CN112110923B - 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof - Google Patents
6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, synthesis, activity and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/36—Sulfur atom
- C07D473/38—Sulfur atom attached in position 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
The present invention discloses 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine (AA in the formula is Met, Pro, Ser, Val and Trp residue), and discloses their preparationThe preparation method discloses the antitumor activity of the compounds. Therefore, the invention discloses the application of the compounds in preparing antitumor drugs.
Description
Technical Field
The invention relates to 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, a preparation method thereof and antitumor activity thereof. Therefore, the invention relates to the application of the series of compounds in preparing antitumor drugs. The invention belongs to the field of biological medicine.
Background
6-mercaptopurine is a common medicine for clinically treating acute lymphoblastic leukemia of children. However, it is also used for the treatment of chorionic epithelial cancer. However, some toxic side effects limit the clinical use of 6-mercaptopurine. For example, 6-mercaptopurine has a more severe myelosuppressive effect, a shorter half-life, and a higher dose. Although there have been numerous studies over the past decades attempting to overcome these disadvantages of 6-mercaptopurine, there has been no apparent success. The inventor finds that CH is used after years of exploration 2 CO-AA-OBzl (AA in the formula is Met, Pro, Ser, Val and Trp residue) modifies 6-SH and 9-N of 6-mercaptopurine, and can eliminate myelosuppression of 6-mercaptopurine, prolong half-life and reduce dosage. Based on these findings, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, wherein AA is Met, Pro, Ser, Val and Trp residue.
In a second aspect, the invention provides a process for the preparation of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, wherein AA is a Met, Pro, Ser, Val or Trp residue, which process comprises:
1. synthesizing 6-S, 9-N-diacetyl-O-ethylmercaptopurine;
2. synthesizing 6-S, 9-N-dicarboxymethylmercaptopurine;
3. a liquid phase method using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst is adopted to condense 6-S,9-N- (dicarboxymethylmercapto) purine with AA-OBzl to prepare 6-S, 9-N-diacetyl-AA-OBzl-mercaptopurine, wherein AA is Met, Pro, Ser, Val and Trp residues.
The third aspect of the present invention is to evaluate the antitumor effect of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine.
Drawings
FIG. 1. Synthesis of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine I) ethyl bromoacetate, dimethylformamide, K 2 CO 3 ,65℃;ii)CH 3 OH,2N NaOH aqueous solution; iii) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine, dimethylformamide. AA in 3a-e is Met residue, Pro residue, Ser residue, Val residue and Trp residue, respectively.
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-S,9-N- (diacetyl-O-ethylmercapto) purine (1)
To 3.001g (19.70mmol) of 6-mercaptopurine was added 50mL of N, N-dimethylformamide, and the mixture was stirred at 65 ℃ until the 6-mercaptopurine was completely dissolved, whereby the solution was yellow, clear and transparent. 5.400g (39.50mmol) of K are added 2 CO 3 As a catalyst, the reaction mixture was activated for 30min, 6.60mL (59.20mmol) of ethyl bromoacetate was added, and the reaction was continued at 65 ℃. After 48h of reaction TLC (petroleum ether/ethyl acetate-1/1) showed disappearance of 6-mercaptopurine, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate-1/1) to give 1.500g (23%) of the title compound as a colorless solid. ESI-MS (M/e):325[ M + H] + ; 1 H-NMR(300MHz,DMSO-d 6 )δ/ppm=8.692(s,1H),8.489(s,1H),5.214(s,2H),4.260(s,2H),4.215~4.098(dq,J 1 =6.9Hz,J 2 =7.2Hz,4H),1.238~1.165(dt,J 1 =7.2Hz,J 2 =11.0Hz,6H); 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm=167.93,167.55,166.54,150.30,147.67,137.81,132.98,61.00,60.64,53.03,31.11,14.16。
