CN112010927B - EGH and hydroxymethyl modified benzimidazole quinazoline, and synthesis, activity and application thereof - Google Patents
EGH and hydroxymethyl modified benzimidazole quinazoline, and synthesis, activity and application thereof Download PDFInfo
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Abstract
EGH and hydroxymethyl modified benzimidazole quinazoline, and synthesis, activity and application thereof. The invention discloses a 6-hydroxymethyl-6- (His-Gly-Glu-OCH) compound with the following formula2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline, discloses a preparation method thereof, discloses immunosuppressive activity thereof, and discloses that the quinazoline can prolong the survival time of transplanted myocardium after ears of mice, so that the invention discloses application thereof in preparing immunosuppressant.
。
Description
Technical Field
The invention relates to 6-hydroxymethyl-6- (His-Gly-Glu-OCH)2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline, to a process for its preparation, and to its immunosuppressive activity. The invention thus relates to the use of such compounds in the preparation of immunosuppressive drugs. The invention belongs to the field of biological medicine.
Background
The first example of organ transplant surgery was successful in the last 60 s of the century. Through decades of development, patients who lose organ functions are cured. However, the immune rejection of the human autoimmune system to foreign organs severely affects the recent and long-term health of patients. Ultimately, immune rejection affects the survival time of the patient after transplantation. How to avoid this immune rejection is of great importance. Although various measures are clinically implemented, the results are not ideal. In the case of kidney transplantation, although acute cellular and humoral rejection can be effectively controlled by plasmapheresis and intervention with potent immunosuppressive agents, the treatment is not as effective as chronic rejection. Thus, the present invention is directed to novel immunosuppressive agents. Also, the effects of the novel immunosuppressive agents of the present invention are not ideal. With the interest in the development of novel immunosuppressive agents, the inventors have been working on modifying N-containing heterocycles with peptides. After 3 years of exploration, the inventor finds that the purpose of designing the compound is to combine two structures with immunosuppressive activity to obtain a novel immunosuppressive agent. The inventors found that hydroxymethyl and His-Gly-Glu-OCH were used2Modification 56-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline produced 6-hydroxymethyl-6- (His-Gly-Glu-OCH)2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline showed excellent activity in an experimental model of myocardial transplantation behind the mouse ear. Based on this finding, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide 6-hydroxymethyl-6- (His-Gly-Glu-OCH) compound of the formula2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline.
The second aspect of the present invention is to provide 6-hydroxymethyl-6- (His-Gly-Glu-OCH)2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A process for the preparation of a quinazoline, the process comprising:
1) synthesizing (6, 6-dihydroxymethyl-5, 6-dihydrobenzo [4,5] imidazole [1,2-c ] quinazoline;
2) synthesis of 6-hydroxymethyl-6- [ Boc-Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
3) synthesis of 6-hydroxymethyl-6- [ Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
4) synthesizing Boc-His (Boc) -Gly by using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst through a liquid phase method;
5) the liquid phase method which adopts dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst is adopted to prepare the 6-hydroxymethyl-6- [ Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Condensation of quinazoline with Boc-His (Boc) -Gly to 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
6) synthesis of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole[1,2-c]A quinazoline;
7) synthesis of 6-hydroxymethyl-6- (His-Gly-Glu-OCH2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline.
The third aspect of the present invention is to evaluate 6-hydroxymethyl-6- (His-Gly-Glu-OCH)2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]The immunosuppressive action of quinazoline.
