of the medicine can disappear along with the reduction of the dosage, the effective dosage is reduced by 6400 times compared with the amino n-hexanoic acid and tranexamic acid, and the structure modification has outstanding technical effect. Based on these findings, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention provides (N-amino-N-caproylcycloacyl) -amino-N-caproyl-AA of the formula (wherein AA is a L-Phe residue, a L-Tyr residue and a L-Trp residue).
The second aspect of the present invention provides a method for synthesizing (N-amino-N-caproylcyclohexyl) -amino-N-caproyl-AA (AA is L-Phe residue, L-Tyr residue and L-Trp residue), which comprises:
(1) condensing Boc-tranexamic acid and amino methyl hexanoate to obtain Boc-tranylcarbonylamino methyl hexanoate (1);
(2) removing Boc from Boc-cycloacyl-amino-n-hexanoic acid methyl ester in ethyl acetate solution of hydrogen chloride to obtain cycloacyl amino-n-hexanoic acid methyl ester (2);
(3) condensing Boc-amino N-hexanoic acid and methyl carbamoylamino N-hexanoate (2) to obtain (N-Boc-amino N-hexanoyl carbamoylamino) -amino N-hexanoate methyl ester (3);
(4) saponifying and demethylating the compound 3 to obtain (N-Boc-amino-N-caproyl carbamoylamino) -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) and condensing the compound 4 with AA-OBzl (AA is L-Phe residue, L-Tyr residue and L-Trp residue) to obtain (N-Boc-amino-N-hexanoyl carbamoylamino) -amino-N-hexanoyl amino acid benzyl ester (5 a-c).
(7) The compound 5a-c is subjected to hydrogenolysis to remove benzyloxycarbonyl and then subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain (N-amino-N-hexanoyl carbamyl) -amino-N-hexanoyl-AA (6 a-c).
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-AA (AA is L-Phe residue, L-Tyr residue and L-Trp residue) in C57BL/6 mice.
The fourth aspect of the present invention is the evaluation of the use of (N-amino-N-hexanoyl carbamoyl) -amino-N-hexanoyl-AA (AA is the L-Phe residue, the L-Tyr residue and the L-Trp residue) for inhibiting tumor growth in S180 mice.
The fifth aspect of the present invention is to evaluate the inhibitory effect of (N-amino-N-hexanoyl carbamoyl) -amino-N-hexanoyl-AA (AA is L-Phe residue, L-Tyr residue and L-Trp residue) on the inflammation of ICR mice.
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FIG. 1 is a synthetic scheme of (N-amino-N-hexanoylcarbamoyl) -amino-N-hexanoyl-AA.5 a and 6a, AA is an L-Phe residue; AA in 5b and 6b is L-Tyr residue; AA in 5c and 6c is L-Trp residue;
i) dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), anhydrous Tetrahydrofuran (THF); ii) ethyl hydrogen chloride acetate (4M); iii) CH3OH, aqueous NaOH (2M); iv) Pd/C, H2,CH3OH。
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 and 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 to obtain a filtrate. 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)
The procedure of example 1 was used to obtain 3.36g (14.55mmol) Boc-amino-n-hexanoic acid and 4.67g (14.57mmol) Compound 2 as a pale yellow solid. The solid was thoroughly triturated with ethyl acetate and 6.20g (85%) of the title compound were 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 pH 12, 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)
From 1.30g (2.69mmol) of compound 4, 0.87g (84%) of the title compound was obtained as a colorless solid by the method of example 2. 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):/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-hexanoylaminocycloacyl) -amino-N-hexanoylphenylphenylalanine benzyl ester (5a)
From 2.00g (4.14mmol) of compound 4 and 1.20g (4.12mmol) of HCl Phe-OBzl, 2.14g (72%) of the title compound are obtained as colorless solid by the method of example 1. ESI-MS (m/e): 721[ M + H]+。
EXAMPLE 7 preparation of (N-Boc-amino-N-hexanoylaminocycloyl) -amino-N-hexanoyl tyrosine benzyl ester (5b)
From 2.30g (4.76mmol) of Compound 4 and 2.11g (4.76mmol) of Tos. Tyr-OBzl, 1.10g (31%) of the title compound were obtained as a colorless solid by the method of example 1. ESI-MS (m/e): 737[ M + H]+。
EXAMPLE 8 preparation of (N-Boc-amino-N-hexanoylaminocycloyl) -amino-N-hexanoyl tryptophane benzyl ester (5c)
From 2.00g (4.14mmol) of compound 4 and 1.93g (4.14mmol) of Tos. Trp-OBzl, 1.30g (41%) of the title compound were obtained as a colorless solid by the method of example 1. ESI-MS (m/e): 760[ M + H [ ]]+。
EXAMPLE 9 preparation of (N-amino-N-hexanoylaminocycloacyl) -amino-N-hexanoylphenylalanine (6a)
1.60g (2.22mmol) of compound 5a are dissolved in 20mL of methanol, 160mg of Pd/C are added and hydrogen is passed through at room temperature for 10 h. TLC (dichloromethane/methanol-10/1) showed the reaction was complete. Pd/C was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. The residue was slowly mixed at-10 ℃ with 8mL of hydrogen chloride in ethyl acetate (4M), held at-10 ℃ and stirred for 5 h. TLC (ethyl acetate/water/glacial acetic acid-6/1/1) showed the reaction was complete. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in anhydrous ethyl acetate and concentrated under reduced pressure. This operation was repeated 3 times. The solid was suspended thoroughly with anhydrous ether, left to stand and the ether was removed. The colorless solid obtained was saturated NaHCO at 0 deg.C3Adjusting pH to 7 with water solution, and separating with C18 column layerThis was purified by chromatography to give 452mg (38%) of the title compound as a colourless solid. Mp 247-.