EXAMPLE 2 preparation of 6-S,9-N- (dicarboxymethylmercapto) purine (2)
0.170g (0.52mmol) of 6-S,9-N- (diacetyl-O-ethylmercapto) purine (1) was completely dissolved in 5mL of methanol, and the solution was clear and transparent. The solution was adjusted to pH 13 with 2N aqueous NaOH at 0 ℃, stirred for 4h at 0 ℃ and monitored for completion by TLC (petroleum ether/ethyl acetate 1/2). Saturated KHSO is used for reaction liquid 4 The aqueous solution was adjusted to pH 7, concentrated under reduced pressure to precipitate a colorless salt solid, and 5mL of water was added to completely dissolve the solid. The solution is saturated with KHSO at 0 deg.C 4 The aqueous solution was adjusted to pH 2. The mixture was extracted with ethyl acetate (20 mL. times.3), the ethyl acetate layers were combined and washed with saturated NaCl (15 mL. times.3), and the resulting ethyl acetate phase was dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave 0.138g (98%) of the title compound as a colorless solid. ESI-MS (M/e):267[ M-H] + ; 1 H-NMR(300MHz,DMSO-d 6 )δ/ppm=13.011(s,2H),8.501(s,1H),8.078(s,1H),4.799(s,2H),4.026(s,2H); 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm=174.90,171.01,159.64,158.52,151.60,140.33,122.48,54.85,32.01。
EXAMPLE 3 preparation of 6-S,9-N- (diacetyl-Met-OBzl-mercapto) purine (3a)
0.496g (1.85mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, 0.498g (3.70mmol) of 1-hydroxybenzotriazole was added at 0 ℃ and stirred for 10min, and then 1.140g (7.40mmol) of dicyclohexylcarbodiimide was added and stirred for 30 min. 2.300g (7.40mmol) Met-OBzl was added to the reaction mixture at 0 deg.C, the reaction mixture was adjusted to pH 9 with N-methylmorpholine, stirred at room temperature for 12h and monitored for completion by TLC (petroleum ether/ethyl acetate-1/3). The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 50mL of ethyl acetate, the insoluble material was filtered off, and the filtrate was taken with saturated NaHCO 3 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution 3 The ethyl acetate phase was dried over anhydrous sodium sulfate for 12 hours, after washing with an aqueous solution (30 mL. times.3) and saturated aqueous NaCl solution (30 mL. times.3). Filtration and concentration of the filtrate under reduced pressure gave a yellow oil which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/3) to give 1.310g (49%) of the title compound. FT-MS (M/e) 709.20[ M-H] - ; 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm=8.994~8.969(d,J=7.5Hz,1H),8.784~8.759(d,J=7.5Hz,1H),8.619(s,1H),8.434(s,1H),7.343(m,10H),5.173~5.079(dd,J 1 =13.2Hz,J 2 =2.4Hz,4H),5.058(s,2H),4.513~4.444(dd,J 1 =7.8Hz,J 2 =5.4Hz,2H),4.235~4.120(dd,J 1 =15.0Hz,J 2 =4.2Hz,2H),2.539~2.411(m,4H),2.242~1.834(m,10H); 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm=171.79,171.64,168.05,166.79,158.76,151.67,149.22,146.15,136.33,136.26,130.63,128.87,128.55,128.49,128.30,128.23,66.64,66.52,51.92,51.80,45.54,32.23,31.09,31.04,29.87,29.83,15.00。
EXAMPLE 4 preparation of 6-S,9-N- (diacetyl-Pro-OBzl-mercapto) purine (3b)
0.400g (1.49mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, and 0.808g (2.98mmol) of 1-hydroxybenzotriazole was added thereto at 0 ℃ and stirred for 10min, and then 1.230g (5.97mmol) of dicyclohexylcarbodiimide was added thereto and stirred for 30 min. 2.270g (5.97mmol) Pro-OBzl were added to the reaction mixture at 0 deg.C, the reaction mixture was adjusted to pH 9 with N-methylmorpholine, stirred at room temperature for 12h and monitored for completion by TLC (dichloromethane/methanol-40/1). The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 50mL of ethyl acetate, the insoluble material was filtered off, and the filtrate was taken with saturated NaHCO 3 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution 3 The ethyl acetate phase was dried over anhydrous sodium sulfate for 12 hours, after washing with an aqueous solution (30 mL. times.3) and saturated aqueous NaCl solution (30 mL. times.3). Filtration and concentration of the filtrate under reduced pressure gave a yellow oil which was purified by silica gel column chromatography (dichloromethane/methanol ═ 90/1) to give 0.400g (41%) of the title compound. FT-MS (M/e) 641.58[ M-H] - ; 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm=8.662(s,1H),8.366(s,1H),7.441~7.322(m,10H),5.297~5.211(m,2H),5.102~5.035(m,4H),4.422~4.394(m,2H),3.785~3.764(m,2H),3.427~3.342(m,4H),2.346~2.234(m,2H),2.008~1.897(m,6H); 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm=172.35,171.78,166.66,165.36,158.78,151.76,149.37,136.44,130.55,128.93,128.46,67.37,66.38,59.70,59.35,47.49,47.02,45.23,32.19,29.32,24.99,22.68。