Drawings
FIG. 1.6-hydroxymethyl-6- (His-Gly-Glu-OCH2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Synthetic routes to quinazolines (i) 2M hydrochloric acid solution, 1, 3-dihydroxyacetone; (ii) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, Boc-Glu (OBzl), N-methylmorpholine; (iii) hydrogen chloride in ethyl acetate (4M); (iv) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine; (v) Pd/C, H2。
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 (6, 6-dihydroxymethyl-5, 6-dihydrobenzo [4,5] imidazo [1,2-c ] quinazoline (1)
6.40g (30.6mmol) of 2- (2-aminophenyl) -1H-benzimidazole was suspended in 100mL of methanol, and 2.76g (30.7mmol) of 1, 3-dihydroxyacetone was added to the suspension. The reaction mixture was adjusted to pH 2 with 2M hydrochloric acid, at which time the reaction solution turned green. The reaction mixture was stirred at room temperature for 12 hours, TLC (dichloromethane/methanol ═ 20/1) showed the disappearance of the starting point and a large amount of yellow-green solid precipitated. The reaction was terminated, and a 4M aqueous solution of sodium hydroxide was added dropwise to the reaction solution to adjust the pH of the reaction solution to neutral, followed by filtration to obtain 7.03g of the title compound as a yellow-green solid. The filtrate was concentrated under reduced pressure and filtered to give 2.52g of the title compound as a dark green solid. The yield of the reaction of this step was 100%. ESI-MS (M/e):282[ M + H]+。
Mp 214-215℃。1H-NMR(300MHz,DMSO-d6):δ/ppm＝7.86(d,J＝7.2Hz,1H),7.69(m,1H),7.59(m,1H),7.15(m,3H),6.85(d,J＝8.1Hz,1H),6.70(m,2H), 5.26(t,J＝5.4,2H),4.08(dd,J1＝6.0Hz,J2＝5.7Hz,2H),3.82(dd,J1＝5.7Hz,J2＝6.0Hz, 2H)。
EXAMPLE 2 preparation of 6-hydroxymethyl-6- [ Boc-Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (2)
337mg (1.00mmol) of Boc-Glu (OBzl),250mg (1.20mmol) of dicyclohexylcarbodiimide and 135 mg (1.00mmol) of 1-hydroxybenzotriazole are dissolved in 10mL of DMF. The resulting solution was stirred in an ice bath for 30 minutes, after which 1.12g (4.00mmol) of 6, 6-dimethylol-5, 6-dihydrobenzo [4,5] -c-ydro-benzo]Imidazole [1,2-c ]]Quinazoline (1). The reaction mixture was adjusted to pH 7-8 with N-methylmorpholine. After that, the reaction mixture was stirred at room temperature for 12 hours, and TLC (dichloromethane/methanol ═ 20/1) showed disappearance of Boc-glu (obzl). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50mL of ethyl acetate, filtered, the filtrate was washed with a saturated aqueous solution of sodium bicarbonate (30mL × 3), a saturated aqueous solution of sodium chloride (30mL × 3), dried over anhydrous sodium sulfate for 12 hours, filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with dichloromethane, sonicated, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 80/1) to give 370mg (62%) of the title compound as a pale yellow-green solid. ESI-MS (M/e):635[ M + Cl]-。
Mp 80-82℃；1H-NMR(300 MHz,DMSO-d6):δ/ppm＝7.86(d,J＝7.8Hz,1H),7.72(dd,J1＝7.8Hz,J2＝19.5Hz,1H), 7.59(m,1H),7.35(s,5H),7.14(m,4H),6.96(d,J＝19.5Hz 1H),6.82(t,J＝6.3Hz,1H), 5.54(m,1H),5.03(s,2H),4.79(m,1H),4.45(m,1H),4.16(m,1H),3.95(m,1H),3.78(m, 1H),2.13(m,1H),1.45(m,1H),1.32(s,9H)。
EXAMPLE 3 preparation of 6-hydroxymethyl-6- [ Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (3)
300mg (0.500mmol) of 6-hydroxymethyl-6- [ Boc-Glu (OBzl)-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (2) was dissolved in 1mL of anhydrous ethyl acetate, 5mL of a hydrogen chloride ethyl acetate solution (4M) was added under ice-bath, TLC (dichloromethane/methanol) ═ 20/1) showed disappearance of compound 2 after 4 hours of reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in anhydrous ethyl acetate and concentrated under reduced pressure, and the residue was dissolved in anhydrous ethyl acetate again. This operation was repeated 3 times. The residue was dispersed in 10mL of anhydrous ether, allowed to stand, and ether was discarded to give 280mg (100%) of the title compound as a green solid. ESI-MS (m/e): 535[ M + Cl]-。
EXAMPLE 4 preparation of Boc-His (Boc) -Gly-OBzl
5.23mg (14.7mmol) of Boc-His (Boc),3.70g (16.0mmol) of dicyclohexylcarbodiimide and 2.00g (15.0mmol) of 1-hydroxybenzotriazole were dissolved in 150mL of anhydrous tetrahydrofuran and stirred at 0 ℃ for 30 minutes. To the reaction mixture was added 3.00g (15.0mmol) Gly-OBzl, the reaction mixture was adjusted to pH 7-8 with N-methylmorpholine, stirred at room temperature for 12 hours, and TLC (dichloromethane/methanol ═ 20/1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, the residue was diluted with 100mL of ethyl acetate, filtered, the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate (30mL × 3), saturated aqueous solution of sodium chloride (30mL × 3), dried over anhydrous sodium sulfate for 12 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol ═ 80/1) to give 2.23g (30%) of the title compound as a yellow oil. ESI-MS (M/e) 503[ M + H]+。