ESI-MS(m/e):531[M+H]+.IR (cm-1):3292,3086,2928,2858,1634,1548,1391,698.1H-NMR(300MHz,D2O):/ppm＝7.14(m, 5H),4.32(dd,J1＝9.3Hz,J2＝4.5Hz,1H),3.06(dd,J1＝13.8Hz,J2＝4.5Hz,1H),2.90(m,4H), 2.76(t,J＝7.5Hz,2H),2.69(m,2H),2.10(t,J＝7.5Hz,2H),2.01(t,J＝7.2Hz,2H),1.97(m, 1H),1.65(m,4H),1.50～1.43(m,4H),1.31～1.16(m,9H),0.88～0.81(m,4H)。
EXAMPLE 10 preparation of (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyltyrosine (6b)
380mg (62%) of the title compound are obtained as a colourless solid from 0.82g (1.11mmol) of compound 5b by the method of example 9. Mp 243-.
ESI-MS(m/e):547[M+H]+.IR(cm-1):3304, 3080,2931,2859,1625,1548,1513,1460,1377,1352,1234,1189,680.1H-NMR(300MHz, MeOD):/ppm＝7.09(d,J＝8.4Hz,1H),6.75(d,J＝8.4Hz,1H),4.42(dd,J1＝8.4Hz,J2＝ 4.5Hz,1H),3.14(m,1H),3.11(t,J＝5.7Hz,2H),3.03(d,J＝6.6Hz,2H),2.97(d,J＝7.5Hz,2 H),2.81(dd,J1＝13.8Hz,J2＝8.7Hz,2H),2.25(t,J＝7.5Hz,2H),2.17(t,J＝7.2Hz,2H),2.11 (m,1H),1.81(m,4H),1.74～1.60(m,4H),1.47～1.35(m,9H),1.16(m,2H),1.00(m,2H)。
EXAMPLE 11 preparation of (N-amino-N-hexanoylaminocyclohexyl) -amino-N-hexanoyltryptophan (6c)
469mg (63%) of the title compound are obtained as a colourless solid from 1.00g (1.32mmol) of compound 5c using example 9. Mp 219-.
ESI-MS(m/e):570[M+H]+.IR(cm-1):3319,3081, 2930,2855,1639,1551,1454,1435,1345,1233,735.1H-NMR(300MHz,MeOD):/ppm＝7.64 (d,J＝7.5Hz,1H),7.40(d,J＝8.1Hz,1H),7.16(s,1H),7.14(t,J＝8.1Hz,1H),7.06(t,J＝7.5 Hz,1H),4.54(dd,J1＝7.5Hz,J2＝4.8Hz,1H),3.37(dd,J1＝14.7Hz,J2＝4.8Hz,1H),3.12(dd, J1＝14.7Hz,J2＝7.5Hz,1H),3.06(m,4H),2.94(t,J＝7.5Hz,2H),2.25(t,J＝7.5Hz,2H),2.11 (t,J＝7.5Hz,2H),2.09(m,1H),1.79(m,4H),1.69～1.59(m,4H),1.44～1.32(m,9H), 1.08～0.95(m,4H)。
EXAMPLE 12 determination of the anti-tumor metastasis Activity of Compounds 6a-c
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. After the mice are inoculated for 10 days, tumors with the diameter of about 4-5mm grow out, namely 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. Injecting tumor cell suspension into mouse axilla subcutaneously by holding 1mL sterile syringe in right hand, each injection0.2 mL. 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 recognized physiological saline solution of the anti-tumor metastasis peptide RGDS (dose of 20. mu. mol/kg/day) or compounds 6a-c (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 dose per day 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. Compounds 6a-c were not only effective in inhibiting tumor lung metastasis at 0.5 μmol/kg dose, but also had 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 Compounds 6a-c
a) P <0.01 to saline, p >0.05 to RGDS and compound 7; n is 12.