EXAMPLE 5 preparation of 6-S,9-N- (diacetyl-Ser-OBzl-mercapto) purine (3c)
0.070g (0.26mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 5mL of anhydrous N, N-dimethylformamide, 0.070g (0.52mmol) of 1-hydroxybenzotriazole was added at 0 ℃ and stirred for 10min, then 0.414g (1.04mmol) of dicyclohexylcarbodiimide was added and stirred for 30 min. 0.386g (1.04mmol) of Ser-OBzl was added to the reaction mixture at 0 deg.C, the pH of the reaction mixture was adjusted to 9 with N-methylmorpholine, and the reaction was monitored for completion by TLC (dichloromethane/methanol ═ 20/1) after stirring at room temperature for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 20mL of ethyl acetate, filtered, and the residue was washed with methylene chloride and methanol and dried naturally to give 0.112g (71%) of the title compound. FT-MS (M/e) 621.18[ M-H] - ; 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm=8.928~8.902(d,J=7.8Hz,1H),8.662~8.632(m,2H),8.430~8.420(m,1H),7.368~7.296(m,10H),5.225~5.189(t,J=5.4Hz,1H),5.142~5.119(m,5H),5.085(s,2H),4.486~4.405(m,2H),4.210~4.205(d,J=1.5Hz,2H),3.811~3.648(m,4H); 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm=170.65,170.54,168.12,166.78,158.64,151.75,146.25,136.37,136.33,130.55,128.84,128.80,128.43,128.36,128.07,127.98,66.49,66.38,61.67,55.57,55.47,45.49,32.05。
EXAMPLE 6 preparation of 6-S,9-N- (diacetyl-Val-OBzl-mercapto) purine (3d)
0.500g (1.86mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, 1.060g (7.46mmol) of 1-hydroxybenzotriazole was added thereto at 0 ℃ and stirred for 10min, and then 1.530g (7.46mmol) of dicyclohexylcarbodiimide was added thereto and stirred for 30 min. 2.850g (7.46mmol) Val-OBzl were added to the reaction mixture at 0 deg.C, the pH of the reaction mixture was adjusted to 9 with N-methylmorpholine, and the reaction was monitored for completion by TLC (dichloromethane/methanol 30/1) after stirring at room temperature for 12 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 50mL of ethyl acetate, insoluble materials were filtered off, and the filtrate was taken with saturated NaHCO 3 Aqueous washing (30 mL. times.3), saturated aqueous NaCl washing (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution 3 The ethyl acetate phase was dried over anhydrous sodium sulfate for 12 hours, after washing with an aqueous solution (30 mL. times.3) and saturated aqueous NaCl solution (30 mL. times.3). Filtration and concentration of the filtrate under reduced pressure gave a yellow oil which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/2) to give 0.940g (78%) of the title compound. FT-MS (M/e) 645.26[ M-H] - ; 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm=8.818~8.791(d,J=8.1Hz,1H),8.625(s,1H),8.599~8.572(d,J=8.1Hz,1H),8.424(s,1H),7.375~7.310(m,10H),5.191~5.125(m,4H),5.088(s,2H),4.284~4.236(m,2H),4.262~4.146(dd,J 1 =15.3Hz,J 2 =7.8Hz,4H),2.131~2.048(m,2H),0.915~0.851(m,12H); 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm=171.57,171.46,168.18,166.88,158.84,151.69,149.22,146.27,136.30,136.24,130.58,128.88,128.85,128.59,128.53,128.45,66.52,66.40,58.26,58.17,45.44,32.26,30.61,30.55,19.34,18.50,18.46。
EXAMPLE 7 preparation of 6-S,9-N- (diacetyl-Trp-OBzl-mercapto) purine (3e)