EXAMPLE 5 preparation of Boc-His (Boc) -Gly
1.32g (2.64mmoL) of Boc-his (Boc) -Gly-OBzl was dissolved in 100mL of methanol, and 140mg of Pd/C was added to the resulting solution, followed by hydrogen gas introduction, stirring at room temperature for 12 hours, and TLC (dichloromethane/methanol ═ 20/1) showed completion of the reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 1.16g (100%) of the title compound as a colorless solid. ESI-MS (M/e):413 [ M + H]+。
EXAMPLE 6 preparation of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (4)
240mg (0.60mmol) of Boc-His (Boc) -Gly,130mg (0.630mmol) of dicyclohexylcarbodiimide and 75.0mg (0.550mmol) of 1-hydroxybenzotriazole were treated with 10mL of anhydrous tetrahydrofuran under ice bathDissolving, stirring for 30 minutes, adding 270mg (0.60mmol) of 6-hydroxymethyl-6- [ Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (3). The reaction mixture was adjusted to pH 8 with N-methylmorpholine and stirred at room temperature for 6 hours, and TLC (dichloromethane: methanol ═ 15:1) showed disappearance of compound 3. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 50mL of ethyl acetate, filtered, the filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate (30mL × 3), a saturated aqueous solution of sodium chloride (30mL × 3), dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid, which was purified by silica gel column chromatography (dichloromethane/methanol ═ 30/1), and 81.0mg (41%) of the title compound was obtained as a pale yellow solid. ESI-MS (M/e):896[ M + H]+。
Mp 110-111℃。1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.18(d,J＝7.2Hz, 1H),8.06(m,2H),7.87(d,J＝6.9Hz,1H),7.73(m,1H),7.59(m,1H),7.34(m,5H),7.16 (m,4H),6.89(m,2H),6.82(d,J＝6.9Hz,1H),6.72(t,J＝6.9Hz,1H),5.55(q,J＝6.6Hz,1 H),5.02(s,2H),4.56(m,2H),4.20(m,2H),4.04(m,2H),3.62(m,2H),2.87(m,1H),2.70 (m,1H),2.15(t,J＝8.1Hz,2H),1.53(s,11H),1.32(s,9H)。13C-NMR(300MHz, DMSO-d6):δ/ppm＝172.1,171.4,169.4,155.7,148.0,147.9,147.1,144.4,143.5,139.9,137.0, 136.6,133.4,133.3,131.9,128.8,128.4,124.9,122.5,122.3,119.2,118.1,144.8,133.0,122.7, 111.4,78.7,76.4,65.9,63.9,63.6,54,2,51.4,42.3,30.8,30.0,28.5,27.8,26.0。
EXAMPLE 7 preparation of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (5)
60.0mg (0.067mmoL) of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (4) gave 55 mg (100%) of the title compound as a green solid. ESI-MS (M/e):806[ M + H]+。
EXAMPLE 8 preparation of 6-hydroxymethyl-6-[His-Gly-Glu-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (6)
55.0mg (0.067mmol) of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Quinazoline (5) was dissolved with 2mL of hydrogen chloride in ethyl acetate (4M) and stirred for 4 hours. TLC (ethyl acetate/water/glacial acetic acid ═ 2/1/1) showed the disappearance of compound 5. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated 3 times. The residue was washed with dry ether 3 times. The resulting green solid was purified by C18 column (water/methanol 80/20) and the fractions were lyophilized to give 9.60mg (26%) of the title compound as a green solid. ESI-MS (M/e):606[ M + H]+。
Mp 181-183℃。IR(cm-1):3029.60, 2321.11,2166.95,2109.11,1741.91,1682.54,1628.73,1568.08,1531.98,1492.60,1386.95, 1337.38,1261.81,1186.85,1073,10,1019.19,823.60,750.73,622.09。1H-NMR(300MHz, DMSO-d6):δ/ppm＝8.89(s,2H),8.53(dd,J1＝6.3Hz,J2＝15.0Hz,1H),7.89(d,J＝7.5Hz, 1H),7.74(dd,J1＝6.3Hz,J2＝15.0Hz,1H),7.62(d,J＝6.0Hz,1H),7.44(s,1H),7.20(m,4 H),6.88(m,1H),6.76(q,J＝6.6Hz,1H),5.62(m,1H),4.75(m,q H),,4.47(m,1H),4.18 (m,3H),3.97(m,2H),3.81(m,1H),3.62(m,2H),2.04(m,2H),1.53(m,2H)。13C-NMR (300MHz,DMSO-d6):δ/ppm＝174.1,173.8,171.4,169.2,168.1,147.4,144.1,134.6,133.3, 132.4,126.9,125.4,123.6,118.5,118.3,114.9,113.6,77.2,65.8,63.8,63.5,51.6,42.0,30.1, 26.6,26.1。
Example 9 evaluation of the immunosuppressive Effect of Compound 6