EXAMPLE 13 determination of the anti-tumor growth Activity of Compounds 6a-c
Doxorubicin, compound 7 and compounds 6a-c 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 by the x dilution factor ═ cell number/mL, and the cell viability rate ═ viable cell number/(viable cell number + dead cell number) × 100%, the fine cell countCell survival rate. 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 daily orally administered with a saline solution of Compound 7 (dose 5. mu. mol/kg/day), or daily orally administered with a saline solution of Compounds 6a-c (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. Compounds 6a-c were not only effective at 0.5 μmol/kg dose in inhibiting tumor growth, but also had no significant difference in activity from compound 7, which was 10-fold higher in dose than them. These data indicate that the present invention has significant technical effects.
TABLE 2 Effect of Compounds 6a-c on tumor growth in S180 mice
a) P <0.01 to saline, p >0.05 to compound 7; n is 12.
EXAMPLE 14 determination of the anti-inflammatory Activity of Compounds 6a-c
Since xylene-induced ear swelling in mice is recognized as an acute inflammation model, the present invention measures the therapeutic effect of compounds 6a-c 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, the 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 compound 6a-c groups (dose of 0.5. mu. mol/kg), and 12 mice were each group. Mice were tested either orally with normal saline, orally with aspirin, orally with compound 7, or orally with compounds 6a-c, as indicated. 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. Compounds 6a-c were not only effective at 0.5 μmol/kg dose in inhibiting xylene-induced ear swelling in mice, but also had no significant difference in activity from compound 7, which was 10-fold higher than them at the dose. These data indicate that the present invention has significant technical effects.
TABLE 3 Effect of Compounds 6a-c on xylene-induced ear swelling in mice
a) P <0.01 to saline, p >0.05 to compound 7; n is 12.
Claims (5)
1. (N-amino-N-hexanoylaminocyclyl) -amino-N-hexanoyl-AA of the formula,
wherein AA is an L-Phe residue, an L-Tyr residue or an L-Trp residue.
2. A process for the preparation of (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyl-AA according to claim 1, which comprises:
(1) condensing Boc-tranexamic acid and amino methyl hexanoate to obtain Boc-tranylcarbonylamino methyl hexanoate (1);
(2) removing Boc from Boc-cycloacyl-amino-n-hexanoic acid methyl ester in ethyl acetate solution of hydrogen chloride to obtain cycloacyl amino-n-hexanoic acid methyl ester (2);
(3) condensing Boc-amino N-hexanoic acid and methyl carbamoylamino N-hexanoate (2) to obtain (N-Boc-amino N-hexanoyl carbamoylamino) -amino N-hexanoate methyl ester (3);
(4) saponifying and demethylating the compound 3 to obtain (N-Boc-amino-N-caproyl carbamoylamino) -amino-N-hexanoic acid (4);
(5) condensing the compound 4 with AA-OBzl to obtain (N-Boc-amino-N-hexanoyl formamide cycloacyl) -amino-N-hexanoyl amino acid benzyl ester (5 a-c);
(6) the compound 5a-c is subjected to hydrogenolysis to remove benzyloxycarbonyl and then subjected to Boc removal in an ethyl acetate solution of hydrogen chloride to obtain (N-amino-N-hexanoyl carbamyl) -amino-N-hexanoyl-AA (6 a-c).
3. Use of (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyl-AA according to claim 1 for the preparation of a medicament against tumor metastases.
4. Use of (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyl-AA according to claim 1 for the preparation of an antitumor medicament.
5. Use of (N-amino-N-hexanoylcycloacyl) -amino-N-hexanoyl-AA according to claim 1 for the preparation of an anti-inflammatory medicament.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53148536A (en) * | 1977-04-21 | 1978-12-25 | Kureha Chem Ind Co Ltd | Carcinostatic agent containing trans-4-aminomethylcyclohexane-1-carboxylic acid derivative |
| JPS5759847A (en) * | 1980-09-29 | 1982-04-10 | Hisamitsu Pharmaceut Co Inc | 4-aminomethylcyclohexanecarboxylic acid derivative |
| EP0079872A1 (en) * | 1981-11-17 | 1983-05-25 | KabiVitrum AB | Antifibrinolytically active compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53148536A (en) * | 1977-04-21 | 1978-12-25 | Kureha Chem Ind Co Ltd | Carcinostatic agent containing trans-4-aminomethylcyclohexane-1-carboxylic acid derivative |
| JPS5759847A (en) * | 1980-09-29 | 1982-04-10 | Hisamitsu Pharmaceut Co Inc | 4-aminomethylcyclohexanecarboxylic acid derivative |
| EP0079872A1 (en) * | 1981-11-17 | 1983-05-25 | KabiVitrum AB | Antifibrinolytically active compounds |
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