0.050g (0.19mmol) of 6-S,9-N- (dicarboxymethylmercapto) purine (2) was dissolved in 10mL of anhydrous N, N-dimethylformamide, 0.050g (0.37mmol) of 1-hydroxybenzotriazole was added thereto at 0 ℃ and stirred for 10min, and then 0.154g (0.74mmol) of dicyclohexylcarbodiimide was added thereto and stirred for 30 min. 0.247g (0.74mmol) of Trp-OBzl was added to the reaction mixture at 0 deg.C, the pH of the reaction mixture was adjusted to 9 with N-methylmorpholine, and the reaction was monitored for completion by TLC (dichloromethane/methanol-30/1) after stirring at room temperature for 12 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in 50mL of ethyl acetate, the insoluble material was filtered off, and the filtrate was taken with saturated NaHCO 3 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO 4 Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution 3 The ethyl acetate phase was dried over anhydrous sodium sulfate for 12 hours, after washing with an aqueous solution (30 mL. times.3) and saturated aqueous NaCl solution (30 mL. times.3). Filtration and concentration of the filtrate under reduced pressure gave a yellow oil which was purified by silica gel column chromatography (dichloromethane/methanol-40/1) to give 0.124g (81%) of the title compound. FT-MS (M/e) 819.28[ M-H] - ; 1 H-NMR(300MHz,DMSO-d 6 ):δ/ppm=10.917(s,1H),10.838(s,1H),9.012~8.989(d,J=6.9Hz,1H),8.729~8.704(d,J=7.5Hz,1H),8.526(s,1H),8.352(s,1H),7.609~6.933(m,20H),5.077~4.962(m,6H),4.653~4.585(dd,J 1 =6.9Hz,J 2 =6.6Hz,2H),4.146(m,2H),3.254~3.132(m,4H); 13 C-NMR(75MHz,DMSO-d 6 ):δ/ppm=171.88,171.79,168.01,166.68,158.55,151.66,149.16,146.11,136.62,136.56,136.09,136.02,130.48,128.78,128.46,128.40,128.13,128.07,127.49,124.32,124.15,121.53,121.48,119.04,118.96,118.40,111.95,111.89,109.48,109.39,66.58 66.47,54.11,45.47,32.06,27.66,27.51。
Example 8 evaluation of the antitumor Effect of 3a-e
6-mercaptopurine and sodium carboxymethylcellulose were purchased from national pharmaceutical group chemical reagents, Inc. Male mice (20 ± 2g) of the SPF grade ICR strain were purchased from experimental animal technology ltd, viton, beijing. The experiment was performed using a transplanted mouse S180 sarcoma model.
The dose of compounds 3a-e was 16. mu. mol/kg/day, the dose of positive control 6-mercaptopurine was 164. mu. mol/kg/day, and the negative control was CMCNa.
The tumor source for modeling the transplanted mouse S180 sarcoma model is S180 mouse sarcoma cells purchased from animal experiment center of department of medicine of Beijing university and self-passaged and reserved according to a suspension cell culture method. A male ICR mouse with the SPF level of S180 ascites tumor after one week of passage is taken, the neck is cut off after the anesthesia of a proper amount of ether, the mouse is soaked in 75% alcohol for disinfection for 1min, the abdominal cavity is cut open, ascites S180 tumor liquid is taken, the centrifugation is carried out for 1000r/min multiplied by 10min, the supernatant is discarded, the residues are washed by a small amount of cooled normal saline to remove non-cell fragments, tissues and floating blood, the cell activity is calibrated by a MUSE flow cytometer, and the result shows that the cell activity reaches 94.67%. Viable cell count, density 4X 10 7 one/mL. The living cells were suspended in cooled physiological saline to a cell density of 2X 10 7 one/mL, used for inoculation as soon as possible. During inoculation, the mouse is fixed by the left hand, a 1mL syringe is held by the right hand to pierce the right armpit of the mouse by about 2mm to the subcutaneous part, a small cavity is separated by slight blunting, and 0.2mL of living cell suspension is injected.
The mice are observed every day after detection and inoculation, until the majority of mice can see mung bean particle solid tumors under the armpit (average about 5 days of inoculation), the mice are grouped, 11 mice in each group are continuously administrated for 10 days, the mice in each group are weighed until 11 days, the mice are anesthetized by ether, cervical vertebra dislocation is killed, the growth parts of the solid tumors under the armpit of the mice are fixed, scissors are taken to cut the skin, the tumor bodies are fully exposed, and sarcomas are taken out and weighed by blunt separation of the upper limbs along the skin. The brain, heart, liver, spleen and kidney were dissected out in sequence and weighed, and the index of each organ was calculated.