Male Balb/c mice (20. + -.2 g) were anesthetized with a 10% urethane (10mg/10g body weight) intraperitoneal injection. Mouse auricles were topically sterilized with 75% alcohol. A3-4 mm long incision perpendicular to the midline of the auricle was made at about 1/3 from the dorsal midline of the auricle, taking care not to damage the auricular veins. The subcutaneous tissue is bluntly separated in the direction of the ear tip through the opening to form an artificial lumen. The C57bl/6j heart-suckling mouse is frozen in crushed ice for one minute, the skin is disinfected by 75% alcohol, and the heart is taken after the chest is cut open. The heart is placed in a watch glass on which physiological saline-wetted gauze is laid to beat, so that the residual blood in the heart cavity is discharged. The heart of a suckling mouse is longitudinally cut into two petals of myocardium with basically equal-size muscle fibers and inclined planes. Myocardium was filled into the artificial lumen of Balb/c recipient mice. The isolated time of the myocardial tissue does not exceed 2 minutes during the operation. Lightly press the artificial lumen filled with myocardium to discharge excessive physiological saline and air bubbles, so that the transplanted myocardium is tightly adhered to the tissues around the ear of the recipient mouse. Compound 6 (at a dose of 0.1. mu. mol/kg/day) or cyclosporin A (at a dose of 2.5. mu. mol/kg/day) or normal saline was administered orally on the day of myocardial transplantation. The electrocardiogram continuously administered to the transplanted myocardium disappeared.
From the seventh day of myocardial transplantation, the electrocardiographic signals of the transplanted myocardial tissues were measured with a biosignal two-channel instrument every day (if no electrocardiographic signals were present from the seventh day to the following days, it was judged that the myocardial transplantation operation failed). When measuring the ectopic electrocardiogram, the positive and negative electrodes are respectively arranged at two sides of the transplanted myocardial tissue, and the grounding electrode is connected with the hind limb of the mouse. The measurement of the heterotropic electrocardiogram is finished after the electrocardiosignals of the transplanted myocardial tissue are completely disappeared, and the survival time (mean value +/-SD) of the transplanted myocardial tissue is counted, and the result is shown in table 1. It can be seen that the activity of compound 6 in prolonging survival of transplanted myocardium at 0.1 μmol/kg/day dose was not significantly different from cyclosporin a at 2.5 μmol/kg/day dose. The invention has outstanding technical effects.
TABLE 1 Effect of Compound 6 on myocardial transplant survival time in mice after ear
a) P <0.01 to saline; b) p <0.05 compared to saline, P >0.05 compared to cyclosporin a; n is 12.
Claims (3)
1. 6-hydroxymethyl-6- (His-Gly-Glu-OCH) of formula2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline in the form of a salt,
2. the 6-hydroxymethyl-6- (His-Gly-Glu-OCH of claim 12) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A process for the preparation of a quinazoline, the process comprising:
2.1. synthesizing (6, 6-dihydroxymethyl-5, 6-dihydrobenzo [4,5] imidazole [1,2-c ] quinazoline;
2.2. synthesis of 6-hydroxymethyl-6- [ Boc-Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
2.3. synthesis of 6-hydroxymethyl-6- [ Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
2.4. synthesizing Boc-His (Boc) -Gly by using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst through a liquid phase method;
2.5. the liquid phase method which adopts dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst is adopted to prepare the 6-hydroxymethyl-6- [ Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]Condensation of quinazoline with Boc-His (Boc) -Gly to 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu (OBzl) -OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
2.6. synthesis of 6-hydroxymethyl-6- [ Boc-His (Boc) -Gly-Glu-OCH2]-5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline;
2.7. synthesis of 6-hydroxymethyl-6- (His-Gly-Glu-OCH2) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]A quinazoline.
3. The 6-hydroxymethyl-6- (His-Gly-Glu-OCH of claim 12) -5, 6-dihydrobenzo [4,5]]Imidazole [1,2-c ]]The application of quinazoline in preparing immunosuppressant.
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| CN102796171A (en) * | 2011-05-27 | 2012-11-28 | 首都医科大学 | Double saturated aliphatic chain alcohol His-Gly-Glu-Asp tetrapeptide esters and preparation method and application thereof |
| CN104211761A (en) * | 2013-06-05 | 2014-12-17 | 首都医科大学 | Conjugates of saturated aliphatic chain alcohol, dexamethasone, and His-Gly-Glu, preparation, nano structure, and applications thereof |
| CN106317185A (en) * | 2015-06-23 | 2017-01-11 | 首都医科大学 | His-Gly-Tyr-Asp and synthesis, activity and application thereof |
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