The in-situ tumor weight of the data is represented by a mean value +/-SD g, the SD value is subjected to variance analysis through SPSS software, the homogeneity of the variance is detected, and statistical comparison among groups is performed by adopting t-test detection.
As a result, all of the compounds 3a-e exhibited antitumor activity, wherein the antitumor activity of 3a, c, e was comparable to that of 6-mercaptopurine at a 9-fold decrease in the dose of 6-mercaptopurine. This is the unexpected technical effect of this case.
S180 antitumor Activity of tables 13 a-e
Compound (I) | Dosage (mu mol/kg/day) | Tumor weight (mean + -SD g) |
CMCNa | - | 2.34±0.67 |
6-mercaptopurine | 164 | 1.10±0.33 |
3a | 16 | 1.50±0.53 b |
3b | 16 | 1.71±0.62 a |
3c | 16 | 1.46±0.45 b |
3d | 16 | 1.64±0.39 a |
3e | 16 | 1.46±0.46 b |
a) P <0.05 to CMCNa; b) p <0.05 to CMCNa, p >0.05 to 6-mercaptopurine; n is 11.
EXAMPLE 9 evaluation of myelosuppressive toxicity of 3a, c, e
The method comprises the steps of taking 20 mu L of eyeball blood before mice are sacrificed for 10 days after continuous administration treatment, placing the eyeball blood into a 0.5mL special EDTA blood collection tube, tightly covering the tube opening, shaking up and down uniformly, and detecting by using a full-automatic three-classification blood cell analyzer within 4 h. 3a, c, e are representatives of 6-S,9-N- (diacetyl-AA-OBzl-mercapto) purine, control CMCNa.
Results table 2 shows that the white blood cell count and platelet count of the 6-mercaptopurine group mice were significantly lower than those of the CMCNa group mice, and the red blood cell count did not significantly decrease. This indicates that myelosuppressive toxicity caused by 6-mercaptopurine is mainly manifested by inhibition of leukocytes and platelets. The white blood cell number and the platelet number of the mice in the 3a, c and e groups are obviously higher than those of the mice in the 6-mercaptopurine group, and are very close to those of the mice in the CMCNa group, namely, the acetyl-AA-OBzl modified 6-S and 9-N can reduce the myelosuppression side effect of the 6-mercaptopurine. This is the unexpected technical effect of this case.
TABLE 2 Compound 3a, c, e group mouse myelosuppressive toxicity assay
Example 10 evaluation of plasma half-lives of 3a, c, e
Under the anesthesia state, the plasma of the mouse is taken out, centrifuged at 3000r/min for 10min, and the serum is taken out. 6-mercaptopurine and 3a, c, e were dissolved in 1mL of serum to a concentration of 1 mg/mL. Incubating 100 μ L of sample at 37 deg.C, sampling at 0min,10min,30min,1h,2h, etc., precipitating protein with methanol, concentrating to obtain sample with the same concentration, and measuring ultraviolet absorption of 3a, c, and e with ultraviolet spectrophotometer.
The absorbance value at 0min is taken as A 0 Calculating the content of the compound at different time points according to the formula, wherein the content is A 0 and/A. The data are shown in Table 3. The results show that the half-lives of 3a, c and e in the plasma of mice are 59.5min,63.6min and 60.7min respectively, and are significantly longer than the half-life of 6-mercaptopurine in the plasma of mice (19.2 min). This is the unexpected technical effect of this case.
TABLE 33 half-lives of a, c, e in mouse plasma
Compound (I) | Half-life period (min) |
6-mercaptopurine | 19.2 |
3a | 59.5 |
3c | 63.6 |
3e | 60.7 |
Claims (3)
2. A process for the preparation of 6-S, 9-N-diacetyl-AA-OBzl-mercaptopurine of claim 1 which comprises:
2.1. synthesizing 6-S, 9-N-diacetyl-O-ethylmercaptopurine;
2.2. synthesizing 6-S, 9-N-dicarboxymethylmercaptopurine;
2.3. 6-S, 9-N-diacetyl-AA-OBzl-mercaptopurine is prepared by condensing 6-S,9-N- (dicarboxymethylmercapto) purine and AA-OBzl by a liquid phase method using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst.
3. Use of 6-S, 9-N-diacetyl-AA-OBzl-mercaptopurine according to claim 1 for the preparation of antitumor medicaments.
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